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Dedication

The authors dedicate this book to George, Ahmad, Giovanna, Nicos, Meigui, Sumitra, Christine,
Minh-Quan, Hamid, Pranee, Eduard, Karim, and all other patients with thalassaemia, who are not
with us any more but whose will and determination to live have inspired researchers and health
professionals across the world to promote scientific knowledge and quality care.

It is our fervent hope that this book will serve not only as a manual for promoting clinical
management, but also as a tool for improving communication and collaboration amongst all of
those, patients, parents, health professionals and others who are striving towards the same goal,
the establishment of effective control of thalassaemia and the promotion of equal access to
quality health care for every patient with Thalassaemia.

1
EED
DIITTOORRSS AANNDD AAUUTTHHOORRSS::
Maarriiaa--D
M Doom
meenniiccaa CCaappppeelllliinnii,, M
MDD – Professor, Centro Anemie Congenite, Ospedale Maggiore
Policlinico IRCCS, University of Milan, Italy

Allaann CCoohheenn,, M
A MDD – Professor of Paediatrics, University of Pennsylvania, School of Medicine, USA
AAnnddrroouullllaa EElleefftthheerriioouu,, PPhh..DD.. – Ex-Director of the Virus Reference Laboratory, Ministry of Health
Cyprus, Executive Director - Thalassaemia International Federation

AAnnttoonniioo PPiiggaa,, M
MDD – Professor, Dipartimento di Scienze Pediatriche e dell’Adolescenza, Universita
degli Studi di Torino, Italy

JJo
ohhnn PPoorrtteerr,, M
MDD – Professor, Department of Haematology, University College, London, UK
AAllii TTaahheerr,, M
MDD – Professor Medicine - Hematology & Oncology, Department of Internal Medicine,
American University of Beirut Medical Center, Beirut Lebanon

AUUTTHHOORRSS OOFF CCHHAAPPTTEERRSS::


A
Athanasios Aessopos, MD - Professor of Cardiology, First Department of Internal Medicine,
University of Athens - "Laiko" General Hospital, Athens, Greece

Emanuel Angelucci, MD - Professor of Haematology, U.O. Ematologia Ospedale Oncologico


"Armando Businco", Cagliari, Italy

Michael Antoniou, Ph.D. - Division of Medical & Molecular Genetics, GKT School of Medicine, Guy's
Hospital, London, UK

Ratna Chatterjee, MD – Consultant/Senior Lecturer in Reproductive Health, University College


London, London, UK

Demetrios Farmakis, MD - First Department of Internal Medicine, University of Athens - "Laiko"


General Hospital, Athens, Greece.

Susan Perrine, MD - Director of Haemoglobinopathy/Thalassaemia Research Unit, Professor of


Paediatrics – Medicine Pharmacology and Experimental Therapeutics Boston, Boston University
School of Medicine, Boston, Massachusetts, USA

Vicenzo De Sanctis, MD- Professor of Paediatric Endocrinology, Divisione Pediatrica Azienda,


Ospedaliera – Archispedale S. Anna, Ferrara, Italy

Malcolm John Walker, MD - Consultant Cardiology – Hatter Institute, Cecil Fleming House,
University College London Hospital, London, UK

COO--OORRDDIINNAATTIINNGG EEDDIITTOORR::
C

Androulla Eleftheriou, B.Sc., M.Sc., Ph.D., Dipl.MBA

2
COONNTTRRIIBBUUTTOORRSS::
C

Constantina Politis, MD – Associate Professor, Director of the 3rd Reg. Blood Transfusion Centre,
'George Gennimatas' General Hospital, Athens, Greece

Ala Sharara, MD – Professor, Director of Division of Gastroenterology- American University of


Beirut Medical CenterEndoscopy Unit, Beirut, Lebanon

Nicos Skordis, MD - Consultant of Paediatric Endocrinology, Department of Paediatrics,


Thalassaemia Centre, Makarios III Hospital, Ministry of Health Cyprus, Nicosia, Cyprus.

Ersi Voskaridou, MD - Director of the Thalassaemia Unit and WHO Collaborating Centre, Geniko
Laiko Nosokomio Athinon, Greece

ACCKKNNOOW
A WLLEEDDGGEEM
MEENNTTSS::
The Thalassaemia International Federation would like to express its most sincere appreciation and
Drr.. HHeelleenn PPeerrrryy – Editor, DDrr M
gratitude to D Miicchhaaeell AAnnggaassttiinniioottiiss - Thalassaemia International
Federation, Medical Advisor and D Drr.. M
Maatthheeooss DDeem meettrriiaaddeess – Thalassaemia International
Federation, Projects’ Coordinator for their invaluable contribution to the completion of the
book.

3
Contents

Foreword 6

Introduction 9

CHAPTER 1 12
Genetic Basis and Pathophysiology

CHAPTER 2 18
Blood Transfusion Therapy in ‚-Thalassaemia Major

CHAPTER 3 31
Iron Overload

CHAPTER 4 64
Endocrine Complications In Thalassaemia Major

CHAPTER 5 70
Management of Fertility and Pregnancy in ß-thalassemia

CHAPTER 6 79
Diagnosis and Management of Osteoporosis in ‚-thalasaemia

CHAPTER 7 83
The Management of Cardiac Complications in Thalassaemia Major

CHAPTER 8 92
The Liver in Thalassaemia

CHAPTER 9 106
Infections in Thalassaemia Major

CHAPTER 10 116
Splenectomy in ‚-thalassaemia

CHAPTER 11 121
Thalassaemia Intermedia and HbE

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CHAPTER 12 132
Stem Cell Transplantation

CHAPTER 13 136
Alternative Approaches to the Treatment of Thalassaemia

CHAPTER 14 139
Gene Therapy: Current Status and Future Prospects

CHAPTER 15 142
Psychological Support in Thalassaemia

CHAPTER 16 149
General Health Care and Lifestyle in Thalassaemia

CHAPTER 17 155
Organisation and Programming of a Thalassaemia Centre

CHAPTER 18 159
Outline of Diagnostic Dilemmas in Thalassaemia

References 170

Index 196

About thalassaemia 202

5
Foreword

The fight against thalassaemia has entered new and exciting territory, with major advances
dramatically improving patient care. At the forefront of that fight, the Thalassaemia International
Federation (TIF) remains true to its goal: to secure equal access to quality healthcare for every
patient with thalassaemia around the world. This book is a key tool in achieving that goal.

Written by some of the world’s leading authorities on haemoglobin disorders, this fully updated
second edition of Guidelines for the Clinical Management of Thalassaemia provides medical
professionals with a clear, comprehensive guide to the optimal treatment of thalassaemia, based
on scientific evidence, clinical studies and observations. The information provided here has been
meticulously compiled by experts fully aware of the many different circumstances in which medical
personnel strive to treat patients with thalassaemia. As such, it sets out to provide a full guide to
the treatment to which every patient everywhere is entitled, including access to sufficient
quantities of safe blood and iron chelation therapy, as well as offering a comprehensive
assessment of groundbreaking advances in chelation therapy, other treatment options and the
long-awaited final cure, including stem cell transplantation and gene therapy.

With the support of member associations, dedicated scientists and healthcare workers, patients,
families and friends, TIF focuses on three categories of projects, each contributing to the overall
goal of reaching its objectives and achieving its mission:

TIF projects aim to promote and support:

ñ Awareness about thalassaemia, its prevention and its medical and other care;

ñ Research focused on the continuous improvement of medical care and on realising a total cure
for thalassaemia, and;

ñ Dissemination of the knowledge, experience and expertise of countries with successful control
programmes to countries in need.

TIF’s activities in achieving the above include:

1. The establishment of new and promotion of existing national patient organisations;

2. The development of a collaborative network of national and international


ñ thalassaemia and other disease-specific patient organisations;
ñ medical and scientific communities involved in the field;
ñ research institutes and medical centres of excellence;
ñ health-related organisations, and;
ñ pharmaceutical industries

3. The coordination of or participation in national, regional and international projects contributing


to worldwide improvements in:
ñ Epidemiology

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ñ Medical and other care
ñ Social integration and quality of life
ñ Extending knowledge of the disease, its prevention and treatment to policy makers, health
professionals, patients and parents, and the community at large
ñ Securing the rights of every patient for equal access to quality medical care, and
ñ The safety and adequacy of blood

4. The establishment of programmes for the continuous education of health professionals,


patients and parents, and the community, including:
ñ Organisation of local, national, regional European and international workshops, conferences,
seminars and meetings.
ñ The preparation, publication, translation and free distribution of educational and awareness-
raising material.

The recent launch of a unique e-MSc in Haemoglobinopathies, offered by University College


London (UCL) and part-funded by TIF, is just one example of the scope and ambition of TIF’s
educational programme.

TIF’s achievements are the result of voluntary, dedicated work by


scientists and medical professionals from around the world, without
which TIF’s educational programme, one of its most important tools
for the dissemination of knowledge and experience, would never have
achieved the level of success it currently enjoys.
The authors and all other contributors that have made this book possible deserve particular
recognition for their work. The first edition of this book served for many years as the reference
text for the treatment of thalassaemia. We are confident that this second edition will make a
similar if not greater contribution to efforts to spread existing knowledge and the advances
achieved in the last seven years in the field of the clinical management of thalassaemia. Special
acknowledgement is also due to a number of other specialists, including Antonio Cao, Vilma
Gabutti, Renzo Galanello, Giuseppe Masera, Bernadette Modell, Annuziata di Palma, Calogero Vullo
and Beatrix Wonke, who led the way in the early, difficult years, when knowledge on this subject
was very limited. They are amongst the pioneers in the promotion of the clinical management of
thalassaemia and in the setting out of standards of care to which every patient is entitled.

The first edition of the Guidelines for the Clinical Management of Thalassaemia, published in 2000,
was the first of its kind to be produced at a time when specialists, patients and parents considered
its preparation essential, in view of the rapid achievements in the treatment of thalassaemia. This
new, fully updated, second edition is a timely response to the many further advances that have
been made since then.

This new edition of Guidelines for the Clinical Management of Thalassaemia offers an invaluable tool
to medical staff involved in the treatment of thalassaemia. National governments, thalassaemia

7
centres and individual health personnel caring for patients with thalassaemia are strongly
encouraged to follow the recommendations of the panel of experts, as presented here.

At the same time, it is extremely important that the prevention of


thalassaemia receives similar attention.
While outside the scope of this book, the prevention of thalassaemia remains a crucial objective for
TIF. Unless new births of affected children are prevented or minimized, even the best updated
treatment programmes will eventually collapse, unable to provide for an ever-increasing number of
patients. In this context, the development of national prevention programmes is at the heart of
TIF’s activities. TIF, based on its long-time experience, can offer considerable support to countries,
including detailed advice on the structure of, and challenges to implementing, such programmes.

On behalf of the Board of Directors of TIF I would like to once again extend our deepest gratitude
to the experts who have dedicated work, time and effort to producing this updated second edition
of Guidelines to the Clinical Management of Thalassaemia. Last but by no means least, I would like
to express our most sincere appreciation to the Non-Communicable Diseases Genetics Department
of the World Health Organisation (WHO), with which TIF has been collaborating on an official basis
since 1996, and whose support and guidance in promoting our mission have been multi-faceted
and invaluable.

Panos Englezos
TIF President

8
Introduction

Haemoglobin (Hb) disorders are hereditary, genetic diseases consisting mainly of sickle cell
disease and the thalassaemias, which account for a great proportion of births affected by a
genetic disease.

The thalassaemias are a heterogeneous group of the haemoglobin disorders in which the
production of normal haemoglobin is partly or completely suppressed as a result of the
defective synthesis of one or more globin chains. Several types of thalassaemia have been
described and named according to the affected globin-chain, the most common types of clinical
importance being ·-, ‚‰- and ·-thalassaemia.

Haemoglobin disorders are thought to have originated in countries


where malaria was or is endemic—areas to which it was for many
years believed such disorders were confined.
Sub-Saharan Africa accounts for more than 70% of births affected by sickle cell disorders every
year, with the remainder occurring at various rates (from low to high) in other parts of the
world. Thalassaemia, including HbE, is more prevalent in the Mediterranean basin, the Middle
East, Southern and Eastern Asia, the South Pacific and South China, with reported carrier rates
ranging from 2% to 25%.

Although reliable data are still lacking for many regions of the world, recent data indicate that
about 7% of the world’s population is a carrier of a haemoglobin disorder, and that 300,000-
500,000 children are born each year with the severe homozygous states of these diseases.
(World Bank 2006, report of a joint WHO-March of Dime meeting 2006)

It is now well recognised that Hb disorders are not confined to any particular region, occurring
widely across the world and constituting a global public health problem. Hb disorders have
spread through the migration of populations from endemic areas to countries where their
prevalence in indigenous populations had been extremely low. Such countries include the USA,
Canada, Australia, South America, the United Kingdom and France, where migration occurred up
to a century ago and where large ethnic minority groups are now entering their fourth and even
fifth generation.

More recent migration movements from highly endemic countries have been to Northern and
Western Europe, where the prevalence of Hb disorders in the indigenous population is very low,
including Germany, Belgium, the Netherlands and, more recently, Scandinavia.

These changes have challenged health professionals and policy-makers throughout the region in
providing equitable access to quality services for the prevention and treatment of Hb disorders.
In some regions, such as Scandinavia, to which there is currently large-scale migration, the
proportion of births in ‘at-risk groups’ is predictive of the future genetic make-up of the
population, as has been the case in some of the countries mentioned above, where large scale
migration from affected countries had occurred much earlier.

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Carrier prevalence will clearly continue to rise in Northern and Western Europe, even in the
absence of further migration, as a result of reproduction and inter-community marriages, and
Hb disorders are likely to become the leading recessive disorder throughout the region, posing a
serious public health problem. Clearly, the earlier classification of endemic and non-endemic
countries for Hb disorders is no longer relevant. However, effectively addressing the control of
these disorders in these countries will require considerable work, financial backing and certainly
political commitment. The main difficulty is that the populations of these countries are not
homogeneous, as was the case in the Mediterranean countries where the earliest control
programmes were successfully established. Some countries in Europe, such as the United
Kingdom and France, have already accumulated considerable experience and knowledge in the
most cost-effective and practical ways of intervention to address this highly important public
health problem.

Recognition of the problem in Northern and Western Europe has raised concerns and stirred up
interest amongst national and EU health policy-makers who, in addition to and complementary
to the work of World Health Organisation (WHO), which was traditionally involved in the
promotion of control programmes for Hb disorders, have already taken significant steps in the
context of their agenda on rare diseases.

Unlike affected countries of the developing world, these countries already have strong health
care infrastructure and systems in place, and the resources and quality health services required.
The European countries need to address ethnic minorities, which are widely scattered
geographically, and to raise strong health professional and patient/parent awareness—tasks that
are essential in the promotion of effective control programmes.

Recent improvements in the resources and health care structures of Eastern European countries
such as Bulgaria and Romania have contributed to a greater recognition of the importance of
developing and implementing control systems for Hb disorders occurring in the indigenous
population, which in some regions can reach very high carrier levels.

Southern European countries with Hb disorders occurring in the indigenous population, albeit at
considerably lower prevalence rates, include Portugal and Spain—countries that are, however,
able to respond effectively to public health requirements and to adopt effective policies.

Low prevalence European countries where haemoglobinopathies have not yet penetrated to a
significant degree through migration include Poland, Hungary and the Czech Republic, although
these, along with Spain and Portugal, constitute potential targets for increasing migration.

Albania is a separate example, having higher prevalence rates of Hb disorders than the rest of
the Balkan countries in the indigenous population with carriers and affected individuals widely
scattered across the country. Although appropriate services are still largely underdeveloped,
significant progress has been achieved during the last few years, especially in the area of clinical
management. Unfortunately data on the epidemiology and status of control programmes in
Russia remains scanty.

10
In lower and middle-income countries on the other side of the world, where haemoglobin
disorders are most prevalent in the indigenous population, 50-80% of children with sickle cell
disease and a significant number of children with ‚-thalassaemia die each year—undiagnosed or
misdiagnosed, sub-optimally treated or not treated at all.

There is an urgent need to bridge this wide gap until every patient in every part of the world has
equal access to quality medical care. An essential means of doing so is through global
collaboration on Hb disorders, enabling all countries to benefit from each other’s experience.
Health authorities need to recognise Hb disorders as a significant threat to public health—one
that deserves the development and implementation of national policies for treatment and
prevention. The instruments required to support such policies include:

ñ Standards and guidelines for laboratory services


ñ National guidelines for the management of thalassaemia
ñ Epidemiological information and surveillance
ñ Establishment of an educational programme for health
professionals, patients, parents and the community
It is evident that all countries would benefit from the sharing of experience and expertise. The
difficulties encountered in service development for haemoglobin disorders apply equally to many
other inherited disorders. Professionals and support groups alike would benefit from forming
wider partnerships with similar groups representing other disorders.

It is hoped that this book will offer valuablel information to all medical professionals involved in
the treatment of patients with thalassaemia. It includes updated information on new approaches
for more effective, safe and less laborious treatment, and an overview of the progress achieved
to date towards a total cure for thalassaemia, using methods such as gene therapy and stem cell
transplantation.

Until the final goal of a complete cure for thalassaemia is found, it is the obligation of national
health authorities and health professionals to provide, and the right of patients to receive, the
most complete and up-to-date systems of treatment available. We hope that these guidelines,
which constitute the authors’ consensus on the most effective treatment of ‚-thalassaemia
major, will prove an indispensable tool for health professionals involved in this field.

Androulla Eleftheriou, B.Sc., M.Sc., Ph.D., Dipl.MBA


TIF Executive Director
Coordinating Editor

11
Genetic Basis and
Pathophysiology

structure of the globin chains is coded by


Haemoglobin Types genes contained in the DNA of chromosomes
16 (the · gene cluster) and 11 (the ‚ gene
Oxygen is transported from the lungs to the cluster). Flanking the structural genes, i.e. in
tissues by a highly specialised protein front (on the 5’ side of the DNA sequence,
molecule, haemoglobin, which is located in “upstream”) and following them (on the 3’
the red cells of the blood. Each red blood side of the DNA sequence, “downstream”), lie
cell contains approximately 300 million several nucleotide sequences which have a
molecules of this protein, totalling about 30 “regulatory” role, i.e. they determine which
picograms in weight per cell. Each molecule gene is to be turned on and which off, as
of haemoglobin is formed by two pairs of well as how efficient its expression will be. In
identical sub-units, the globin chains, which adult life, most of the globin synthesis occurs
are named with letters of the Greek alphabet in the erythroblasts in the bone marrow.
and belong to two groups: the ·-globin Haemoglobin must have the correct
cluster, comprising the ˙- and ·-globin structure and be trimmed in such a way that
chains, and the ‚-globin cluster, comprising the number of ·-chains precisely matches
the globin chains Â, Á, ‚ and ‰. The globin that of the ‚-chains. When the above
chains appear sequentially during ontogeny conditions are not met, the result is a
and, after pairing, form the following four complete or partial defect in one or both
major types of haemoglobin: “allelic” globin genes.

a) “embryonic” haemoglobins, which are


detectable from the 3rd to the 10th
week of gestation and represent ˙2Â2, The Thalassaemias:
·2Â2 and ˙2Á2 tetramers;
b) “fetal” haemoglobin (HbF ·2Á2), which
Definitions and
constitutes the predominant oxygen Worldwide
carrier during pregnancy ;
c) “adult” haemoglobin (HbA ·2‚2), which
Distribution
replaces HbF shortly after birth, and;
d) a minor adult component, HbA2 (·2‰2). The term “thalassaemia” refers
to a group of blood diseases
Under normal conditions, the red cells of the characterised by decreased
adult human contain approximately 98% HbA, synthesis of one of the two
2.0% HbA2 and traces of HbF.
types of polypeptide chains (·
or ‚) that form the normal adult
Globin Genes and human haemoglobin molecule
(HbA, ·2‚2), resulting in
Globin Synthesis decreased filling of the red cells
The globin chains have an extremely precise with haemoglobin, and anaemia.
structure, ensuring their prompt loading with
oxygen in the lung alveoli and its controlled Depending on which of the genes the defect
gradual delivery into the tissues. The precise occurs and the corresponding effect on the

12
production of globin chains, ·-thalassaemia alterations of their red cells, an increased
or ‚-thalassaemia results. The present book level of HbA2, and a low ‚/·- globin chain
mainly addresses the latter group of ratio on biosynthesis, which is occasionally
thalassaemias, which are now recognised to associated with low normal or slightly
occur widely across the world well beyond subnormal haemoglobin levels. Under normal
the countries where these were originally circumstances, the thalassaemia trait is not
thought to be endemic i.e. countries around related to any significant clinical effects,
the Mediterranean Basin, the Middle East, mainly because the activity of the normal ‚
Trans-Caucasus and India for ‚- and the Far gene on the allelic chromosome makes
East for ·-thalassaemia (see Figure 1). enough stable globin. In contrast, inheritance
of two defective ‚-globin genes results in a
wide spectrum of clinical conditions, ranging
‚-Thalassaemia from transfusion dependence (thalassaemia
major) to mild or moderate anaemia
Ph en o ty pi c h eter o gen ei ty (thalassaemia intermedia). Molecular studies
As a rule, heterozygous carriers of ‚- may reveal a large array of abnormalities
thalassaemia (one affected allele), display a underlying the above phenotypes and may
low mean cellular haemoglobin (MCH), low assist in their identification.
mean cell volume (MCV), mild morphological

CELL TYPE

SITE OF
ERYTHROPOIESIS

PERCENTAGE
OF TOTAL
GLOBIN
SYNTHESIS

Figure 1: Globin synthesis at various stages of embryonic and fetal development

13
below outlines the pathophysiology of ‚-
Pathophysiology of thalassaemia and describes the chain of
‚-thalassaemia events following globin chain imbalance and
the accumulation of excess ·-chains – that is,
ineffective erythropoiesis leading to anaemia,
Advances in the management of thalassaemia bone marrow expansion, skeletal deformities
were achieved only after the pathophysiology and increased GI iron absorption.
of the disease was elucidated and clearly
understood by the scientific and medical The degree of globin chain imbalance is
community involved in the field. Figure 2 determined by the nature of the mutation of

PATHOPHYSIOLOGY OF ‚-THALASSAEMIA MAJOR

Figure 2: Effects of excess production of free ·-globin chains

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the ‚-gene. ‚o refers to the complete Table 1 includes the common types of
absence of production of ‚-globin on the ‚-thalassaemia mutations according to ethnic
affected allele. ‚+ refers to alleles with some distribution and severity. A more
residual production of ‚-globin (around 10%). comprehensive list of ‚ mutations can be
In ‚++ the reduction in ‚-globin production is found on the internet at
very mild. More than 200 thalassaemic http://globin.cse.psu.edu/globin/html/huisman .
mutations have been reported to date.

Population ‚ - g e n e M u t a ti o n S e ve r i ty

Indian -619 del ‚Ô


Mediterranean -101 ‚++
Black -88 ‚++
Mediterranean; African -87 ‚++
Japanese -31 ‚++
African -29 ‚++
Southeast Asian -28 ‚++
Black -26 ‚++
Mediterranean; Asian Indian IVS1-nt1 ‚o
Mediterranean; Asian Indian IVS1-nt5 ‚o
Mediterranean πøS1-nt6 ‚+/++
Mediterranean IVS1-nt110 ‚+
Chinese IVS2-nt654 ‚+
Mediterranean IVS2-nt745 ‚+
Mediterranean codon 39 ‚o
Mediterranean codon 5 ‚o
Mediterranean; African-American codon 6 ‚o
Southeast Asian codons 41/42 ‚o
African-American AATAAA to AACAAA ‚++
Mediterranean AATAAA to AATGAA ‚++
Mediterranean Hb Knossos ‚++
Southeast Asian HbE ‚++

Table 1: Common types of ‚-thalassaemia, their severity and ethnic distribution

15
are variable in severity— ranging from those
Beta structural characterising thalassaemia intermedia to
haemoglobin variants those described for severe transfusion-
dependent thalassaemia major. The reasons
relevant to for this variability have only partially been
thalassaemia defined, since patients with seemingly
identical genotypes present with clinical
management manifestations very different in severity.

Haemoglobin E disorder is the most common Hb Lepore is another structural


structural variant resembling thalassaemia
desorders (see relevant Chapter 11:
‚ variant resulting from a fusion
Thalassaemia Intermedia). of the ‰ and ‚ globin genes.
HbE results from a mutation (G➔A) at codon The homozygous state of Hb
26 of the ‚-globin gene causing the Lepore can result in moderate
substitution of lysine for glutamic acid – a to severe transfusion-
mutation that results in a qualitative and
quantitative ‚-globin gene defect since it is
dependent ‚-thalassaemia
related to the activation of a cryptic splice syndromes.
site at codon 24-25, leading to an alternative
splicing pathway. The overall result is the HHaaeem
mo
oggllo
obbiinn SS ddiissoorrddeerrss: HbS, the most
production of reduced amounts of the common haemoglobin variant in the world,
variant haemoglobin (HbE). results from a substitution of valine for
glutamic acid at position 6 of the ‚-globin
HbE is the most common abnormal chain. The interaction of ‚-thalassaemia with
haemoglobin in South East Asia, with a carrier HbS results in a syndrome that most closely
frequency of more than 50% in some resembles the sickling disorders, which
regions. It is also prevalent in parts of the typically do not require lifelong transfusions
Indian subcontinent, including Bangladesh. and are not consequently associated with
Heterozygotes for HbE are clinically normal iron overload. As for thalassaemia, Guidelines
and manifest with 25-30% of HbE on for the management of sickle cell disorders
electrophoresis and with only minimal have been formulated in recent years and a
changes in red blood cell indices. useful web-site for more information is:
Homozygotes for HbE are clinically silent and http://www.nhlbi.nih.gov/health/prof/blood/
may be only mildly anaemic. On microscopic sickle/sick-mt.htm.
examination, the peripheral blood smear
demonstrates microcytosis with 20-80% of
target red cells, while Hb electrophoresis ·-thalassaemia
shows 85-95% of HbE and 5-10% of HbF.
·-thalassaemias are inherited disorders
HbE/‚-thalassaemia constitutes the most characterised by reduced or suppressed
common combination of ‚-thalassaemia with production of ·-globin chains. The human ·-
a structural variant, most prevalent in South globin genes are duplicated and located in
East Asia. The related clinical manifestations the telomeric end of the short arm of
chromosome 16. ·-thalassaemia is caused

16
most commonly by deletions of large DNA crisis, mainly in response to oxidant drugs
fragments that involve one or both ·-globin and infections.
genes.
Silent carrier state: The presence of a single Other relevant structural variants include Hb
·-globin gene deletion results in the silent Constant Spring, characterised by ineffective
carrier state occurring widely across the synthesis of a-globin chains, resulting from a
world. defect on the relevant gene that causes their
elongation. This mutation is found primarily
·-thalassaemia trait is in Asia and its co-inheritance with the
characterised by the presence deletion of two ·-genes results in a severe
form of HbH disease.
of two residual functional a-
genes and is not related to any Hb Bart’s hydrops fetalis, the most severe
serious clinical or laboratory clinical manifestation of ·-thalassaemia, is
findings: generally associated with the absence of all
four ·-globin genes and death in utero.
Miilldd aannaaeem
M miiaa aanndd m
miiccrrooccyyttoossiiss.. Absence of ·-globin genes in the “cis”
position on the same chromosome (·Ô-
Deletions or abnormalities of three globin
thalassaemia) is common in South East Asia,
genes result in HbH disease, usually
while it is rare in the Mediterranean area and
characterised by a moderate haemolytic
even rarer in Africa.
anaemia, splenomegaly and acute haemolytic

With permition from the Source: March of Dimes: Global Report 2006

17
Blood Transfusion Therapy in
‚-Thalassaemia Major

relevant laws and taking into account


Goals of Blood national needs, resources and prevalence of
Transfusion Therapy infectious agents, should safeguard the
quality of blood transfusion services. Blood
Appropriate goals of transfusion therapy and donation practices, donor selection (e.g.,
optimal safety of transfused blood are the through questionnaire) and product
key concepts in the protocol for routine screening constitute some of the most
administration of red blood cells to patients important strategies that contribute to the
with thalassaemia. The major goals are: safety and adequacy of blood. For more
information on EU directives visit:
ñ Maintenance of red cell viability and http://europa.eu.int and http://europa.eu.int
function during storage, to ensure /consus/health/index_en.html.
sufficient transport of oxygen; On recommendations of the Council of
ñ Use of donor erythrocytes with a normal Europe visit http://www.coe.int, while on
recovery and half-life in the recipient; WHO guidelines and American Standards visit
ñ Achievement of appropriate haemoglobin www.who.int/bloodsafety/gcbs/structure/en/
level, and; and http://www.aabb.org/content,
ñ Avoidance of adverse reactions, including respectively. Other sites are also available
transmission of infectious agents. should the reader require to obtain more
information.

Quality and Adequacy Transfusion Therapy


of Blood in Thalassaemia
To safeguard the health of the
transfusion recipient, including This chapter will address five of the most
patients with thalassaemia, common questions related to the transfusion
blood should be obtained from therapy of patients with thalassaemia major:
carefully selected regular (i) When to initiate transfusion therapy and
voluntary, non-remunerated whom to transfuse;
donors and should be collected, (ii) How blood is processed for effective
processed, stored and and safe transfusion therapy in
distributed, in the context of thalassaemia major;
(iii) Is there an optimal haemoglobin (Hb)
dedicated, quality assured level for effective transfusion;
national blood transfusion (iv) Do transfusion requirements affect the
centres. success of iron chelation therapy;
(v) What are the most serious transfusion
Nationally developed legislation-based on EU, related (TR) reactions (common and less
Council of Europe, North American, World frequent);
Health Organisation (WHO) or other
international directives, recommendations or

18
FFoorr ddeecciiddiinngg wwhhoom
m ttoo ttrraannssffuussee, the
following should be included in the Recommended blood
investigations: product
(i) Confirmed laboratory diagnosis of Patients with ‚-thalassaemia
thalassaemia major;
(ii) Laboratory criteria:
major should receive
Hb < 7g/dl on 2 occasions, > 2 weeks leucoreduced packed red blood
apart (excluding all other contributory cells with a minimum
causes such as infections) or haemoglobin content of 40g.
(iii) Laboratory and clinical criteria,
including: Reduction to 1 X 106 or less leucocytes per
- Hb > 7g/dl with: unit (mean counts as low as 0.05 x 106 are
- Facial changes achievable) (Council of Europe, RE 2006) is
- Poor growth considered the critical threshold for
- Fractures, and eliminating adverse reactions attributed to
- Extramedullary haematopoiesis contaminating white cells (see Table 1,
below) and for preventing platelet
alloimmunisation.

REEAACCTTIIOONNSS
R CAAUUSSAATTIIVVEE AAGGEENNTTSS
C

Febrile non-haemolytic transfusion HLA-antibodies in patients, cytokines


reactions (FNHTR) produced by donor leucocytes
HLA- alloimmunisation of recipients HLA antigens on donor leucocytes
Transfusion-transmitted infections Cell-associated infectious agents
Graft-versus-Host-Disease (GVHD) Donor T-lymphocytes

[Morell A, ZLB Central Laboratory Swiss Red Cross, Bern Switzerland, 2000.
Pathogen inactivation of labile blood products]

Table 1: Contaminating Leucocytes as pathogens: Some adverse effects of Leucocytes in labile blood products.

19
Meetthhooddss ffoorr lleeuuccoorreedduuccttiioonn iinncclluuddee::
M immunoglobulin A (IgA) deficiency, in which
the recipient’s preformed antibody to IgA
ñ P
Prre
e--ssttoorraaggee ffiillttrraattiioonn of whole blood is may result in an anaphylactic reaction.
the preferred method for leucoreduction. Washing usually does not result in adequate
The delay in filtration (4-8 hours) may leucocyte reduction and should not be used
allow some phagocytosis of bacteria (e.g. as a substitute for leucoreduction. Instead,
Yersinia enterocolitica) (Buchholz, 1992). washing should be used in conjunction with
This method of leucocyte removal offers filtration. In addition, washing of red cell
high efficiency filtration and provides units may remove some erythrocytes from
consistently low residual leucocytes in the the transfusion product, and it is therefore
processed red cells and high red cell valuable to monitor post-transfusion
recovery. Packed red cells are obtained haemoglobin levels to ensure attainment of
by centrifugation of the leucoreduced the targeted Hb level.
whole blood.
F r oz e n ( o r c ry o p r e s e rv e d ) re d c e l l s
Frozen (or cryopreserved) red cells is
ñ P
Prre
e--ttrraannssffuussiioonn, laboratory filtration the component derived from whole blood in
refers to the filtration at the blood bank which red cells are frozen, preferably within 7
laboratory of packed red cells, prepared days of collection, using a cryopreservant
from donor whole blood. and stored at -60oC to -80oC or below, based
ñ B eddssiiddee ffiillttrraattiioonn refers to the packed red on the method used. These are used to
Be
maintain a supply of rare donor units for
cell unit which is filtered at the bedside,
certain patients who have unusual red cell
at the time of transfusion. This method,
antibodies or who are missing common red
although equally sensitive to those above,
cell antigens. The Council of Europe is
may not allow optimal quality control
promoting an international network of rare
because the techniques used for bedside
blood donor units and may be contacted as
filtration may be highly variable.
follows:
CCoouunncciill ooff EEuurrooppee –– PPooiinntt II
FF6677007755 SSttrraassbboouurrgg CCeeddeexx
Blood products for FFrraannccee
TTeell:: + +3 33 33 38 8884 4112 2000 00 0
special patient FFaaxx:: + +333 33 38 8884 4112 27 78 81 1
EEm maaiill:: ppooiinntt__ii@
@cco
oee..ffrr
populations IInntteerrnneett:: wwwwww..ccooee..ffrr//iinnddeexx..aasspp

Waasshheedd rreedd cceellllss may be beneficial for


W RReedd cceellllss oobbttaaiinneedd bbyy ddoonnoorr
patients with thalassaemia who have aapphheerreessiiss:: This method whereby two units
repeated severe allergic transfusion of red cells are collected from the same
reactions. Saline washing of the donor donor for transfusion of one patient is
product removes plasma proteins that associated with reduction of donor exposures
constitute the target of antibodies in the and consequently to a decreased risk (i) of
recipient. Other clinical states that may transmission of infections, and (ii) of
require washed red cell products include developing alloimmunisation and other
transfusion related complications.

20
N e oc y t e or y o u n g r e d c e l l t r a n s f u s i o n the additive solution a suitable osmotic
may modestly reduce blood requirements strength. Thus the introduction of additives
(Spanos, 1996). However, patients are such as AS-1, AS-3, AS-5 (see Table 2b) has
exposed to a higher number of donors, with permitted considerably longer storage of red
a consequent increase in cost, risk of cells for up to 42 days.
transmission of infections, and risk of
developing alloantibodies. The maximum duration of
storage (expiry date) as noted
Storage of donor red on each unit varies with the
type of preparation
cell units (concentration of cells, formula
of anticoagulant, use of additive
The anticoagulant preservative solutions used suspension fluid, etc) and
in blood collection (see Table 2a) have been should be determined for each
developed to prevent coagulation and to
permit storage of red cells for a certain
type on the basis of achieving a
period of time. All of these solutions contain mean 24 hours post-transfusion
sodium citrate, citric acid and glucose, some survival of no less than 75% of
of them may also contain adenine, guanosine the transfused red cells.
and phosphate (e.g., CPD-A).
The haemoglobin oxygen release function
When red cell concentrates are prepared, a (which is extremely important in thalassaemia
considerable part of the glucose and adenine major) is impaired during storage due to
is removed with the plasma. If not progressive loss of 2, 3-biphosphoglycerate
compensated for in other ways, sufficient (2, 3-BPG, previously known as 2, 3-
viability of the red cells can only be diphosphoglycerate, DPG). Although, the
maintained if the cells are not over- storage time of whole blood in CPDA-1 for
concentrated. Normal CPD-adenine red cell example is 35 days (CoE Re 2006), after 10
concentrate should therefore not have a days of storage all 2, 3 – BPG is lost (CoE Re
haematocrit (Hct) above 0.70 on average 2006). In the case of additives such as the
(CoE Re 2006). Newly developed additive ones mentioned above (see Table 2b),
solutions, however, allow maintenance of red although storage times up to 42 days are
cell viability even if more than 90% of the advocated and high levels of ATP are
plasma is removed, as they contain maintained up to the 28th day of storage, 2,
considerably higher levels of the necessary 3-BPG and P50 values may not be fully
nutrients (see Table 2b). The use of glucose maintained even for this length of time. In
and adenine is necessary for the addition, information about the red cell half-
maintenance of red blood cell post- life in the recipient after prolonged storage
transfusion viability, phosphate may be used of donor blood is limited. Taking into
to enhance glycolysis, and other substances consideration all the above and in view of the
(e.g.; mannitol, citrate) may be used to fact that in thalassaemia major, decreased
prevent in vitro haemolysis. Sodium chloride recovery and a shortened red cell half-life
or di-sodium phosphate may be used to give may increase transfusion requirements and

21
as a consequence the rate of transfusional increased volume resulting from additive
iron loading. the current practice is to use solutions. In general, for all patients, the
red cells stored in additive solutions for less lower haematocrit of red cell units containing
than two weeks, and in CPD-A for even less newer additive solutions should be taken into
days – as fresh as possible. In patients with consideration when calculating the annual
cardiac disease and in small children, rate of transfusional iron loading (see Tables
particular attention should be paid to the 2a & 2b).

AC
A CD
D--AA CP
CPD
D CP
C P22D
D CP
C PD
DAA--11
Trisodium citrate 22.00 26.30 26.30 26.30
Citric acid 8.0 3.27 3.27 3.27
Dextrose 24.50 25.50 51.10 31.90
Monobasic sodium phosphate 2.22 2.22 2.22
Adenine 0.275

[Source: Brecker M, ed Technical Manul, 14TH ed Bethesda, MD: American Association of Blood
Banks, 2003: 162]

Table 2a: Content of anticoagulant-preservative solutions (g/L)

ASS--11 ((AAd
A dsso
oll)) ASS--33 ((N
A Nuuttrriicceellll)) ASS--55 ((O
A Oppttiisso
oll))
Dextrose 2,200 1,100 900
Adenine 27 30 30
Monobasic sodium phosphate 0 276 0
Mannitol 750 0 525
Sodium Chloride 154.00 70.00 15.00
Sodium Citrate 0 588 0
Citric acid 0 42 0

[Source: Brecker M, ed Technical Manul, 14TH ed Bethesda, MD: American Association of Blood
Banks, 2003: 183]
Table 2b:Content of additive solutions (mg/100mL)

22
Compatibility testing ñ Before each transfusion it is
necessary to perform a full
Development of one or more specific red cell crossmatch and screen for
antibodies (alloimmunisation) is a common new antibodies.
complication of chronic transfusion therapy If new antibodies appear, they must be
(Spanos, 1990; Singer, 2000). Thus it is identified so that in future blood lacking
important to monitor patients carefully for the corresponding antigen(s) can be
used. A complete and detailed record of
the development of new antibodies and to
antigen typing, red cell antibodies and
eliminate donors with the corresponding
transfusion reactions should be
antigens. Anti-E, anti-C and anti-Kell maintained for each patient, and should
alloantibodies are the most common. be readily available when and if the
However, 5-10% of patients present with patient is transfused at a different centre.
alloantibodies against rare erythrocyte Transfusion of blood from first-degree
antigens or with warm or cold antibodies of relatives should be avoided because of
unidentified specificity. the risk of developing antibodies that
might adversely affect the outcome of a
It is recommended that: later stem cell transplant.

ñ Before embarking on
transfusion therapy, patients Transfusion
should have extended red cell
antigen typing that includes programmes
at least C, c, E, e and Kell, in
order to help identify and The recommended treatment
for thalassaemia major involves
characterise antibodies in lifelong regular blood
case of later immunisation; transfusions, usually
administered every two to five
ñ All patients with thalassaemia weeks, to maintain the pre-
should be transfused with transfusion haemoglobin level
ABO and Rh(D) compatible above 9-10.5 g/dl.
blood.
In addition, the use of blood that is also This transfusion regimen promotes normal
matched for the C, E and Kell antigens is growth, allows normal physical activities,
adequately suppresses bone marrow activity
highly recommended in order to avoid
in most patients, and minimises transfusional
alloimmunisation against these antigens. iron accumulation (Cazzola, 1995 and 1997).
Some centres use even more extended A higher target pre-transfusion haemoglobin
antigen matching. level of 11-12 g/dl may be appropriate for
patients with heart disease or other medical

23
conditions and for those patients who do not (Michail-Merianou, 1987; Spanos, 1990; see
achieve adequate suppression of bone Table 3). Presence of alloantibodies and
marrow activity at the lower haemoglobin autoantibodies (see below) may severely
level. Although shorter intervals between compromise transfusion therapy in patients
transfusions may reduce overall blood with thalassaemia intermedia, for example,
requirements, the choice of interval must who receive their first transfusions in
take into account other factors such as the adolescence or later.
patient’s work/school schedule and other
lifestyle issues. Recommendations regarding the volume of
transfused red cells are complicated by the
The decision to initiate lifelong transfusion use of different anticoagulant-preservatives
therapy should be based on a definitive and additive solutions. For CPD-A units with a
diagnosis of ‚-homozygous thalassaemia. This haematocrit of approximately 75%, the
diagnosis should take into account the volume per transfusion is usually 10-15
molecular defect, the severity of anaemia on ml/kg, administered over 3-4 hours. Units
repeated measurements, the level of with additive solutions may have lower
ineffective erythropoiesis, and clinical criteria haematocrits in the range of 60-70%, and
such as failure to thrive or bone changes. consequently larger volumes with a higher
The initiation of regular transfusion therapy haematocrit level are needed to administer
for severe thalassaemia usually occurs in the the same red cell mass (see Table 4). For
first two years of life. Some patients with most patients, it is usually easier to avoid
milder forms of thalassaemia who only need these differences in red cell concentration by
sporadic transfusions in the first two decades ordering a certain number of units (e.g. one
of life may later need regular transfusions or two) rather than a particular volume of
because of a falling haemoglobin level or the blood. Younger children may require a
development of serious complications (see fraction of a unit to avoid under- or over-
Chapter 11: Thalassaemia Intermedia and transfusion. Patients with cardiac failure or
HbE). The risk of alloimmunisation appears to very low initial haemoglobin levels should
be greater in patients who begin transfusion receive smaller amounts of red cells at slower
therapy after the first few years of life rates of infusion.

Aggee aatt FFiirrsstt TTrraannssffuussiioonn AAllllooiim


A mm
muunniissaattiioonn RRaattee
< 1 year old 7.7%
> 1 year old 27.9% [Machail-Merianou et al, 1987]

Aggee aatt FFiirrsstt TTrraannssffuussiioonn AAllllooiim


A mm
muunniissaattiioonn RRaattee
< 3 years old 20.9%
> 3 years old 47.5% [Spanos et al, 1990]

Table 3: Age and alloimmunisation in Thalassaemia

24
Haaeem
H maattooccrriitt ooff DDoonnoorr RReedd CCeellllss
50% 60% 75% 80%
TTaarrggeett 1 g/dl 4.2 ml/kg 3.5 ml/kg 2.8 ml/kg 2.6 ml/kg
IInnccrreeaassee iinn
Haaeem
H moogglloobbiinn 2 g/dl 8.4 ml/kg 7.0 ml/kg 5.6 ml/kg 5.2 ml/kg
LLeevveell 3 g/dl 12.6 ml/kg 10.5 ml/kg 8.4 ml/kg 7.8 ml/kg
4 g/dl 16.8 ml/kg 14.0 ml/kg 11.2 ml/kg 10.4 ml/kg

As an example, to raise the haemoglobin level by 4g/dl in a patient weighing 40kg and
receiving AS-1 blood with a haematocrit of 60% would require 560ml. This calculation
assumes a blood volume of 70ml/kg of body weight.

Table 4: Guidelines for choosing how much blood to transfuse

The post-transfusion Hb should A careful record of transfused


not be greater than 14-15g/dl blood should be maintained for
and should be monitored each patient, including the
occasionally to allow assessment volume or weight of the
of the rate of fall in the administered units, the
haemoglobin level between haematocrit of the units or the
transfusions in evaluating the average haematocrit of units
effects of changes in the with similar anticoagulant-
transfusion regimen, the degree preservative solutions, and the
of hypersplenism, or patient’s weight. With this
unexplained changes in information, it is possible to
response to transfusion. calculate the annual blood
requirements as volume of
Although erythrocytapheresis, or automated
red cell exchange, has been shown to reduce
transfused blood and pure red
net blood requirements and thus the rate of cells (haematocrit 100%) per kg
transfusional iron loading (Berdoukas, 1986; of body weight.
Friedman, 2003], its use may be limited due
to a two- to three-fold increase in donor The latter (RBC at 100% ht) when multiplied
blood utilisation, increased (i) costs, (ii) risk of with 1.08, the estimated amount of iron per
transmission of infections and (iii) ml of RBC (see Chapter 3: Iron Load and Iron
development of alloimmunisation. Chelation) yields an approximate value for

25
the amount of transfusional iron that the for donor blood. The rate of transfusional
patient receives per kilogram of body weight iron loading may be very important in
in a year. Figure 1 shows a detailed example choosing the appropriate dose of an iron
of how the daily rate of iron loading chelator. For example, the recommended
(mg/kg/day) is calculated and Table 5 shows dose of the chelator deferasirox is based in
the relationship between the annual part on the daily or annual rate of
transfusion requirements and the daily rate transfusional iron loading.
of iron loading at two common haematocrits

Patient weight: 40kg


Transfusion amount and schedule: 600ml every 4 weeks.
Average haematocrit of transfused red cells: 60%

Annual blood requirement: 13 transfusions x 600ml/40kg = 195ml/kg


Annual pure red cell requirement: 195ml/kg/yr x 60% (average haematocrit) = 117ml/kg/yr

Annual transfusional iron loading:


117ml/kg/yr of pure red cells x 1.08mg iron per ml pure red cells = 126mg iron
Daily transfusional iron loading: 126mg iron/yr/365 days = 0.34mg/kg

Figure 1: Calculation of annual blood requirements and transfusional iron loading.

AAnnnnuuaall BBlloooodd AAnnnnuuaall BBlloooodd VVoolluum mee ooff DDaaiillyy IIrroonn


RReeqquuiirreem
meenntt RReeqquuiirreem
meenntt PPuurree RRBBCCss//kkgg LLooaaddiinngg
((HHaaeem
maatto
occrriitt 6
600%%)) ((HHaaeem
maatto
occrriitt 7
755%%)) ((HHaaeem
maatto
occrriitt 1
10000%%))

100 – 150 ml/kg 80 – 120 ml/kg 60 – 90 ml/kg 0.18 – 0.27 mg/kg


150 – 200 ml/kg 120 – 160 ml/kg 90 – 120 ml/kg 0.27 – 0.36 mg/kg
200 – 250 ml/kg 160 – 200 ml/kg 120 – 150 ml/kg 0.36 – 0.44 mg/kg
250 – 300 ml/kg 200 – 240 ml/kg 150 – 180 ml/kg 0.44 – 0.53 mg/kg

Table 5: Relationship between annual blood requirements and rate of daily iron loading.

26
Knowing the annual transfusion Adverse reactions
requirements is also valuable in
identifying changes that may Blood transfusion exposes the
constitute important evidence patient to a variety of risks.
of hypersplenism or accelerated Thus, it is vital to continue to
destruction of donor red cells. improve blood safety and to
Specific guidelines for consideration of find ways of reducing
splenectomy in the presence of increasing transfusion requirements and
transfusion requirements are difficult to the number of donor exposures.
establish because of a lack of information on Adverse events (see Table 6) associated with
the haematocrit levels of the transfused transfusion include:
blood in earlier recommendations and
uncertainty with regard to long-term ñ N
No onnhhaaeem moollyyttiicc ffeebbrriillee ttrraannssffuussiioonn
consequences of splenectomy, including rreeaaccttiioonnss:: These were common in past
sepsis and thrombosis. Moreover, the decades, but have been dramatically
decision to proceed to splenectomy must reduced by leucoreduction, especially
take into consideration the individual pre-storage leucoreduction, which sharply
patient’s ability to control iron stores at a reduces cytokine accumulation and
given level of transfusional iron loading. leucocyte alloimmunisation. In the
Nevertheless, as the annual transfusion absence of effective leucoreduction,
requirements rise above 200ml/kg/yr of pure patients experiencing such reactions
red cells, splenectomy should be considered should be given antipyretics before their
as a potential strategy to reduce the rate of transfusions. Since fever may accompany
iron loading. a haemolytic transfusion reaction or the
administration of a unit with bacterial

ACCUUTTEE
A FFR
REEQQUUEENNCCYY DEELLAAYYEEDD
D FFR
REEQQUUEENNCCYY

Haemolytic (Intravascular) 1/25,000 Alloimmune 1/100


Anaphylactic 1/50,000 Haemolytic (Extravascular) 1/ 2,500
Febrile non-haemolytic 1/100 Graft Vs Host Disease Rare
Allergic (Urticarial) 1/100
TR Acute Lung Injury 1/10,000

Table 6: Broad categorisation of immune-mediated transfusion related (TR) reactions and reported
frequencies

27
contamination, these causes should adherence to standard protocols for
always be considered in a patient who screening for antibodies and carrying out
develops fever during administration of the necessary full crossmatching of donor
red cells. units and (4) use of multiple patient
identifiers before transfusing the blood.
ñ A
Alllle
errggiicc rreeaaccttiioonnss are usually due to In many transfusion units, two staff
plasma proteins and range from mild to members check the identification of the
severe. Milder reactions include urticaria, unit and the recipient prior to beginning
itching and flushing, and they are the transfusion.
generally mediated by IgE. More severe
reactions, such as stridor, bronchospasm, If signs and symptoms suggest an acute
hypotension or other symptoms of haemolytic reaction, the transfusion
anaphylaxis may occur, especially in should be stopped immediately and
patients with IgA deficiency and anti-IgA intravenous fluids should be administered
antibodies. Occasional mild allergic to maintain intravascular volume.
reactions often can be prevented by the Diuretics may help to preserve renal
use of antihistamines or corticosteroids function. Disseminated intravascular
before transfusion. Recurrent allergic coagulation (DIC) may require additional
reactions can be markedly reduced by measures such as heparin. The
washing the red cells to remove the identification of the patient and the
plasma. Patients with IgA deficiency and donor unit should be re-checked. The
severe allergic reactions may require blood bank should also be alerted to the
blood from IgA -deficient donors. possibility of an undetected alloantibody.

ñ A
Accu
uttee hhaaeem
moollyyttiicc rreeaaccttiioonnss begin within ñ D
Deellaayyeedd ttrraannssffuussiioonn rreeaaccttiioonnss usually
minutes or sometimes hours of beginning occur 5-14 days after transfusion and are
a transfusion and are characterised by the characterised by unexpected levels of
abrupt onset of fever, chills, lower back anaemia, as well as malaise and jaundice.
pain, dyspnea, hemoglobinuria and shock. These reactions may be due to an
These unusual reactions most commonly alloantibody that was not detectable at
arise from errors in patient identification the time of transfusion or to the
or blood typing and compatibility testing. development of a new antibody. A
The risk of receiving the wrong blood is sample should be sent to the blood bank
greater for a patient with thalassaemia to investigate the presence of a new
who travels to another centre or is antibody and to repeat cross-matching of
admitted to a hospital not familiar with the last administered unit(s).
his/her case and medical history.
Haemolytic reactions in these patients ñ A
Auuttooiim
mmmuunnee hhaaeem
moollyyttiicc aannaaeem
miiaa is a very
can still be avoided by (1) the use of serious complication of transfusion
optimal methods for identifying the therapy that usually but not always
patients and labelling of the sample when occurs in patients with alloantibodies.
blood is obtained for crossmatch, (2) Even red cells from seemingly compatible
proper linkage of the sample to the units (i.e., those units that do not contain
donor unit in the blood bank, (3) the antigen to which there is a known
alloantibody) may demonstrate markedly

28
shortened survival, and the haemoglobin complication of transfusion.
concentration may fall well below the Immunosuppressed patients are at
usual pre-transfusion level. Destruction particular risk, but TI-GVHD may also
both of the donor’s and the recipient’s occur in immunocompetent recipients of
red cells occurs. The serologic evaluation red cells from a haploidentical donor such
by the blood bank usually shows an as a family member. TI-GVHD usually
antibody that reacts with a wide range of occurs within 1-4 weeks of transfusion
test cells and fails to show specificity for and is characterised by fever, rash, liver
a particular antigen. Steroids, dysfunction, diarrhoea and pancytopenia
immunosuppressive drugs and due to bone marrow failure. To reduce
intravenous immunoglobulin are used for the risk of TI-GVHD, donated blood from a
the clinical management of this situation, family member should be avoided or if
although they may give little benefit. used should always be irradiated before
Some patients have also been treated transfusion. Leucodepletion alone is
with rituximab, but the effectiveness of inadequate for the prevention of this
its use in this situation is presently not complication.
well defined. Autoimmune haemolytic
anaemia occurs more frequently in ñ TTrraan
nssffuussiioonn--aassssoocciiaatteedd cciirrccuullaattoorryy
patients who begin transfusion therapy oovveerrllooaadd may occur in the presence of
later in life (Rebulla, 1991), and should be recognised or unrecognised cardiac
carefully considered before instituting dysfunction, or when the rate of
transfusion therapy for teenagers and transfusion is inappropriately fast. Signs
adults with thalassaemia intermedia. and symptoms include dyspnoea and
tachycardia, and the chest radiograph
ñ TTrraannssffuussiioonn--rreellaatteedd aaccuuttee lluunngg iinnjjuurryy shows the classic findings of pulmonary
((TTRRAALLII)) is a potentially severe oedema. Treatment focuses on volume
complication that is usually caused by reduction and cardiac support, as
specific anti-neutrophil or anti-HLA required.
antibodies (Swanson, 2006). This
complication is characterised by ñ TTrraan
nssm
miissssiioonn ooff iinnffeeccttiioouuss aaggeennttss
dyspnoea, tachycardia, fever and including viruses, bacteria and parasites,
hypotension during or within six hours of are a major risk in blood transfusion (see
transfusion. Hypoxemia is present and the Chapter 9: Infections in Thalassaemia
chest radiograph shows bilateral infiltrates Major). Even in countries where residual
typical of pulmonary oedema although risk of transmission through blood of
there is no reason to suspect volume clinically significant pathogens (HIV, HBV,
overload. Management includes oxygen, HCV and Syphilis) has been reduced to
administration of steroids and diuretics, minimal levels, problems continue to exist
and, when needed, assisted ventilation. or emerge because:

ñ TTrraan nssffuussiioonn--iinndduucceedd ggrraafftt vveerrssuuss hhoosstt − A limited range of known pathogens


ddiisseeaassee ((TTII--GGVVHHDD)) is caused by viable is targeted in mandatory donor
lymphocytes in units of transfused red screening (excludes HPV B-19, HCMV,
cell. It is a rare but often fatal EBV, HAV, Yersinia enterolitica,
parasites, e.g., malaria);

29
− Transmission of viruses still occurs In many regions of the developing world,
(window period, sensitivity threshold where thalassaemia is most prevalent,
of tests); continued transmission of hepatitis B,
− The clinical significance of newly hepatitis C and HIV underscores the
identified infectious agents (HGV, importance of promoting the quality of
GBV-C, TTV, SEN-V, HSV6,7,8) is not national blood transfusion services, including
yet completely clarified and donors voluntary blood donations, careful donor
are not screened for these agents; selection and screening, and public health
− Newly emerging infectious agents services’ provision of necessary
(WNV, SARS, Avian Flu, prions), immunisation.
constitute serious threats, and;
− Absence of widely accepted tests for
bacteria (endogenous and exogenous)
and for parasitic protozoa associated,
for example, with Chaga’s disease,
toxoplasmosis and babesiosis.

SSu
ummm
maarryy RReeccoom
mmmeennddaattiioonnss::
ñ Careful donor selection and screening – voluntary, regular non-remunerated blood
donation.
ñ Confirm diagnosis of thalassaemia major.
ñ Before initiation of transfusion therapy, confirm laboratory and clinical criteria.
ñ Before first transfusion, extended red cell antigen typing of patients at least for C, E
and Kell.
ñ At each transfusion, give ABO, Rh(D) compatible blood. Matching for C, E and Kell
antigen is recommended.
ñ Before each transfusion, full cross-match and screen for new antibodies.
ñ Keep record of red cell antibodies, transfusion reactions and annual transfusion
requirements for each patient.
ñ Use leucoreduced packed red cells. Pre-storage filtration is recommended, but blood
bank pre-transfusion or bedside filtrations are acceptable alternatives.
ñ Washed red cells for patients who have severe allergic reactions.
ñ Use red cells stored in CPD-A, as fresh as possible (less than one week old) and in
additive solutions for less than 2 weeks.
ñ Transfuse every 2-5 weeks, maintaining pre-transfusion Hb above 9-10.5 g/dl, but
higher levels (11-12 g/dl) may be necessary for patients with heart complications.
ñ Keep post-transfusion Hb not higher than 14-15 g/dl.

30
Iron Overload

IIr
roon
noovve
errlload occurs when iron intake is based on the assumption that
increased over a sustained period of time,
either as a result of red blood cell
200 mg of iron is contained in
transfusions or increased absorption of iron each donor unit.
through the gastrointestinal tract (GI). Both
Thus, irrespective of whether the blood used
of these occur in thalassaemia, with blood
is packed, semi-packed or diluted in additive
transfusion therapy being the major cause of
solution, if the whole unit is given, this will
iron overload in thalassaemia major and
approximate to 200 mg of iron intake.
increased GI iron absorption being more
important in thalassaemia intermedia.
According to the recommended transfusion
scheme for thalassaemia major, the
In the absence of any equivalent of 100–200 ml of pure RBC per kg
mechanism of the human body per year are transfused (equivalent to 116-
to excrete excess iron, chelation 232 mg of iron per kg body weight per year
or 0.32-0.64 mg/kg/day). Regular blood
therapy is essential and transfusion therapy therefore increases iron
constitutes the second stores to many times the norm unless
important arm, besides chelation treatment is given.
transfusion therapy, of the
IIncreased gas tro-intest inal absorpt ion
clinical management of these
o f i r on :
o
patients. Normal intestinal iron absorption is about 1-2
mg/day. In patients with thalassaemia who
do not receive any transfusion, iron
The Rate of Iron absorption increases several-fold.

Loading It has been estimated that iron


absorption exceeds iron loss
B l o o d t ra n s fu s i o n : when expansion of red cell
Knowledge of the rate of iron loading from precursors in the bone marrow
transfusion to as high a level of accuracy as exceeds five times that of
possible will contribute significantly to the
formulation of chelation therapy appropriate
healthy individuals.
for each patient. Simple calculations, such as Transfusion regimens aimed at keeping the
those described in the Blood Transfusion pre-transfusion haemoglobin above 9 g/dl
Chapter of this book, can provide the have been shown to prevent such expansion
treating physician with this information. (Cazzola 1997). In individuals who are poorly
transfused, absorption rises to 3-5 mg/day or
In case organisational or other more representing an additional loading of
difficulties do not allow such 1-2 grams of iron loading per year.
estimations, a rough
approximation can be made

31
Paattiieenntt’’ss wweeiigghhtt
P 200 kkgg
2 355 kkgg
3 500 kkgg
5 655 kkgg
6
Pure red cell volume (ml) 2,000-4,000 3,500-7,000 5,000-10,000 6,500-13,000
transfused yearly
(if 100-200 ml/kg/yr)
Yearly iron loading from 2.3-4.6 4.1-8.2 5.8 -11.6 7.5 -15.1
transfusion (g)
Daily iron loading from 4.7 -9.5 11.1-22.2 15.9-31.8 20.6-41.5
transfusion (mg)

Table 1: Examples of increase in iron stores from transfusion in the absence of chelation

Figure 1: A simplified scheme of iron turnover in healthy adults is shown above in bold arrows. The broken line
indicates the effect of transfusion on iron turnover, with an increased daily delivery of haem iron to
macrophages which leads to increased iron release rates from macrophages, saturation of transferrin
and the appearance of Non-Transferrin-Bound Iron (NTBI) in blood. This in turn causes increased iron
uptake by the liver and other parenchyma, such as the heart and endocrine glands.
(Adapted from Porter JB. Hematol Oncol Clin North Am. 2005;19:1-6)

(atoms or molecules with unpaired


Toxicity from Iron electrons). These can damage lipid
membranes, organelles and DNA causing cell
Overload death and the generation of fibrosis. In
health, iron is ‘kept safe’ by binding to
Meecchhaanniissm
M m ooff iirroonn ttooxxiicciittyy molecules such as transferrin, but in iron
Iron is highly reactive, easily alternating overload their capacity to bind iron is
between two states – iron III and iron II – in a exceeded both within cells and in the plasma
process which results in the gain and loss of compartment. The resulting ‘free iron’
electrons, generating harmful free radicals damages many tissues in the body and is
fatal unless treated by iron chelation therapy.

32
Coom
C mpplliiccaattiioonnss ooff iirroonn oovveerrllooaadd increase serum ferritin, while vitamin C
Untreated transfusional iron overload in deficiency may depress it. A sudden and
thalassaemia major is fatal in the second unexpected rise in ferritin level should
decade of life, usually as a result of cardiac prompt a search for hepatitis, other
complications (Zurlo 1989). Iron overload also infections or inflammatory conditions. In
causes pituitary damage, leading to thalassaemia intermedia, serum ferritin tends
hypogonadism and poor growth. Endocrine to underestimate the degree of iron
complications, namely diabetes, overloading (Pootrakul 1981; Galanello,
hypothyroidism and hypoparathyroidism, are 1994). Therefore although there is a broad
also seen. Liver disease with fibrosis and correlation between serum ferritin level and
eventually cirrhosis, particularly if liver iron, the prediction of iron loading from
concomitant chronic hepatitis is present, is serum ferritin can be unreliable (Olivieri
also a serious complication. (These 1995). Importantly, however, at least five
complications are described in greater detail studies have shown an association between
in the relevant chapters of this book.) the control of serum ferritin and prognosis
(Gabutti V and Piga A. 1996; Olivieri, N. et al
1994; Telfer PT, et al. 2000; Davis BA, et al.
2004; Borgna-Pignatti et al. 2004). Studies
Monitoring of Iron have identified a significantly lower risk of
cardiac disease and death in at least two-
Overload thirds of cases where serum ferritin levels
have been maintained below 2,500 Ìg/L
Monitoring closely and assessing as accurately (with desferrioxamine) over a period of a
as possible iron overload is essential in decade or more (Olivieri, 1994). Observations
establishing effective iron chelation regimes, with larger patient numbers show that
such as those mentioned in this chapter, maintenance of an even lower serum ferritin
tailored to the individual patient’s specific of 1,000 Ìg/L may be associated with
needs. However, some general principles of additional advantages (Borgna-Pignatti et al,
monitoring iron overload apply to all 2004) (see Table 2).
treatments:
LLiivve
err iirroonn ccoonncceennttrraattiioonn ((LLIICC))
SSe
erruum
m ffeerrrriittiinn Liver iron concentration is now regarded as
This is a relatively easy test to perform, well the reference standard for estimating body
established, generally correlating with body iron loading and has been shown accurately
iron stores and prognostically relevant in to predict total body iron stores (Angelucci,
thalassaemia major. Up to a value of about 2000), using the formula:
3,000 Ìg/L serum ferritin is secreted in an
iron-free form from macrophages, but above TToottaall bbooddyy iirroonn ssttoorreess iinn m
mgg//kkgg =
= 1100..66 xx tthhee
this value increasing proportions of iron- LLIICC ((iinn m
mgg//gg ddrryy wwtt))
laden ferritin ‘leaks’ from hepatocytes
(Worwood, 1984; Davis, 2004). Day-to-day Normal LIC values are up to 1.8 mg/g dry wt,
variations are particularly marked: high with levels of up to 7 mg/g dry wt seen in
degrees of iron loading, inflammation, some non-thalassaemic populations without
hepatitis and/or liver damage may falsely apparent adverse effects (see Figure 2).

33
Several studies link high Liver Iron Content Telfer, 2000), liver fibrosis progression
(LIC) (above 15-20 mg/g dry wt) to (Angelucci, 1997) or liver function
worsening prognosis (Brittenham, 1994; abnormalities (Jensen, 2003).

TTaab
bllee 22:: M
Meeaassuurriinngg aanndd iinntteerrpprreettiinngg sseerruum
m ffeerrrriittiinn
Addvvaannttaaggeess
A Diissaaddvvaannttaaggeess
D

ñ Easy to assess ñ Indirect measurement of iron burden


ñ Inexpensive ñ Fluctuates in response to inflammation,
ñ Repeat measures are useful for monitoring abnormal liver function, metabolic
chelation therapy deficiencies
ñ Positive correlation with morbidity and ñ Serial measurement required
mortality

LLIIV
VEERR IIRROONN AANNDD RRIISSKK FFRROOM
M IIRROONN OOVVEERRLLOOAADD

Figure 2: Liver risk and iron overload (Olivieri & Brittenham, 1997)

34
LIC determination should be considered, by LIC can also be measured accurately using a
the treating physicians for those patients method known as SQUID (supercoducting
whose serum ferritin levels deviate from quantum interference device). However, only
expected trends (i.e. those with suspected four such machines are currently available
co-existing hepatitis, or patients on chelation worldwide: they are expensive to purchase
regimens with variable or uncertain and maintain, and require dedicated trained
responses), as this may reduce the risk of staff. Liver iron measured by SQUID has the
giving either inadequate or excessive doses advantage of possessing a wide linear range
of chelation therapy. Since the relationship but each SQUID machine has to be
of serum ferritin to iron overload and iron individually calibrated.
balance has not yet been established,
assessment of LIC may be particularly useful LIC can also now be measured using MRI
when new chelating regimes are being used. techniques, previously limited to a relatively
narrow linear range. One recently described
Measurement of LIC can be done by chemical approach, is the R2 or Ferriscan technique
determination on a liver biopsy sample which appears to have acceptable linearity
(fresh, fixed or from dewaxing of paraffin- and reproducibility over the range of clinical
embedded material)(see Table3) or by non- interest (St Pierre TG, et al, 2005). The
invasive methods such as magnetic technique demonstrates an average
biosusceptometry (SQUID) (Brittenham 1994) sensitivity of >85% and specificity of >92%
or magnetic resonance imaging (MRI)(see up to an LIC of 15 mg/g dry wt, and has
Table 4). Biopsy is an invasive procedure, but been registered in the EU and US. For
in experienced hands has a low complication calibration, the MRI machine must use a
rate (Angelucci 1997). Inadequate sample Phantom supplied by the company, while the
size (<1 mg/g dry weight, 4 mg wet wt or data acquired is sent via internet for analysis
about a 2.5 cm core length) or uneven by dedicated Ferriscan software (payment
distribution of iron, particularly in the per scan analysed). A particular advantage of
presence of cirrhosis (Villeneuve 1996), may this technique is that it can be applied with
give misleading results. little training, at any centre with a reasonably
up-to-date MRI machine (see Table 4).

TTaab
bllee 33:: M
Meeaassu
urriin
ngg LLIIC
Cbbyy lliivveerr b
biio
oppssyy
Ad
A dvvaan
nttaag
geess Diissaad
D dvvaan
nttaag
geess

ñ Direct measurement of LIC ñ Invasive, painful procedure associated with


ñ Validated reference standard potentially serious complications
ñ Quantitative, specific, and sensitive ñ Risk of sampling error, especially in
ñ Allows for measurement of non-heme patients with cirrhosis
storage iron ñ Requires skilled physicians and
ñ Provides information on liver standardized laboratory techniques
histology/pathology
ñ Positive correlation with morbidity and
mortality

35
Heeaarrtt ffuunnccttiioonn
H myocardial T2* to <20 ms (implying
Regular monitoring of left ventricular increased myocardial iron) is associated with
ejection fraction (LVEF) has allowed an increased chance of decreased LV
identification of a group of patients with function (Anderson et al, 2001). For example,
poor prognosis at high risk of subsequent patients with T2* values >20 ms have a very
heart failure and death who responded well low chance of decreased LVEF. T2* values of
to intensification of desferrioxamine (Davis et 10-20 ms indicate up to a 10% chance of
al, 2004). Patients with a fall in ejection decreased LVEF; 8-10 ms indicates an 18%
fraction below reference values for the chance; 6 ms indicates a 38% chance; and
method used have a 35-fold increased risk of T2* values of just 4 ms indicate a 70% chance
cardiac failure and death, with a median of decreased LVEF (Westwood et al, 2005). In
interval to progression of 3.5 years allowing centres where such methodology is available,
time for intensification of chelation the T2* value may identify patients at high
treatment. Left ventricular function can be risk of developing a fall in LVEF before it
quantified using MRI, MUGA or occurs permitting a more informed choice
echocardiography. The first two methods regarding patients whose chelation
have advantages over echocardiography in treatment should be intensified.
that they are less operator-dependent and
therefore more easily adapted to longitudinal The ability to estimate heart iron offers an
monitoring. additional way to stratify risk, opening up a
new diagnostic window. However, factors
affecting the risk of developing heart failure
Myyo
M occaarrddiiaall iirroonn eessttiim
maattiioonn ((TT22** oorr from myocardial iron overload are complex,
ootthheerr m
meeaassuurreess)) while T2* measures storage iron – not in
Estimation of myocardial iron using MRI is itself directly toxic to cells. Factors that may
becoming increasingly available but requires increase the availability of labile intracellular
expertise in its use and standardisation. iron to cause intracellular damage such as
The T2* value in tissues shortens as the iron myocarditis, or lack of continuous exposure
concentration increases. A shortening of to intracellular chelation, may influence the

TTaab
bllee 44:: M
MRRII aasssseessssm
meenntt ooff LLIICC
Addvvaannttaaggeess
A Diissaaddvvaannttaaggeess
D

ñ Assesses iron content throughout ñ Indirect measurement of LIC


the liver ñ Requires MRI imager with dedicated
ñ Potentially widely available imaging method
ñ Pathological status of liver and heart
can be assessed in parallel

Liver iron levels can be assessed using a technique known as R2 (spin echo) MRI, which is a
validated and standardised method for measuring LIC

MRRII=Magnetic Resonance Imaging


M

36
risk posed by excess heart iron, and explain of which can redox cycle. One
why only a proportion of people with short way of measuring the NTBI
T2* values show abnormal heart function at
any moment in time. Prospective data on the
fraction that is labile and can
relationship between myocardial T2* and
redox cycle is the labile plasma
survival are still required. However, the iron’ assay (LPI assay). However,
relationship between short T2* values although the measurement of
(<10ms) and the risk of heart dysfunction is NTBI (or LPI) has proved a useful
clear (see Table 5). tool for examining how
chelators interact with plasma
Urriinnaarryy iirroonn eessttiim
U maattiioonn iron pools, its value as a guide
Measurement of the urinary iron excretion to routine treatment or
can assist in assessing the effect on iron prognosis has yet to be
excretion of desferrioxamine (about half of demonstrated.
total iron excreted in urine) or deferiprone
(over 80% of iron excreted in urine). Otthheerr m
O maarrkkeerrss ooff ooxxiiddaattiivvee ddaam
maaggee
However, the inherent variability in daily iron A wide variety of markers for oxidative
excretion necessitates repeated damage have been investigated.
determinations. Faecal iron excretion Malondialdehyde (MDA) is increased in iron
contributes an additional, but variable (30- overload, while a wide range of antioxidants
100%) to the amount of urinary iron are depleted.
excretion, depending on the level of iron
stores, the dose of desferrioxamine and the There has been interest in the
level of haemoglobin (Pippard 1982).
use of antioxidants or naturally
PPllaassm
maa nnoonn--ttrraannssffeerrrriinn bboouunndd iirroonn occurring products that contain
antioxidant properties, such as
((NNTTBBII)) Curcumin. However, until
In iron overload, transferrin, the normal
carrier of iron in plasma becomes saturated
controlled data are available
leaving iron unbound i.e. Non-Transferrin
caution is advised in the use of
Bound Iron (or NTBI). these, as the effects of
NTBI is cleared by different cells than antioxidants in the presence of
transferrin iron, and is mainly responsible for iron can be unpredictable due
the abnormal pattern of iron distribution in to redox cycling of iron
transfusional iron overload. Because these between the iron (II) and iron
forms of iron rapidly reappear once iron (III) states.
chelators are cleared from the blood, experts
suggest that the optimal treatment is 24- Otthheerr m
O maarrkkeerrss ooff oorrggaann ddyyssffuunnccttiioonn..
hour chelation (Porter, 1996). These are discussed more fully in other
chapters. However, iron overloaded patients
NTBI consists of several chemical should be monitored for evidence of
entities, only some of which are hypoganadotrophic hypogonadism (growth
readily chelatable and only some and sexual development and biochemical

37
markers of HH), diabetes mellitus (yearly GTT), Iron appears to be removed
hypothyroidism and hypoparathyroidism. more quickly from some tissues,
such as the liver, than others –
Treatment of Iron for example, the heart.
Overload Increasing the dose of chelators given in an
attempt to speed up iron removal runs the

Gooaallss ooff iirroonn cchheellaattiioonn tthheerraappyy


G
risk of increasing the toxicity of an iron
chelator, by chelating the iron needed for
The primary goal of chelation normal tissue metabolism. The twin goals of
therapy is to maintain safe levels iron chelation in iron overloaded patients is
of body iron at all times. therefore to decrease tissue iron to safe
Unfortunately, once iron levels, while simultaneously making the iron
overload has accumulated, as safe as possible by binding the toxic iron
removal of storage iron is slow pools responsible for causing tissue damage.
and inefficient, because only a Iron is constantly being turned over, either as
a result of the breakdown of red cells in
small proportion of body iron is macrophages or the breakdown of ferritin
available for chelation at any within cells. These same fractions are redox-
given time. active and potentially harmful; the plasma
component of this iron (NTBI) is mainly
Consequently, when an iron chelator is given,
responsible for the iron loading of tissues.
only a small proportion of the drug binds
As mentioned above, NTBI appears within
iron, before it is excreted or metabolised.
minutes of a chelator being cleared from the
Once a patient is iron overloaded, it may take
body. Thus, in order to achieve the second
months or years to reduce body storage iron
goal of chelation – the minimisation of toxic
to safe levels, even with the most intensive
(labile) iron pools – 24-hour chelation
treatment. Chelation must therefore begin
coverage is the ideal. Once low levels of iron
soon after (2-3 years) the initiation of
have been achieved, it is more appropriate to
transfusion therapy.
reduce the dose of chelator than to interrupt
or decrease the frequency of chelation.

TTaab
bllee 55:: M
MRRII aasssseessssm
meenntt ooff ccaarrddiiaacc iirroonn
Addvvaannttaaggeess
A Diissaaddvvaannttaaggeess
D
ñ Rapidly assesses iron content in ñ Indirect measurement of cardiac iron
the septum of heart ñ Requires MRI imager with dedicated
ñ Iron levels can be quantified reproducibly imaging method
ñ Functional parameters can be examined ñ Technically demanding
concurrently ñ Methodology remains to be standardized
ñ Pathological status of liver and heart and validated
can be assessed in parallel
Cardiac iron levels can be rapidly and effectively assessed using a technique know as T2* (gra-
dient echo) MRI, which is becoming the new standard method

MRRII=Magnetic Resonance Imaging


M

38
approximately 14%. Iron excretion with
Desferrioxamine desferrioxamine increases with dose, with
body iron stores and with the addition of
(Desferal® or vitamin C.

deferoxamine) EEvviiddeennccee ffoorr tthhee eeffffeeccttiivveenneessss ooff


ddeessffeerrrriiooxxaam
miinnee
Desferrioxamine has been in clinical use since EEffffeeccttss oonn sseerruum
m ffeerrrriittiinn
the 1970s and widely used as subcutaneous Clinical experience over a period of three
infusions since about 1980. Provided that decades indicates that ferritin can be
treatment is 1) begun within 2-3 years of controlled with desferrioxamine
beginning transfusion therapy, 2) monotherapy, and that maintaining serum
administered regularly and 3) administered in ferritin <2500 Ìg/L with this drug is closely
adequate doses, desferrioxamine has a well- linked to protection from heart disease and
established impact on survival and on cardiac to improved survival (Olivieri, 1994).
and other complications of iron overload
described above (Brittenham, 1994; Piga, However, the results of a formal
1996; Borgna-Pignatti, 2004). prospective study on the dose
required to stabilise or decrease
The main disadvantages of the serum ferritin in large
treatment are that it is costly populations have only recently
and that it must be become available.
administered parenterally. The study – a prospective evaluation of
changes in ferritin levels and LIC as a function
M
Me ecchhaanniissm
m ooff aaccttiioonn aanndd of dose in 290 thalassaemia major patients
pphhaarrm
maaccoollooggyy (Cappellini, 2006) – demonstrated that a
mean daily dose of 42 mg/kg resulted in a
Due to its molecular size, desferrioxamine is small decrease in serum ferritin of 364 Ìg/L
poorly absorbed from the gut. The higher at one year, whereas a mean daily dose of 51
the dose, the higher the proportion of iron mg/kg resulted in an average ferritin
excreted in the faeces rather than the urine. decrease of approximately 1,000 Ìg/L over
Iron excreted in the urine is derived from the one year. Therefore, if the serum ferritin is
breakdown of red cells in macrophages, >2,500 Ìg/l, a mean daily dose of at least 50
whereas faecal iron is derived from iron mg/kg/day is recommended (except in
chelated within the liver (Hershko, 1979; children – see below).
Pippard, 1982). Desferrioxamine has a short
plasma half-life (initial half-life 0.3h), being
EEffffe
eccttss oonn lliivveerr iirroonn
eliminated rapidly in urine and bile. The
Administered at least 5 times a week and in
process of iron chelation ceases soon after
sufficient doses, desferrioxamine is effective
an infusion of desferrioxamine is complete.
in controlling liver iron and hence total body
The efficiency of desferrioxamine (measured
iron stores (Brittenham, 1994). The
in terms of percent of dose excreted in the
relationship between dose and change in LIC
iron bound form) administered at standard 8-
was not examined systematically until
12 hour intervals 5-7 days a week is
recently (Cappellini, 2006), in a study

39
establishing that a mean dose of 37 mg/kg Early intervention for decreased LV function
stabilised LIC for patients with baseline LIC is therefore recommended (Davis, 2004).
values of between 3 and 7 mg/g dry wt. For
patients with LIC values between 7 and 14 EEffffe
eccttss oonn hheeaarrtt iirroonn ((TT22**))
mg/g dry wt, a mean dose of 42 mg/kg
resulted in a small decrease of 1.9 mg/kg dry Treatment with continuous
wt. In patients with LIC values >14 mg/g dry
wt, a mean dose of 51 mg/kg resulted in LIC
intravenous desferrioxamine has
decreases of an average of 6.4 mg/g dry wt. been shown to improve
myocardial iron, even in the
Thus a dose of 50 mg/kg at least 5 days a most overloaded hearts, with
week is recommended if a significant average myocardial T2* values of <6 ms
decrease in LIC optimal levels (see above) is
(Anderson et al, 2004). The average rate of
required. It should be emphasised that these
are average changes and that the dose improvement at this level of iron loading of
required may increase or decrease depending the heart is about 3 ms/year in severely
on transfusion requirement (Cohen, 2005). overloaded hearts: if improvement is linear it
would take several years to normalise the T2*
EEffffe
eccttss oonn hheeaarrtt ffuunnccttiioonn to >20 ms (Porter 2002).
Subcutaneous therapy has long been known
to improve asymptomatic cardiac disease In patients with baseline T2* values of
(Freeman, 1983, 1989; Wolfe, 1985; Aldouri between 8-20 ms, subcutaneous treatment
et al, 1990). Since the introduction of at relatively low doses of 35 mg/kg showed
desferrioxamine, the incidence of iron- an average improvement in T2* of 1.8 ms
induced heart disease has fallen progressively over one year (Pennell 2006). At a slightly
in cohorts of patients – with a key factor higher dose of 40-50 mg/kg, five days a
being the age of starting treatment week, patients showed an improvement of 3
(Brittenhan, 1994; Borgna-Pignatti, 2004). ms over one year (Porter et al, 2005).
Symptomatic heart disease can be reversed Improvement in cardiac T2*, even at low,
by high dose intravenous treatment (Marcus, intermittent doses, has been confirmed by
1984; Cohen, 1989). The same results can be two prospective randomised studies (Pennell,
obtained with excellent long-term prognosis 2006; Tanner, 2007).
with lower doses (50-60 mg/kg/day – see
below) and consequently less drug toxicity EEffffe
eccttss oonn m
moorrbbiiddiittyy
using continuous dosing (Davis, 2000 and Regular subcutaneous therapy started before
2004). Continuous intravenous doses of 50- the age of 10 years reduces the incidence of
60 mg/kg/day typically normalised LVEF in a hypogonadism (Bronspiegel-Weintrob, 1990),
period of three months (Anderson LJ, et al., as well as other endocrine disturbances,
2004), significantly before liver or heart iron including diabetes mellitus (Brittenham,
stores had been normalised. However, if 1994; Olivieri, 1994; Borga-Pignatti, 2004)
advanced heart failure has developed before (See Table 6).
treatment is intensified, the chances of
successful rescue are decreased.

40
EEffffeeccttss oonn ssuurrvviivvaall aanndd ccoom
mpplliiccaattiioonnss demonstrated by the improving survival in
ooff iirroonn oovveerrllooaadd patients born between the 1960s and the
present day (see Figure 3). Note that only
As mentioned previously, desferrioxamine
was first used to treat iron overload in patients born after 1980 will have started
thalassaemia in the 1970s but was only treatment at an early age, and that age of
widely used by infusion after 1980. The starting treatment is a key factor in outcome
benefits of its regular use are clearly (Borgna-Pignatti, 2004; Brittenham et al,
1994; Davis et al, 2004).

Biirrtthh 11997700––7744**
B Biirrtthh 11998800––8844††
B

Death at 20 years 5% 1%
Hypogonadism 64.5% 14.3%
Diabetes 15.5% 0.8%
Hypothyroidism 17.7% 4.9%

* IM, DFO introduced in 1975


† SC, DFO introduced in 1980
In 1995, 121 patients switched to DFP (censored at the time)

Table 6: Decreasing complications in cohorts born after desferrioxamine was already available.
Survival probability

Age (years)

Figure 3: Increasing probability of survival (% alive at ages shown) with desferrioxamine therapy for
thalassaemia, mainly as a result of decreased cardiac iron toxicity, in patient cohorts born
between 1960-64 and 1995-97 (Borgna-Pignatti, 2004)

41
Desferrioxamine needs to be infections such as Klebsiella may also be
exacerbated by continued treatment with
taken at least five times a week desferrioxamine.
in order to optimise survival
(Piga, 1996). Fatal complications It is therefore recommended to cease
from iron overload are also administration of desferrioxamine in anyone
decreased if body iron (as with an unexplained fever, until the cause
measured by liver iron) is kept has been identified and effective antibiotic
treatment begun. The decision as to when to
below certain levels recommence treatment with desferrioxamine
(Brittenham, 1994) (see below). requires clinical judgement and a careful
balancing of the potential risks and benefits.
For example, a patient with high cardiac iron
Unwanted effects of or poor heart function may be at high risk if
desferrioxamine is withheld during a septic
desferrioxamine episode, outweighing the risks of infection
once antibiotics have been commenced.
Local skin reactions, such as itching, Severe allergy to desferrioxamine is a rare
erythema, induration and mild to moderate event and can be treated by careful
discomfort are common and may be due to desensitisation, carried out under close
inadequate dilution of desferrioxamine. medical supervision (Bosquet, 1983; Miller,
Ulceration at the site of a recent infusion 1981). Desensitisation is usually successful
results from an intradermal infusion of but may need to be repeated. If
desferrioxamine and should be addressed by unsuccessful, an alternative chelator, such as
deeper placement of the needle in Deferiprone or Deferasirox (see below), may
subsequent infusions. be considered.
Infection with Yersinia enterocolitica is an
important risk associated with Dose-related
desferrioxamine treatment (described in
detail in the Chapter 9: Infections in complications
Thalassaemia Major). Such an infection may
be difficult to diagnose. However, where Administration of excessive dosage of
there is reasonable clinical suspicion of desferrioxamine may cause the following
infection, with Yersinia enterolitica treatment complications in patients who are not heavily
with desferrioxamine should be temporarily iron loaded:
discontinued. Infection should be considered
in any patient with a febrile illness, especially
when associated with abdominal pain,
ñ H e a r i n g p ro b l e m s :
Hearing problems: High frequency
sensory neural loss, tinnitus and deafness
diarrhoea or joint pains, and should be may occur when desferrioxamine is given
treated as a medical emergency. in high doses, particularly to young
Desferrioxamine can usually be reintroduced children whose iron burden is low
once symptoms have subsided and a full (Olivieri, 1986), and when the therapeutic
course of antibiotics completed. Other

42
index is exceeded (>0.025) (Porter, essential in all children (see Chapter 4:
1989). Minor sensory neural deficit has Endocrine Complications).
been reversible in some cases, but
significant hearing loss is usually ñ S ke l e t a l c h a n g e s :
Skeletal changes: These are more
permanent. It is therefore advisable to common in cases of excessive dosage of
monitor audiometry yearly, bearing in desferrioxamine where patients have a
mind that audiometric changes due to low level of iron loading (De Virgillis,
excessive desferrioxamine are usually 1988; Olivieri, 1992; Gabutti, 1996).
symmetrical; asymmetry suggests other Rickets-like bony lesions and genu valgum
pathology. may be seen in association with
metaphyseal changes, particularly in the
ñ E ff e c t s o n t h e e y e :
Effects on the eye: These were first vertebrae, giving a disproportionately
noted when very high doses (>100 short trunk. Radiographic features include
mg/kg/day) were given (Davies, 1991). vertebral demineralisation and flatness of
Symptoms may include night-blindness, vertebral bodies. Patients should be
impaired colour vision, impaired visual regularly observed for such changes, as
fields and reduced visual acuity. Severe they are irreversible.
cases may show signs of retinitis
pigmentosa on fundoscopy, whereas ñ R ar e c o m p li c a t io n s :
Rare complications: Renal impairment
milder cases are only demonstrable with and interstitial pneumonitis have been
electroretinography. The main risk factor reported at very high doses of 10
appears to be high dose (Olivieri, 1986) mg/kg/h or more. In patients without
but complications are also more likely in iron overload, desferrioxamine has
patients who have diabetes (Arden, 1984) induced reversible coma when used with
or those receiving concomitant a phenothiazine derivative (Blake, 1985).
phenothiazine treatment (Blake, 1985). Rapid intravenous injection, as may occur
Treatment with desferrioxamine should during flushing of a line containing
be temporarily suspended in patients who desferrioxamine, must be avoided.
develop complications, to be
reintroduced at lower doses once
investigations indicate resolution of the
problem.
Recommended
ñ G ro w t h re t a r d a t i o n:
Growth retardation: This may occur if standard therapy
desferrioxamine is administered at too
high a dose. Another risk factor is a SSttaan
nddaarrdd ddoossee aanndd ffrreeqquueennccyy
young age of starting treatment (<3yrs) The standard recommended
(De Virgillis, 1988; Piga, 1988). Growth method is slow subcutaneous
velocity resumes rapidly when the dose is
reduced to <40 mg/kg day, while it does
infusion over 8-12 hours of a
not respond to hormonal treatment. It is 10% desferrioxamine solution,
therefore recommended that doses do using an infusion pump.
not exceed 40 mg/kg until growth has In general, average doses should not exceed
ceased. Regular monitoring of growth is 40 mg/kg until growth has ceased. The
standard dose is 20-40 mg/kg for children,

43
and up to 50-60 mg/kg for adults, as an 8- Liver iron concentration (by biopsy, SQUID or
12-hour subcutaneous infusion for a MRI) has recently been advocated as a more
minimum of 6 nights a week. To achieve reliable alternative to serum ferritin (see
negative iron balance in patients with below). To avoid wasting a costly drug such
average transfusion requirements, a dose of as desferrioxamine, the dose can be adjusted
50 mg/kg/day at least 5 days a week is to the nearest whole vial (500 mg or 2 g),
required (Capellini, 2006). It is important that alternating dose volumes between the higher
patients with high degrees of iron loading or and lower number of vials to achieve the
at increased risk of cardiac complications desired mean daily dose.
receive adequate doses.
W
Wh heenn ttoo ssttaarrtt ddeessffeerrrriiooxxaam
miinnee
UUssee ooff ddeessffeerrrriiooxxaam
miinnee bbyy tthheerraappyy
ssuubbccuuttaanneeoouuss bboolluuss In thalassaemia major, this should start as
If an infusion pump is not available or if 10- soon as transfusions have deposited enough
hour infusions are not tolerated, bolus iron to cause tissue damage. This has not
subcutaneous treatment may be considered been formally determined, but current
if the patient is not at high risk of heart practice is to start after the first 10-20
disease. A randomised study has shown that transfusions or when the ferritin level rises
serum ferritin and liver iron can be controlled above 1,000Ìg/l. If chelation therapy begins
equally effectively by giving an equivalent before 3 years of age, particularly careful
total dose (45 mg/kg x 5 per week) either as monitoring of growth and bone development
two subcutaneous ‘boluses’ or as a nightly is advised, along with reduced
10-hour subcutaneous infusion (Yarali, 2006). desferrioxamine dosage. In thalassaemia
intermedia, the rate of iron loading is highly
Doossee aaddjjuussttm
D meenntt variable and the relationship between serum
At low ferritin levels, the dose of ferritin and body iron can be different from
desferrioxamine may need to be reduced and that seen in thalassaemia major. If possible,
desferrioxamine-related toxicities monitored an estimation of liver iron is advisable before
particularly carefully. Dose reductions can be starting treatment to see whether iron has
made using the therapeutic index (see Figure exceeded safe levels (see Figure 4).
4) (Porter, 1989):
Use of vitamin C:
Use of vitamin C: Vitamin C increases iron
Figure 4: Therapeutic Index excretion by increasing the availability of
chelatable iron, but if given in excessive
Therapeutic index = doses may increase the toxicity of iron. It is
me
m eaan
nddaaiillyy d
doossee ((m
mgg//kkgg))** // ffeerrrriittiinn ((ÌÌgg//ll)) recommended not to give more than 2-3
The aim is to keep the index < 0.025 at all mg/kg/day as supplements, taken at the time
times of the desferrioxamine infusion so that
**m meeaann ddaaiillyy ddoossee = = ((aaccttuuaall ddoossee rreecceeiivveedd oonn eeaacchh liberated iron is rapidly chelated. Where a
iinnffuussiioonn xx ddoosseess ppeerr ddaayy//77)) patient has just started on desferrioxamine
and it has been decided to administer
Although a valuable tool in protecting the vitamin C, the vitamin supplement should
patient from excess chelator, this index is not not be given until after several weeks’
a substitute for careful clinical monitoring. treatment.

44
DDeessffeerrrriiooxxaam
miinnee uussee dduurriinngg SSttrre
ennggtthh ooff iinnffuussiioonn
pprreeggnnaannccyy:: This is discussed in detail in the The manufacturers of desferrioxamine
relevant Chapter 5: Management of Fertility recommend that each 500 mg vial of the
and Pregnancy in ‚-thalassaemia), but drug is dissolved in at least 5 ml of water,
Desferrioxamine is not generally giving a 10% solution. Concentrations in
recommended unless the risk of cardiac excess of this may increase the risk of local
disease in the mother without chelation reactions at the site of infusion.
treatment is high.
SSiitte
e ooff iinnffuussiioonn
Care must be taken to avoid inserting
Practical issues with needles near important vessels, nerves or
organs. The abdomen is generally the best
subcutaneous place. However because of local reactions
such as erythema, swelling and induration, it
infusion is often necessary to ‘rotate’ the sites used
for injection (see Figure 5). Some patients
Because regular use of desferrioxamine is find that the skin over the deltoid or the
critical to a good outcome, every effort lateral aspect of the thigh provides useful
should be made with each individual to help additional or alternative sites.
him or her to find the most convenient way
to infuse the drug.

Figure 5: Rotation of infusion sites Figure 6: Insertion of needles for desferrioxamine


infusion

45
TTyyp
pee ooff nneeeeddllee Compliance requires a sustained and secure
The best needle to use will depend on the relationship between doctor, patient and
individual. Many patients are happy with parents, and regular discussion and support
butterfly needles of 25 gauge or smaller, are keys to maximising compliance. The
which are inserted at an angle of about 45 reasons for poor compliance are varied. In
degrees to the skin surface. The needle tip some cases, parents cannot sanction the
should move freely when the needle is daily “ordeal” of chelation therapy for their
waggled. Other patients prefer needles that child. In others, compliance may only
are inserted vertically through the skin and become a problem when a child reaches
are fixed with an adhesive tape attached to adolescence. Sometimes a previously good
the needle (see Figure 6). Patient preference complier may become less compliant when
is highly variable and clinicians should explore other life events or stresses become a
the best type of needle for each patient in burden (see Chapter 15: Psychosocial
order to maximise compliance. Support). Helping a patient to take control or
‘self-manage’ is often a useful approach of
TTyyp
pee ooff iinnffuusseerr long-term benefit (see TIF’s book on
There are many types of infusers now ‘Compliance to Iron Chelation Therapy with
available. Newer devices, including balloon Desferrioxamine’).

Moonniittoorriinngg ccoom
mpplliiaannccee
pumps, are smaller, lighter, and quieter than
their predecessors. For patients who find M
dissolving, mixing and drawing up There is no perfect way to measure
desferrioxamine a problem, pre-filled syringes compliance. One successful approach may be
or balloons may be useful. Some pumps are to give patients a calendar, in which each
designed to monitor compliance. infusion of desferrioxamine is noted down
during the treatment. Some pumps can log
LLo
occaall rreeaaccttiioonnss usage. Another approach has been to keep a
Persistent local reactions may be reduced by record of empty vials returned to the
varying the injection sites, lowering the provider of the desferrioxamine.

RReessccuuee tthheerraappyy wwiitthh ccoonnttiinnuuoouuss


strength of infusion or, in severe cases, by
adding 5-10 mg of hydrocortisone to the
infusion mixture. iinnffuussiioonnss
In high risk cases, continuous infusion of
SSu
uppppoorrttiinngg ccoom
mpplliiaannccee desferrioxamine is potentially more beneficial
It is clear that compliance with than periodic infusions because it reduces
the exposure to toxic free iron (NTBI), which
therapy determines prognosis. returns to pre-treatment levels within
However, desferrioxamine treatment is
troublesome and time-consuming, and can minutes of stopping a continuous
be painful. Practical approaches to intravenous infusion (Porter, 1996). The
maximising compliance by decreasing local route of administration is not critical,
reactions and providing the most convenient provided that as close to 24-hour exposure
pump system have been discussed above. to chelation is achieved. Intensification of
Especially important, however, is support treatment through continuous, 24-hour
from family and the health care team. intravenous administration of
desferrioxamine via an implanted intravenous

46
delivery system (e.g. Port-a-cath) (Davis, SSu
uggggeesstteedd ddoossiinngg
2000) or subcutaneously (Davis, 2004) has A dose of at least 50 mg/kg/day and not
been shown to normalise heart function, exceeding 60 mg/kg/day is recommended as
reverse heart failure, improve myocardial T2* a 24-hour infusion (Davis, 2000 and 2004).
(Anderson, 2002) and lead to long-term Higher doses have been used by some
survival, provided treatment is maintained. In clinicians however DFO is not licensed at
non-high risk cases, options such as these doses and the risk of retinopathy
encouraging the patient to improve increases. Addition of vitamin C is
compliance or an increase in dose should be recommended only when acute heart
explored before moving to 24-hour dysfunction has settled, which usually occurs
treatment. by three months of continuous treatment
(Anderson, 2004). As ferritin falls, the dose
Coonnssiiddeerraattiioonn ffoorr iinntteennssiivvee tthheerraappyy
C but preferably not the duration of treatment
Intensification should be considered in the can be reduced, in line with the therapeutic
following cases: index (see above).

ñ severe iron overload Maan


M naaggeem meenntt ooff iinn--ddwweelllliinngg
- persistently very high ferritin values*
- liver iron > 15 mg/g dry weight *
iinnttrraavveennoouuss lliinneess
Infection and thrombosis of the catheter
may occur. Careful aseptic procedures must
ñ significant cardiac disease^: be followed in order to prevent possible
- significant cardiac dysrhythmias infection by Staphylococcus epidermidis and
- evidence of failing left ventricular aureus, which when established are difficult
function to eradicate and often removal of the
- evidence of very severe heart iron infusion system becomes necessary. The risk
loading (T2*<6 ms) of thrombosis and infection is likely to be
greater in centres that do not have regular
ñ prior to pregnancy or bone marrow experience in the use of long-term in-
transplantation, when rapid reversal of dwelling lines. Use of prophylactic
iron loading may be desirable anticoagulation is advised as line-thrombosis
* If the only abnormalities are high ferritin or LIC, it would is relatively common in thalassaemia major
be usual to try to increase the dosing (for example, to 50- (Davis, 2000). As development of a
60 mg/kg) or the duration or the frequency of thrombosis can occur at the tip of the
subcutaneous infusions. catheter, it is advisable, if possible to avoid
placing the tip in the right atrium.
When cardiac disease is present,
24-hour intensive therapy is IInnttrraavveennoouuss ddeessffeerrrriiooxxaam
miinnee wwiitthh
necessary and simple bblloooodd ttrraannssffuussiioonn
increments in conventional 8- This has been used as a supplement to
12-hour dosing are not conventional therapy (e.g. 1 g over 4 hours
piggy-backed into the infusion line), but its
recommended. contribution to iron balance is very limited.
Special attention must be given to avoiding

47
accidental boluses due to desferrioxamine However, ten small, randomised controlled
collecting in the dead space of the infusion trials are now underway, involving a
line. Co-administration of desferrioxamine combined total of nearly 400 patients.
and blood can lead to errors in interpreting
side effects such as acute fever, rashes, EEffffe
eccttss oonn sseerruum
m ffeerrrriittiinn
anaphylaxis and hypotension during blood Four prospective randomised trials compare
transfusion. Desferrioxamine should never be the effects of deferiprone on serum ferritin
added directly into the blood unit. at baseline and at follow-up (Maggio, 2002;
Gomber, 2004; Pennell, 2005; Ha, 2006).
Deferiprone Pooled analysis shows a statistically significant
decrease in serum ferritin at six months in
(Ferriprox®, Kelfer®, favour of desferrioxamine (Gomber, 2004;
Ha, 2006), with no difference between the
L1) two drugs at 12 months (Maggio, 2002;
Pennell, 2006). There are numerous non-
randomised cohort studies demonstrating a
Deferiprone is an orally absorbed iron lowering of serum ferritin at doses of 75
chelator that began clinical trials in the UK in mg/kg/day administered in three doses. The
the 1980. It was first licensed for use in effect on serum ferritin at this dose appears
thalassaemia in India, followed by the greater at higher baseline ferritin values. In
European Union and other countries outside these studies significant decreases in serum
the US and Canada, in the late 1990s. ferritin are seen in patients with baseline
values above 2,500 Ìg/L (Al-Refaie et al.,
Phhaarrm
P maaccoollooggyy 1992; Agarwal, 1992; Oliveiri, 1995) but not
Three molecules of deferiprone are required with values below 2,500 Ìg/L (Olivieri,1995;
to bind one iron atom, and the efficiency of Hoffbrand,1998; Cohen, 2000).
iron binding decreases with falling
concentrations of iron or of chelator. The EEffffe
eccttss oonn lliivveerr iirroonn
drug is rapidly metabolised and inactivated in Four trials that measure change in liver iron
the liver by glucuronidation of one of its iron concentration (LIC) from baseline after a
binding sites (Kotoghiorghes, 1998). At period of treatment with deferiprone
currently used doses, about 6% of the drug compared with desferrioxamine are available
binds iron before it is excreted or (Olivieri, 1997; Maggio, 2002; Pennell, 2005;
metabolised (6% efficiency) (Aydinok, 2005). Ha, 2006). One study showed increases in LIC
Unlike desferrioxamine, iron excretion is at 33 months of 5 mg/g dry wt with
almost exclusively in the urine. deferiprone (n=18) and 1 mg/g dry wt with
desferrioxamine (n=18) (Olivieri, 1997). A
EEvviiddeennccee ooff eeffffeeccttiivveenneessss ooff second study showed an average decrease in
ddeeffeerriipprroonnee LIC at 30 months with both deferiprone
There are considerable accumulated (n=21) and desferrioxamine (n=15) (Maggio,
publications about the effects of 2002). A third study found decreases in LIC at
deferiprone. Most of these have not been one year of 0.93 mg/g dry wt with
randomised controlled trials, making deferiprone (n=27) and 1.54 mg/g dry wt
comparison with desferrioxamine difficult. with desferrioxamine (n=30) (Pennell, 2005).

48
Another study reported decreases in LIC at six was reported for either drug (Maggio, 2002).
months with both deferiprone (6.6 mg/g dry A recent study using a new technique
wt, n=6) and desferrioxamine (2.9mg/g dry multislice, multiecho T2* demonstrated
wt, n= 7) (Ha, 2006). In a non-randomised improved T2* values in the Deferiprone
prospective study, using Deferiprone, LIC group compared to the Desferrioxamine
increased from baseline by 28% at two years group (Pepe, 2006).
and by 68% at three years of treatment
(Fischer, 2003). In other studies where only EEffffeeccttss oonn ssuurrvviivvaall aanndd ccoom
mpplliiccaattiioonnss
single biopsies were performed after several
years of Deferiprone treatment, LIC has been
ooff ccaarrddiiaacc ddiisseeaassee
In six randomised prospective comparisons
found to be above 15 mg/g dry wt in with desferrioxamine, mortality was not
variable proportions of patients: 11% (Del reported as an outcome measure while in a
Vecchio et al, 2000), 18% (Tondhury, 1998) seventh, one death reported in the
and 58% (Hoffbrand et al, 1998). Deferiprone arm, but not in the

EEffffe
eccttss oonn hheeaarrtt ffuunnccttiioonn
Desferrioxamine arm was considered as due
to cardiac complications (Ha, 2006). In a
One prospective one-year study found that in retrospective cohort analysis of patients
patients with normal left ventricular ejection treated with deferiprone or desferrioxamine,
fraction, deferiprone given at high doses (92 no deaths were reported (n=157) in the
mg/kg) improved heart function (Pennell, Deferiprone arm in contrast to the
2006). In another randomised study over one desferrioxamine-treated patients (Borgna-
year, no difference in LVEF or other Pignatti, 2006), although some caution was
measures of LV function was seen with either expressed by the authors with regard to the
deferiprone at 75 mg/kg/day or interpretation of these results. In this analysis
desferrioxamine (Maggio, 2002). A the author noted that there were no cardiac
prospective study of the effects of events in 750 patient years of exposure to
deferiprone monotherapy on patients with Deferiprone in more than 150 patients.
abnormal LVEF or symptomatic heart disease
has not been reported. Coom
C mpplliiaannccee wwiitthh ddeeffeerriipprroonnee
EEffffe
eccttss oonn hheeaarrtt iirroonn
One study comparing compliance with
deferiprone and desferrioxamine found rates
The effect of deferiprone monotherapy on of 95% and 72% respectively (Olivieri, 1990),
heart iron has been reported in two while another found 94% and 93%
prospective studies. One study found respectively (Pennell, 2005).
significant improvement in T2* after one year
at 92 mg/kg of deferiprone daily. Patients Two important points to be taken into
with starting T2* values of between 8 and 20 consideration are (i) compliance with any
ms showed an average increase from 13 ms treatment tends to be higher in studies than
to 16.5 ms in the deferiprone group, and in routine use, and (ii) although compliance
13.3 to 14.4 ms in the desferrioxamine group with oral treatment is expected to be better,
(Pennell, 2006). In another randomised it cannot be taken for granted requiring, as
study, of deferiprone and desferrioxamine in the use of Desferrioxamine, constant
administered at standard doses over one supervision and patient support.
year, no change in heart iron estimated by T2

49
Unwanted effects reintroduced, and the use of GM
CSF should be considered in the
with deferiprone case of agranulocytosis; off-
label use of the drug should be
NNeeuuttrrooppeenniiaa,, aaggrraannuullooccyyttoossiiss aanndd avoided.
tthhrroom
mbbooccyyttooppeenniiaa
The most serious and potentially fatal adverse Gaassttrrooiinntteessttiinnaall ssyym
G mppttoom
mss
effect of deferiprone is agranulocytosis Nausea and change in appetite (loss or gain)
(absolute neutrophil count, or ANC*, occur in 3-24% of patients (Ceci 2002; Cohen
<500/mm3). The condition may occur with et al, 2000).
thrombocytopenia, but also isolated
thrombocytopenia has occasionally been EEffffe
eccttss oonn lliivveerr
reported. Onset of agranulocytosis is variable, Variable fluctuation in liver enzymes has been
from a few months to nine years. In a reported. About a quarter of patients show
prospective trial where weekly neutrophil ALT fluctuation of twice the normal upper
counts were undertaken and where limit (Cohen, 2000). One prospective
deferiprone was discontinued when the ANC randomised study showed no significant end-
was <1,500/mm3, agranulocytosis developed of-study changes in liver enzymes with
in 0.2/100 patient years and milder forms of deferiprone or desferrioxamine (Pennel,
neutropenia (ANC 500-1500/mm3) occurred 2006). An observational report about the
in about 2.8/100 patient years (Cohen, 2000 frequency of fibrosis after treatment for
and 2002). Recently, 46 cases of three or more years has led to conflicting
agranulocytosis, were reported, in Europe interpretations (Olivieri, 1998; Tondury, 2001;
with nine related deaths (Swedish Orphan, Hoffbrand, 1998; Wanlass, 2000). A relevant
safety alert, 2006). Five of these cases were prospective randomised study investigating
in patients who had been prescribed the the progression to fibrosis, using Deferiprone
drug for an unspecified ‘off label’ indication, for one year, showed no difference as
and several were not receiving weekly blood compared with Desferrioxamine, over the
count monitoring. Swedish Orphan has same period and no difference in baseline
subsequently issued the following and end-of-treatment liver function tests
recommendations on the use of deferiprone: (Maggio, 2002).

ANC* should be monitored Arrtthhrrooppaatthhyy


A
every week or more frequently The frequency of arthropathy varies greatly
between studies, from as low as 4.5% at one
if there are signs of infection; year (Cohen, 2000) to 15% after four years
concomitant treatment that (Cohen, 2004) in a predominantly European
could affect the white cell patient group, and as high as 33-40% in a
count should be avoided; if study of patients in India (Agarwal et al,
severe neutropenia or 1992; Choudhry et al, 2004). It is not yet
agranulocytosis develop, the clear whether these differences reflect
environmental or genetic differences, or
drug should be stopped and not differences in iron overload between
* ANC: absolute neutrophil count

50
populations at the start of treatment. As a result of the various
Symptoms range from mild non-progressive
arthropathy, typically in the knees,
unwanted effects, 20-30% of
controllable with non-steroidal anti- patients are unable to sustain
inflammatory drugs to (more rarely) severe long-term treatment with
erosive arthropathy that may progress even deferiprone (Hoffbrand, 1998).
after treatment is stopped. Cases involving
other joints, such as wrists, ankles and FFrreeqquueennccyy ooff aaddvveerrssee eevveennttss
elbows, and avascular necrosis of the hips, ccoom
mppaarreedd wwiitthh ddeessffeerrrriiooxxaam
miinnee
have also been described. Adverse effects have been reported in four
randomised studies comparing deferiprone
Treatment should be stopped with desferrioxamine. One trial has reported
where joint symptoms continue data that allows comparison of the
despite a reduction in probability of an adverse event with
deferiprone and desferrioxamine (Maggio,
deferiprone dose and are not 2002), establishing a statistically significant
controlled by non-steroidal anti- two-fold difference between deferiprone
inflammatory drugs. (34%) and desferrioxamine (15%), but no
difference between temporary or permanent
Neeuurroollooggiiccaall eeffffeeccttss
N treatment withdrawal.
Neurological complications are very rare and
have been typically associated with Prreeggnnaannccyy
P
unintentional overdosing. Rare neurological Deferiprone is teratogenic in animals and
effects have included cognitive effects, must never be given to patients attempting
nystagmus, walking disorders, ataxia, dystonia to conceive. Until more is known, potentially
and impaired psychomotor skills. These fertile sexually active women and men taking
effects appear to improve on cessation of deferiprone must use contraception.
treatment. Deferiprone should not be used in pregnant
women.
EEffffe
eccttss oonn eeyyee aanndd eeaarr
There have been isolated reports of loss of RReeccoom mm meennddeedd ttrreeaattm
meenntt rreeggiim
meennss
vision (central scotoma). One study reported
continued audiometric deterioration after
wwiitthh ddeeffeerriipprroonnee
According to the official European licensing
switching from desferrioxamine to
Agency (EMEA*), Deferiprone could be used
deferiprone (Chiodo, 1997). It is therefore
as a second line drug, for removing iron in
advisable to monitor for CNS, audiometric
patients who are unable to use
and visual function in patients on regimes
Desferrioxamine or in whom DFO therapy has
containing deferiprone.
proven ineffective.
Otthheerr eeffffeeccttss
O
SSttaan
nddaarrdd ddoossiinngg aanndd ffrreeqquueennccyy
Zinc deficiency during deferiprone therapy
The daily dose of deferiprone that has been
has also been observed in some patients,
evaluated most thoroughly is 75 mg/kg/day,
especially those with diabetes.
given in three doses. In the EU, the drug is
* EMEA: European Agency for the Evaluation of Medicinal
Products

51
licensed for doses up to 100mg/kg/day but
evidence for the safety of this dose is Combined
limited. The standard dose of 75mg/kg/day
administered in three separate doses is Desferrioxamine and
therefore recommended.
Deferiprone
Doossee eessccaallaattiioonn wwiitthh ddeeffeerriipprroonnee..
D
Doses of 100mg/kg/day have been given in A variety of regimens involving combinations
at least one prospective study (Pennell, of deferiprone and desferrioxamine have
2006), with no increase in side-effects been used by clinicians, either in the context
reported. High dose monotherapy with of a formal trial or on an ad hoc basis, usually
deferiprone has not yet been prospectively when monotherapy with desferrioxamine or
evaluated for safety and effectiveness for deferiprone has failed to control iron
patients with abnormal heart function, and in overload or its effects.
this context monotherapy is not
recommended for this group of patients. Phhaarrm
P maaccoollooggyy
In principle, chelators can be given at the
Aggee ooff ccoom
A mmmeenncceem
meenntt same time as each other (simultaneously) or
Although there have been some following one another (sequentially). There is
retrospective reports of its use in children, considerable variation in the way in which
the safety and efficacy of this drug has not sequential treatment can and has been
been formally evaluated in children under 10 administered. Some investigators have used
years of age. the term ‘alternating therapy’ to describe the
use of two drugs administered on alternate
Ussee ooff vviittaam
U miinn CC days, reserving the term ‘sequential therapy’
for when desferrioxamine is given at night
The effect of vitamin C on iron excretion
with deferiprone is not clear and is thus not and deferiprone during the day. In practice
recommended. regimes may involve a component of
‘sequential’ and ‘alternating’ therapy, such as
SSaaffe
ettyy m
moonniittoorriinngg when desferrioxamine is given three times a
week (alternate nights) and deferiprone
Weekly blood counts are necessary every day. Most regimes have tended to give
throughout treatment so that a falling white deferiprone daily, at standard doses,
cell count can be detected early and combined with varying frequency and dosing
treatment stopped before overwhelming of desferrioxamine.
sepsis develops. If severe neutropenia or
agranulocytosis develops, re-challenge is The pharmacology of combinations of
contra-indicated. Recent reports of eight chelators may be fundamentally different
deaths from agranulocytosis in patients depending on whether the drugs are present
treated in Europe, cited above, only in cells or plasma at the same time. By giving
emphasise the importance of scrupulous desferrioxamine at night and deferiprone by
monitoring of the blood count throughout day (sequentially), 24-hour exposure to iron
treatment. chelation can be achieved (similar to that
achieved with 24-hour desferrioxamine

52
infusion or once daily deferasirox. (For more 30 patients and three different treatments
on deferasirox (Exjade), see below). This has (Gomber et al, 2004), found that the
the theoretical advantage of 24-hour decrease in serum ferritin was greatest with
protection from labile (redox active) iron five nights of desferrioxamine, albeit not
(Cabantchik, 2005). If the drugs are given at significantly different from that achieved
the same time (simultaneously), they may with a combined treatment of
interact in a process that involves the desferrioxamine two nights a week plus
‘shuttling’ of iron, which may lead to deferiprone seven days a week. A third
additional chelation of iron from cells or randomised study, involving 60 patients
plasma and so improved iron removal. (Galanello, 2006), found no difference in the
However, there is also a possibility of level of decrease in serum ferritin in patients
chelation from metalloenzymes, leading to randomised to combined treatment (two
increased drug-related toxicity. days desferrioxamine at 33 mg/kg + seven
days deferiprone at 75 mg/kg) or to
In short, the simultaneous use of these drugs desferrioxamine five nights a week at 33
has not been tested formally in large enough mg/kg.
patient groups to allow firm, evidence-based
recommendations about efficacy and safety. Taken together, these studies suggest that
serum ferritin can be controlled with a
However, data from several prospective relatively small dose of desferrioxamine given
studies indicate that sequential (or twice a week, when combined with
alternating) use of these chelators can be deferiprone at standard doses (75
used to achieve control of iron overload and mg/kg/day). In a more recent randomised
improvement in heart iron measurements. study of 65 patients (Tanner, 2007), serum
ferritin was decreased more by combined
treatment (desferrioxamine five days a week
Evidence of efficacy plus deferiprone seven days a week) than
with standard desferrioxamine monotherapy
of combined (40 mg/kg five times a week).

treatments EEffffe
eccttss ooff sseeqquueennttiiaall uussee oonn lliivveerr iirroonn
One randomised study, assessing the effects
EEffffeeccttss ooff sseeqquueennttiiaall uussee oonn sseerruum
m on liver iron of combined treatment
ffeerrrriittiinn compared to desferrioxamine monotherapy
(n=60), found LIC of <7 mg/g dry wt at
Four randomised studies have compared
levels of serum ferritin in patients using baseline – a figure maintained, on average, in
combined treatments with those under other both arms of the study (Galanello, 2006).
treatment regimes. One study (Mourad et al, Another prospective randomised study,
2003) found the decrease in serum ferritin comparing the effect of desferrioxamine
achieved with five days of desferrioxamine monotherapy administered subcutaneously
monotherapy (n=11) to be similar to that five times a week with that of deferiprone
achieved with two nights of desferrioxamine administered daily at 75 mg/kg daily or
plus seven days of deferiprone at 75 mg/kg deferiprone at 75 mg/kg daily, plus twice-
(n=14). Another randomised study, involving weekly desferrioxamine, found that the

53
decrease in liver iron was highest in the were compared with patients on standard
desferrioxamine monotherapy group and desferrioxamine five times a week (Tanner,
lowest in the deferiprone monotherapy 2007). T2* improved in both groups but was
group, with sequential combination significantly greater (6 ms) with combined
treatment showing an intermediate effect treatment than with desferrioxamine
(Aydinok, 2005). A further randomised study, monotherapy (3 ms). In an observational
comparing deferiprone plus desferrioxamine study, the T2 of the heart improved with
five times a week with desferrioxamine combined therapy (Kattamis, 2006).
monotherapy five times a week (n=65),
found that an improvement in liver T2* (as a SSaaffe
ettyy ooff ccoom
mbbiinneedd ttrreeaattm
meenntt
surrogate measure of LIC) was greater in the Formal safety data on combined treatment
combination arm (Tanner, 2007). are limited. A meta-analysis of the incidence
of agranulocytosis with combined regimes
EEffffeeccttss ooff sseeqquueennttiiaall uussee oonn hheeaarrtt compared with deferiprone monotherapy
ffuunnccttiioonn suggests that the risk may be increased
In the above-mentioned randomised several-fold, although the number of
controlled study of 65 patients (Tanner, patients that qualify for evaluation is small
2007), with baseline LVEF >56% changes in (Macklin, IND submission to FDA, 2004). The
LVEF improved by approximately 2.5% in the increased incidence appeared to occur
combination arm and 0.5% in the mostly in those regimes where the drugs
desferrioxamine monotherapy arm. Two were administered simultaneously. In a
observational studies have also reported recently reported prospective study, one
changes in heart function under combined case of agranulocytosis and two of
treatment. In 79 patients treated with a neutropenia were seen at one year in the
variable desferrioxamine regimen plus combination arm, including 32 patients
deferiprone at 75 mg/kg seven days a week (Tanner, 2006), while no increase in
for a variable time, there was an arthropathy was observed in the same group
improvement in LVEF measured by of patients.
echocardiography (Origa, 2005). In an
observational study of 42 patients with CCoonncclluussiioonnss aanndd ppoossssiibbllee ttrreeaattm
meenntt
sequential use of treatment over three to rreeggiim
meennss
four years (deferiprone 75 mg/kg/day plus
desferrioxamine two to six days a week), the The above-mentioned studies
LV shortening fraction improved (Kattamis,
2006).
suggest that some combined
regimens can control iron
EEffffeeccttss ooff sseeqquueennttiiaall uussee oonn ccaarrddiiaacc overload in the liver and heart
iirroonn where monotherapy is not
In a randomised controlled study of 65 having the desired effects. In
patients with moderate heart iron loading general, if a patient is not doing
(T2* 8-20 ms), myocardial T2* changes with well with monotherapy,
combined deferiprone 75 mg/kg seven days
a week plus desferrioxamine five days a week
combined treatment offers an
additional approach. However,

54
most of the above studies used occurs predominantly by glucuronidation in
the liver. Due to the long plasma half-life
relatively low and intermittent (nine to 11 hours), once-daily administration
doses of desferrioxamine. It is provides 24-hour chelation from labile
recommended that, in the first plasma iron (Nisbet-Brown, 2003; Galanello,
instance, higher-risk patients are 2003; Dar, 2005). The efficiency of chelation
administered at least 50 is 28%, over a wide range of doses and levels
mg/kg/day of desferrioxamine of iron loading.
for as many hours a day as is EEvviiddeennccee ooff eeffffeeccttiivveenneessss ooff
practicable. For patients with ddeeffeerraassiirrooxx
very high levels of heart iron or Deferasirox has undergone preclinical and
cardiac dysfunction, 24-hour clinical evaluation that has included large-
treatment with desferrioxamine scale prospective randomised studies
should be considered. If this is involving over 1,000 patients, to assess
not practicable, some form of safety, efficacy and the dose response
effects of treatment. At this time, evidence
combined treatment may be a of effectiveness is confined to serum ferritin
useful option. and liver iron.

Doossee eeffffeecctt oonn sseerruum


D m ffeerrrriittiinn
Deferasirox (Exjade) A dose-dependent effect on serum ferritin
has been observed in several studies
Deferasirox was developed by Novartis as a (Cappellini, 2006; Piga, 2006). A prospective
once-daily, oral monotherapy for the randomised study comparing the effects of
treatment of transfusional iron overload. The deferasirox in 296 thalassaemia major
drug has been licensed as first-line patients with that of desferrioxamine in 290
monotherapy for thalassaemia major in over patients found that 20 mg/kg daily of
70 countries worldwide, including the US deferasirox stabilised serum ferritin close to
(2005) and the EU (2006). The average follow 2,000 Ìg/L. At 30 mg/kg, serum ferritin was
up in large-scale prospective trials at the time reduced, with an average fall of 1,249 Ìg/L
of writing is three years. over one year (Cappellini, 2006). Longer-term
analysis of ferritin trends shows that the
Phhaarrm
P maaccoollooggyy proportion of patients with ferritin values
<1,000 Ìg/L and less than 2,500Ìg/L is
This is an orally absorbed iron chelator, with
decreasing progressively with time (Porter,
two molecules binding each iron atom. The
2006).
tablet is dissolved in water (or apple juice)
using a non-metallic stirrer, and consumed as
a drink once daily, preferably before a meal.
DDoossee eeffffeecctt oonn lliivveerr iirroonn aanndd iirroonn
Metabolic iron balance studies show iron to bbaallaannccee
be excreted almost entirely in the faeces, In the same prospective study, iron balance
with less than 0.1% of the drug eliminated in was achieved at 20 mg/kg/day, with mean
urine (Nisbet-Brown, 2003). Metabolism LIC constant over one year (Cappellini, 2006).

55
Negative iron balance was achieved at 30 and estimated heart iron were not evaluated
mg/kg/day, while mean LIC fell by 8.9 mg/g formally as part of the drug registration
dry wt (equivalent to a decrease in body iron process, and formal prospective studies on
of 94 mg/kg body weight) over one year. both heart function and heart iron are now
Doses of 10 mg/kg/day are likely to lead to in progress. Retrospective analysis of effects
positive iron balance in most patients. These on myocardial T2* after one year and two
are average trends and a closer analysis years of treatment suggests that this
shows that the blood transfusion rate measure can be improved in a significant
influences the response to treatment proportion of patients with pre-existing
(Cohen, 2005). Thus for patients in the high abnormal T2* values (Porter, 2005). Patients
or low transfusion category (see Table 7), the with normal LVEF showed no change in this
average dose required to achieve iron measure over one year (Porter, 2005).
balance is accordingly adjusted up or down
from 20mg/kg/day (Cohen, 2005).

A more moderate reduction in LIC occurred Unwanted effects


in children under six years old, despite the
administration of an average dose of 21.9 with deferasirox
mg/kg in this subgroup. However, these
patients had the highest mean transfusional G a s t ro i n t e s t i n a l e ff e c t s
iron intake. Gastrointestinal disturbances – typically mild
and transient – occurred in 15% of patients
E f fe c t s o n h e a r t i r o n a n d h e a r t
E and included abdominal pain, nausea and
fu
f un c t i on vomiting, diarrhoea and constipation, lasting
The effects of deferasirox on heart function a median of less than eight days. These

Transfusion rate % of patients LIC change* LIC change*


so transfused at 20mg/kg at 30mg/kg

Low (<0.3 mg/kg/day) 24% -4 -.9.5


Intermediate (0.3-0.5 mg/kg/day) 59% -2 -9.0
High (>0.5 mg/kg/day) 17% +1.8 -4.0

*in mg/g dry wt

Table 7: Relation of transfusion rates with LIC.

56
symptoms rarely required dose adjustment or EEffffe
eccttss oonn tthhee lliivveerr
discontinuation. Overall a decrease in ALT* was seen, which
paralleled improvements in LIC (Daugnier,
SSkkiin
n rraasshheess 2005). Two patients out of 296 developed
These occurred in (11%) of patients and were elevated ALT values greater than twice the
typically pruritic, maculopapular and ULN while receiving deferasirox for one year,
generalised, but occasionally confined to which the investigator reported as related to
palms and soles of the feet. A rash typically the administration of the drug.
developed within two weeks of starting
treatment. A minority of patients required Otthheerr eeffffeeccttss
O
permanent discontinuation of therapy, and No agranulocytosis, arthropathy or growth
mild rashes often resolved without dose failure was associated with deferasirox
modification. administration. Comparing 296 patients who
received deferasirox in a one-year
IIn
nccrreeaassee iinn sseerruum
m ccrreeaattiinniinnee prospective randomised study with 290
An increase in serum creatinine ≥30% on at patients receiving desferrioxamine, deafness,
least two consecutive readings was observed neurosensory deafness or hypoacusis were
in 38% of patients receiving deferasirox, most reported as adverse events in eight patients
frequently at doses of 20 mg/kg and 30 on deferasirox and seven in desferrioxamine.
mg/kg (Cappellini, 2005). These increases Cataracts or lenticular opacities were
were sometimes transient and generally reported as adverse events in two patients
within the normal range, never exceeding on deferasirox and five on desferrioxamine
two times the upper limit of normal (ULN), (Cappellini, 2006).
and were more frequent in the population of
patients having the most dramatic decrease CCoonnvveenniieennccee aanndd iim
mppaacctt oonn qquuaalliittyy ooff
in LIC and serum ferritin. In the randomised lliiffee
study, a dose reduction of 33-50% was Studies comparing satisfaction and
planned if at least two consecutive increases convenience of DFS with DFO in thalassaemia
in serum creatinine were >33% above major show a significant and sustained
baseline. As the creatinine spontaneously preference for DFS (Cappellini et al, 2006).
normalised in a number of cases, dose Total withdrawals in deferasirox-treated
reductions were instituted in only 13%. In patients were 6% at one year compared with
about 25% of those cases, the creatinine 4% with desferrioxamine (Cappellini, 2006).
then returned to baseline, while in the rest it This compares with a dropout rate of 15% at
remained stable or fluctuated between one year with deferiprone (Cohen, 2000).
baseline and the maximum increase observed Based on thalassaemia patient reported
prior to dose reduction. With follow up of a preferences for DFS and DFO, published
median of three years at the time of writing, compliance data with DFO and the probability
no evidence of progressive renal dysfunction of complications from iron overload in
has been reported where the above doses relation to compliance with DFO, the cost
and modifications are used. Further work on effectiveness per quality-adjusted life year
the mechanism of creatinine increases is (QALY) gained is 4.1 per patient for DFO and
being undertaken. 8.1 per patient for deferasirox.

* ALT: Alanine L-Aminotransferase

57
The drug also appears to be palatable to
Recommended children at this young age. On the basis of
present knowledge, the criteria for starting
treatment regimens treatment (ferritin level, age, number of
transfusions) do not differ from those of
with deferasirox desferrioxamine.

Reeccoom
R mm
meennddeedd ddoossiinngg OOtthheerr iinnddiiccaattiioonnss aanndd
The drug is taken orally as a suspension in
water, once daily, preferably before a meal. A
ccoonnttrraaiinnddiiccaattiioonnss
Deferasirox is contraindicated in patients with
starting dose of 20 mg/kg is recommended
renal failure or significant renal dysfunction.
for thalassaemia major patients who have
For patients with evidence of significant
received 10-20 transfusion episodes and
heart dysfunction (e.g. LVEF below reference
currently receive standard transfusion at
range) there is very limited clinical experience
rates of 0.3-0.5 mg of iron/kg/day. In those
and treatment cannot be recommended at
patients in whom there is a higher rate of
this time for patients with heart failure or
iron intake from transfusion (>0.5
poor LV function. The combined use of
mg/kg/day) or in patients with pre-existing
deferasirox with other iron chelators has also
high levels of iron loading, where a decrease
not been formally assessed and therefore
in iron loading is clinically desirable, 30
cannot be recommended at this time. The
mg/kg/day is recommended. For patients
drug should not be used in pregnant women.
with a low rate of iron loading (<0.3
mg/kg/day), a dose of 10-15 mg/kg may be
sufficient to control iron loading. Experience of use in patients
with pre-existing renal disease
Aggee ooff ccoom
A mmmeenncceem
meenntt (baseline creatinine outside
Prospectively randomised studies of reference range) is insufficient
deferasirox in children as young as two years at this time to recommend its
of age have been carried out (Cappellini,
2006; Galanello, 2006).
use. As the median follow up in
A fall in LIC was seen across all large-scale studies is three years
age groups analysed, with no at this time, vigilance in
age-related adverse effects: in monitoring for possible long-
particular, no adverse effects on term effects is still advisable.
growth, sexual development or
bones were seen (Piga, 2005).

58
SSu
ummm
maarryy ooff IIrroonn OOvveerrllooaadd aanndd iittss ttrreeaattm
meenntt::
ñ 1.08 mg of iron in 1ml of pure red cells (HCT = 100%);
ñ Rate of iron loading: volume of RBC x 1.08 (annual transfusion requirements x
donor Hct = volume of RBC). On average 200mg iron/donor unit;
ñ Recommended transfusion 100-200 ml/kg/year is equivalent to 116-232 mg
iron/kg/year or 0.32-0.64 mg/kg/day;
ñ Serum ferritin broadly related to body iron. When high, the following should be
considered:
(i) iron overload;
(ii) inflammation;
(iii) hepatitis; and/or
(iv) liver damage.
When serum ferritin is low, the following should be considered:
(i) low body iron;
(ii) vitamin C deficiency.
In thalassaemia intermedia, ferritin underestimates the degree of iron overload.
Ferritin levels related to low risk are below 2,500 mg/l, preferably below 1,000
mg/l;
ñ Ranges of LIC reflecting levels of RISK:-
Very low risk = <1.8 mg/g dry weight
Low to moderate risk = 1.8 - 7 mg/g dry weight;
Moderately high to high risk = 7 - 15 mg/g dry weight;
Very high risk = > 15 mg/g dry weight;
Total body iron stores = 10.6 x LIC (mg/g dry weight);
LIC is measured by:
a) Liver biopsy – indicated if ferritin levels deviate from expected trends, if co-
existent hepatitis and if uncertain response to chelation;
b) SQUID – not universally available;
c) MRI – R2.
ñ Cardiac iron reflected by heart function tests and measured by MRI T2*;
ñ Urinary iron – used to monitor desferrioxamine or deferiprone dose effects.
Variability in daily excretion, and
ñ NTBI and LPI – not yet routinely used.

59
Deessffeerrrriiooxxaam
D miinnee::
ñ Initiate treatment after first 10-20 transfusions or ferritin level above 1,000 Ìg/l;
ñ If before 3 years of age monitoring of growth and bone development is
recommended;
ñ Therapeutic index = mean daily dose (mg/kg) (Mean daily dose = actual dose of each
infusion x doses/7 days) /ferritin (mg/l). Keep index < 0.025 at all times;
ñ Standard treatment: a) Slow subcutaneous infusion over 8-12 hours, b) 10%
desferrioxamine solution (5 ml water for each 500 mg vial), and c) infusion pump
(several types available);
ñ Standard dose: a) children 20-40 mg/kg (not exceeding 40 mg/kg, until growth has
ceased), and b) adults 50-60 mg/kg. Infuse 8-12 hours 6 nights minimum per week;
ñ Alternative route: subcutaneous bolus – two S.C. boluses/day to a total daily dose of 45
mg/kg;
ñ Vitamin C-dose limited to 2-3 mg/kg/day given orally at the time of infusion;
ñ Pregnancy – desferrioxamine can be used in pregnancy. It should be interrupted during
the first trimester and can be used in the second and third trimesters, in selected
cases;
ñ Intensive chelation with desferrioxamine – continuous 24-hourly infusions IV or SC.
Indications:
a) Persistently high serum ferritin;
b) LIC > 15 mg/g dry weight;
c) Significant heart disease, and;
d) Prior to pregnancy or bone marrow transplantation
Dose: 50 mg/kg/day (up to 60 mg/kg/day)
ñ In-dwelling catheters: danger of infection and thrombosis.

60
Deeffeerriip
D prro
onnee::
ñ Standard dose: 75 mg/kg/day in 3 divided dose (up to 100 mg/kg/day, but as yet
not enough information);
ñ Children above 10 years of age;
ñ Vitamin C concomitant treatment not recommended;
ñ Weekly blood counts (more frequently if signs of infection);
ñ Pregnancy – stop treatment. It is recommended that sexually active patients should
use contraception;

CO
C OM
MBBIIN
NAATTIIO
ONN TTH
HEER
RAAP
PYY.. In patients for whom monotherapy with desferrioxamine or
deferiprone is not controlling body levels of iron or myocardial iron, some combined
regimes offer an alternative that can reduce iron levels in both the liver and heart. No
recommendations as to which is the more effective combination can be made at
present.

CAAU
C UTTIIO
ONN:: agranulocytosis may be more frequent in combination therapy, especially in
simultaneous use.

Deeffeerraassiirro
D oxx::
ñ Recommended dose:
Starting dose 20 mg/kg/day. After 10-20 transfusions (iron intake (0.3-0.5
mg/kg/day);
If pre-existing iron overload (or iron intake > 0.5 mg/kg/day), the dose of 30
mg/kg/day is recommended. For patients with low rate of iron loading (<0.3
mg/kg/day), 10-15 mg/kg/day may be sufficient to control iron loading;
ñ Administration: Tablet dissolved in water (or apple juice), using a non-metallic stirrer.
Taken once a day before a meal.
ñ Continuous Monitoring
ñ Use in children > 2 (FDA) and >6 (EMEA) years of age
ñ Contraindicated in renal failure or significant renal dysfunction;
ñ Can not be given during pregnancy

61
62
KEY:

** Keep ≤ 40 mg/kg/day until growth is completed

* Consider desensitisation to desferrioxamine (see text)

^ Consider dose modification of deferasirox (see text)

£ NB ‘successful’ ferritin decreases greater than 1,000 - 2,000 Ìg/L/year are


unrealistic unless values are in excess of 4000 Ìg/L

£ NB ‘successful’ normalisation of cardiac T2* (to >20 ms) may take several years
especially when values are <10 ms

$ If a monotherapy is consistently unsuccessful, consider switching to another


monotherapy or

Consider switching to combination therapy or to 24h desferrioxamine (with or


without deferiprone) if the situation is serious

# There are many variations of combination therapy: some may be more appropriate
than others (see text)

63
Endocrine Complications
In Thalassaemia Major

EEnnddooccrriinnee aabbnnoorrm
maalliittiieess are among the contributing factors to stunted growth in
common complications of thalassaemia. patients with thalassaemia may include
Despite early establishment of appropriate chronic anaemia, transfusional iron overload,
chelation therapy, problems such as delayed hypersplenism and chelation toxicity
sexual maturation and impaired fertility may (DeSanctis, 1991). Other contributing factors
persist. Determining the prevalence of include hypothyroidism, hypogonadism,
endocrine complications is difficult because growth hormone deficiency/insufficiency,
of differences in the age of first exposure to zinc deficiency, chronic liver disease, under-
chelation therapy, and the continuing nutrition and psychosocial stress.
improvement in survival in well-chelated
patients. Diiaaggnnoossiiss aanndd iinnvveessttiiggaattiioonnss
D
The growth rates and endocrine Diagnosis requires careful clinical evaluation
complications of a sample of 3,817 to establish:
thalassaemia patients in 29 countries are
reported in Table 1 (De Sanctis, 2004). ñ ssllo
oww ggrroowwtthh rraatteess:: growth velocity
expressed in cm/year, below 1SD for age
and sex (based on growth velocity charts)
Growth ñ sshhoorrtt ssttaattu urre
e:: height below the 3rd
centile for sex and age (based on national
Growth retardation is common in growth charts) (see Appendix A)
thalassaemia major. Patterns of growth are ñ ssiig
gnnss o off ootthheerr p
piittu
uiittaarryy h
hoorrmmo on
nee
relatively normal until the age of 9-10 years ddeeffiicciieenncciieess (e.g., gonadotrophins)
when growth velocity begins to slow. Key ñ o otth
he err p poossssiib
blle
e ccaauusseess o off rre
ettaarrd
deed
dggrro
owwtth
h..

Nuum
N mbbeerr ooff ppaattiieennttss %%
Short stature males 664 31.1
females 513 30.5
Primary hypothyroidism males 60 2.8
females 64 3.8
Insulin-dependent diabetes mellitus males 75 3.5
females 46 2.7
Impaired glucose tolerance males 109 5.1
females 136 8
Hypoparathyroidism males 40 6.5
females 125 7.4
Hypogonadism males 353 43.3
females 243 37.7
Growth hormone males 53 7.1
deficiency/insufficiency females 148 8.8
Based on a sample of 3,817 thalassaemia patients in 29 countries

Table 1: Growth and endocrine complications in thalassaemia

64
IInnvveessttiiggaattiioonn ooff aa cchhiilldd wwiitthh patients with thalassaemia receiving irregular
tthhaallaassssaaeemmiiaa wwhhoo hhaass ssttuunntteedd ggrroowwtthh transfusion, as well as in those regularly using
iiss ggeenneerraallllyy ssiim
miillaarr tto
o tthhaatt ooff aa cchhiilldd desferrioxamine. In peri-pubertal patients,
wwiitthhoouutt tthhaallaassssaaeem miiaa.. hypogonadism should be carefully
EEvvaallu
uaattiioonn ooff sshhoorrtt ssttaattuurree//rreettaarrddeedd ggrroowwtthh.. investigated before starting growth hormone
treatment which may result in decreased
insulin sensitivity and abnormal glucose
The first step in the tolerance (de Sanctis, 1999).
investigation of short stature or
retarded growth is the regular Oral zinc sulphate supplementation should be
(six-monthly intervals) and given to patients with proven zinc deficiency.
accurate measurement of
standing and sitting height,
pubertal staging (Tanner 1962) Delayed puberty and
and bone age, including
examination of metaphyses. hypogonadism
Interpretation of absolute
height must take into account Delayed puberty and
the height of the parents. hypogonadism are the most
obvious clinical consequences of
Additional endocrine studies that may be iron overload.
helpful include thyroid function tests (FT4,
TSH), assessment of levels of sex hormones, Delayed puberty is defined as the complete
growth hormone (GF) secretion, zinc, lack of pubertal development in girls by the
calcium, alkaline phosphatase, urine analysis, age of 13, and in boys by the age of 14.
and investigation of glucose tolerance. Hypogonadism is defined in boys as the
Possibly useful tests include: Insulin Growth absence of testicular enlargement (less than
Factor-I (IGF 1) and Insulin Growth Factor 4 ml), and in girls as the absence of breast
Binding Protein-3 (IGFBP-3). The secretion of development by the age of 16 (de Sanctis,
GH is normal in the majority of patients with 1995).
thalassaemia. However, an investigation of
transglutaminase antibodies is also essential, Arrested puberty is a relatively common
to exclude celiac disease. complication in moderately or grossly iron
It is important to bear in mind overloaded patients with thalassaemia, and is
that desferrioxamine toxicity is characterised by a lack of pubertal
progression over a year or more. In such
an important cause of delayed cases, the testicular size remains 6-8 ml, and
growth (see Chapter on Iron breast size at B3 (see Table 2). In such cases
load and Iron Chelation) annual growth velocity is either markedly
reduced or completely absent (de Sanctis,
TTrre
eaattm
meenntt 1995).
Anaemia, folate deficiency and hypersplenism
are traditional causes of poor growth in

65
PPeenniillee ddeevveellooppm
meenntt BBrreeaasstt ddeevveellooppm
meenntt GGrroowwtthh ooff ppuubbiicc hhaaiirr
P1: Prepubertal B1: Prepubertal PH1: Prepubertal

P2: Early puberty B2: Early puberty PH2: Early puberty


(enlargement of scrotum and (breast bud stage) (sparse growth)
testes, 4-5 ml, little or no
enlargement of penis)

P3: Mid-puberty B3: Mid-puberty PH3: Mid-puberty


(enlargement of penis and (breast and areolar (hair extends over
further growth of testes, enlargement) the pubic junction)
8-12 ml, and scrotum)

P4: Advanced puberty B4: Advanced puberty PH4: Advanced puberty


(enlargement of penis in (areola and nipple project (hair corresponds to adult
length and breadth. Increased separately from the growth but less extensive)
pigmentation of scrotal skin contour of the breast)
and enlargement of testicles,
15-25 ml)

P5: Adult B5: Adult PH5: Adult


(Fully developed breast,
the areola no longer projects
separately from the breast
contour)

Table 2: Pubertal assessment according to Tanner

Most women with thalassaemia major present RH), stimulation test for Luteinizing
primary amenorrhoea, with secondary Hormone (LH) and Follicle Stimulating
amenorrhoea developing over time, Hormone (FSH)
particularly in poorly chelated patients. ñ Sex steroids (serum testosterone, serum
Ovarian function in such cases is generally 17-‚ Estradiol)
normal but gonadotrophin response to ñ Pelvic ultrasound to assess ovarian and
Gonadotrophin-Releasing-Hormone (Gn-RH) is uterine size
low compared to patients with normal ñ Transglutaminase antibodies
menstrual cycles. ñ In selected cases, Growth Hormone (GH)
stimulation test
IIn
nvveessttiiggaattiioonnss ñ In selected cases, Insulin Growth Factor-I
(IGF-I), Insulin Growth Factor Binding
ñ Routine biochemical analysis Protein-3 (IGFBP-3), plasma zinc
ñ Bone age (X-ray of wrist and hand)
ñ Thyroid function (TSH and FT4) TTrre
eaattm
meenntt
ñ Hypothalamic-pituitary-gonadal function: The treatment of delayed or
Gonadotrophin-Releasing-Hormone (Gn- arrested puberty and of

66
hypogonadotrophic It is important that the treatment of pubertal
disorders is treated on a patient-by-patient
hypogonadism depends on basis, taking account of the complexity of
factors such as age, severity of the issues involved and the many associated
iron overload, damage to the complications.
hypothalamo-pituitary-gonadal
axis, chronic liver disease, and
the presence of psychological Hypothyroidism
problems resulting from This may occur in severely anaemic and/or
hypogonadism. Collaboration iron overloaded patients, usually appearing in
between endocrinologists and the second decade of life. The condition is
other doctors is critical. uncommon in optimally treated patients (de
Sanctis, 1998; Sabato, 1983).
FFoorr ggiirrllss, therapy may begin with the oral
administration of ethinyl estradiol (2.5-5 Ìg SSiig
gnnss aanndd ssyym
mppttoom
mss
daily) for six months, followed by hormonal Pre-clinical hypothyroidism is asymptomatic.
reassessment. If spontaneous puberty does In mild and overt hypothyroidism, symptoms
not occur within six months after the end of such as growth retardation, decreased
treatment, oral oestrogen is re-introduced in activity, above normal weight, constipation,
gradually increasing dosages (ethinyl estradiol reduced school performance, cardiac failure
from 5-10 Ìg daily) for another 12 months. If and pericardial effusion may be encountered.
breakthrough uterine bleeding does not The incidence of hypothyroidism is slightly
occur, low oestrogen-progesterone hormone higher in females. Typically, the thyroid gland
replacement is the recommended treatment. is not palpable, thyroid antibodies are
negative and thyroid ultrasonography shows
FFoorr ddeellaayyeedd ppuubbeerrttyy iinn m
maalleess, low dosages of an irregular echo pattern with thickening of
intramuscular depot-testosterone esters the thyroid capsule.
(25mg) are given monthly for six months,
followed by hormonal re-assessment. In Annual investigation of thyroid function is
patients with hypogonadotrophic recommended, beginning at the age of 12
hypogonadism, treatment at a dose of 50 years. Free T4 and TSH are the key
mg per month can be continued until growth investigations, and their interpretation, along
rates wane. The fully virilising dose is 75-100 with TRH test and TSH response, are shown in
mg of depot-testosterone esters every 10 Table 3. Bone age may be helpful in
days, administered intramuscularly. The same evaluating hypothyroidism. The majority of
effects can be achieved with topical patients have primary thyroid dysfunction.
testosterone gel. Secondary hypothyroidism caused by iron-
mediated damage of the pituitary gland
For pubertal arrest, the treatment consists of occurs very rarely.
testosterone esters or topical testosterone
gel, administered as for the treatment of
delayed puberty and hypogonadotropic
hypogonadism.

67
Hyyppoo--tthhyyrrooiiddiissm
H m SSe
erruum
m FFTT44 SSe
erruum
m TTSSHH TTSSHH RReessppoonnssee TTrre
eaattm
meenntt
ttoo TTRRHH
Subclinical Normal Marginally Increased Observation
increased
(TSH: 4.5-8mIU/l)
Mild Marginally low Elevated Exaggerated L-thyroxin
Overt Low Elevated Exaggerated L-thyroxin

KEY: FT4-free thyroxine; TSH-thyroid stimulating hormone; TRH-thyrotrophin-releasing hormone (adapted


from Evered, 1973)

Table 3: Hypothyroidism and its treatment

TTrre
eaattm
meenntt The pathogenesis resembles type-2 diabetes,
Abnormal thyroid function may be reversible with differences in the age of onset (it may
at an early stage through intensive chelation, start early in the second decade of life) and
and good compliance. slow progression of disturbances in glucose
metabolism and insulin secretion.
Treatment depends upon the severity of
organ failure. Sub-clinical hypothyroidism The type of glycaemia may be classified as
requires regular medical follow-up and diabetic, borderline or normal.
intensive iron chelation therapy.
ñ Diabetic type: Fasting Plasma Glucose
In patients with mild or overt (FPG) ≥7.0 mmol/l (126 mg/dl) and/or
hypothyroidism, L-thyroxine is given. plasma glucose 2 hours after 75 g
glucose load (2hPG) is ≥11.1mmol/l (200
mg/dl). A casual Plasma Glucose (PG)
≥11.1 mmol/l (200 mg/dl) also indicates
Impaired diabetic type. The persistence of “diabetic
type” indicates that a subject has
carbohydrate diabetes.
ñ Normal type: FPG <6.1 mmol/l (110
metabolism mg/dl) and 2hPG <7.8 mmol/l (140
mg/dl).
Impaired glucose tolerance and ñ Borderline type: includes those who are
neither diabetic nor normal types,
diabetes mellitus may be the according to cut-off values for venous PG
consequence of ‚-cell measurements.
destruction secondary to iron
overload, chronic liver disease, Diabetes in thalassaemia is rarely complicated
viral infection and/or genetic by ketoacidosis.
factors.

68
IIn
nvveessttiiggaattiioonnss after the age of 16 (de Sanctis, 1995). The
Oral Glucose Tolerance Test (OGTT) should be majority of patients show a mild form of the
performed annually from the age of puberty. disease accompanied by paraesthesia. More
For children, a dose of 1.75 g/kg (to a severe cases may demonstrate tetany,
maximum of 75 g) is used for OGTT. seizures or cardiac failure.

TTrre
eaattm
meenntt Investigations should begin from the age of
ñ Impaired glucose tolerance may be 16 and should include serum calcium, serum
improved by a strict diabetic diet, weight phosphate and phosphate balance. In cases
reduction, where applicable, and possibly with low serum calcium and high phosphate
intensive iron chelation therapy levels, parathyroid hormone should also be
ñ In symptomatic patients, insulin evaluated. Parathormone may be normal or
treatment is normally required but low, with low readings for 1,25
metabolic control may be difficult to dihydroxycholecalciferol (vitamin D).
achieve
ñ Where hyperinsulinism is insufficiently Bone radiology shows osteoporosis and
managed by diet alone, acarbose may be malformations.
a useful first-line therapy for glycaemic
control TTrre
eaattm
meenntt
ñ The role of oral hypoglycaemic agents ñ Oral administration of vitamin D or one of
remains to be fully determined its analogues. Some patients require high
doses of vitamin D to normalise their
M
Mo onniittoorriinngg ddiiaabbeetteess aanndd iittss serum calcium levels. This should be
ccoommpplliiccaattiioonnss carefully monitored, as hypercalcaemia is
ñ Blood glucose (daily or on alternate days) a common complication of this
ñ Ketones – check if blood sugar is above treatment.
250 mg/dl ñ Calcitriol, 0.25-1.0 Ìg, twice daily, is
ñ Fructosamine estimation is more helpful usually sufficient to normalise plasma
than glycosylated haemoglobin levels calcium and phosphate levels. Weekly
ñ Urinary glucose is influenced by increased blood tests are required at the start of
renal glucose threshold treatment, followed by quarterly plasma
ñ Renal function (serum creatinine) and daily urinary calcium and phosphate
ñ Serum lipids (cholesterol: HDL, LDL, measurements.
triglycerides) ñ In patients with persistently high serum
ñ Urinary protein phosphate levels, a phosphate binder
ñ Evaluation of retinopathy (other than aluminium) may be
considered.
ñ Tetany and cardiac failure due to severe
hypocalcaemia require intravenous
Hypoparathyroidism administration of calcium, under careful
cardiac monitoring, followed by oral
Hypocalcaemia, due to hypoparathyroidism, vitamin D.
is a recognised late complication of iron
overload and/or anaemia and usually begins

69
Management of Fertility and
Pregnancy in ß-thalassemia

Advances in the primary care of ‚- gonadal axis (Chatterjee and Katz, 2000;
thalassaemia major (HbTh) by optimal blood Skordis, Christou et al, 1998). Also, the
transfusion and chelation therapy have management during pregnancy are different
improved patient survival into adulthood. At in that TI patients have an increased
the same time, patients’ quality of life has thrombotic risk and need transfusion during
also increased significantly, and the pregnancy (Nassar, Usta et al, 2006), whereas
expectation of having a family—an important TM’s, in addition to complications specific to
dimension of quality of life—is consequently iron overload, also face the risk of thrombo-
an important aspiration for many. embolism, particularly those with
splenectomy and autoimmune antibodies.
Although spontaneous fertility can occur in
well-chelated and -transfused patients with
spontaneous puberty, the majority are Management of
infertile due to hypogonadotrophic
hypogonadism (HH) consequent to fertility
transfusional haemosiderosis (Chatterjee and
Katz, 2000) and need AAssisted R
Reproductive Although 80-90% of patients have HH,
TTechniques (AAR
RTT). gonadal function is usually intact in the
majority of patients, indicating that fertility is
Planned pregnancy is essential usually salvageable, i.e. ovulation in females
both in spontaneous and ART and spermatogenesis in males can be
induced by exogenous gonadotrophin
conceptions, as HbTh therapy, ‘bypassing’ the H-P axis. However,
pregnancies are high risk for the other endocrine disorders, namely diabetes
mother and the baby. However, and hypothyroidism, may also influence the
these risks can be minimised outcome of fertility treatment and need to
through pre-pregnancy be corrected by standard care. Successful
spontaneous pregnancies, as well those
counselling with the resulting from the induction of
haematologist, the reproductive gametogenesis, have been documented in
medicine specialist, the HbTh females and males (Aessopos et al,
cardiologist and the 1999).
obstetrician, in conjunction with
the specialist nurse. Management of infertility requires a
thorough work-up, including pre-pregnancy
The management of patients of thalassaemia counselling of the couple (see below).
intermedia (TI) is similar to that of Fertility assessment of patients with
thalassaemia major (TM), with minor thalassaemia should also include evaluation
modifications. Older patients with of the partner according to standard criteria
thalassaemia major usually have (see http://www.rcog.org.uk). The fertility
hypogonadotrophic hypogonadism and are options are dependent on two factors (a)
unlikely to conceive spontaneously, whereas partners’ carrier status and (b) site of
patients with thalassaemia intermedia are damage to the H-P-G axis.
potentially fertile with intact pituitary-

70
If both partners are homozygous for ‚- H-P damage, when gonadotrophins are
thalassaemia, use of donor gametes, pulsatile. But majority of patients with HH are
preferably donor sperm is the ideal option, as apulsatile with functional gonads, and are
sperm can be more easily available from therefore likely to benefit from HMG/HCG
sperm banks, whereas the use of donor eggs therapy with 80% success rate. Patients with
is technically more complicated with an endometrial damage respond better to IVF
unpredictable success rate (Deech, 1998 programmes.
review). If the partner is heterozygous, then Induction of ovulation should only be
PPre-implantation GGenetic D PGGD
Diagnosis (P D) is undertaken by a specialist reproductive team,
another option, where diagnosis can be according to Human Fertilisation and
made prior to conception. This method may Embryology Authority (HFEA) guidelines
be more acceptable to certain communities (Deech, 1998 review). Patients should be
with religious beliefs against termination of counselled regarding risk of hyper-
affected pregnancy. Lastly, in patients with stimulation syndrome, multiple pregnancy,
severe organ damage or where both partners ectopic pregnancy and miscarriage. The risk
have HbTh, another option may be adoption, of hyper-stimulation and multiple births can
where there is good family support. be minimised by vigilant monitoring of the
induced cycle, followed up through, vaginal
ultrasound scans. For such procedures, it is
Methods for important to obtain the consent both and
imperative of the patients and involved
induction of clinicians and carefully documented notes
should be kept throughout. The regime to be
ovulation followed will be dependent on the team’s
local protocol (See Figure 1 for an
Induction of ovulation with pulsatile GnRH established protocol).
infusion is only possible at the early stage of
FIGURE1

71
Key points in induction of ovulation: patients. The induction process must be
ñ Careful monitoring of the cycle by serial undertaken according to HFEA guidelines,
vaginal ultrasound scans with an emphasis on consent and counselling
ñ DFO should be continued until HCG is (Deech, 1998 review) (See Figure 2 for an
injected/biochemical pregnancy is established protocol).
confirmed
ñ Luteal support with progesterone may be However, the recent advent of
required micromanipulation techniques such as intra-
ñ After a maximum of six cycles, reassess cytoplasmic sperm injection (ICSI) has
and refer for IVF improved conception rates, even in oligo-
asthenospermic patients. Therefore, sperm
should be cryopreserved in all subjects unless
Induction of azoospermic, to better preserved fertility and
so the chance of conception. However, our
spermatogenesis recent literature on sperm DNA damage in
HbTH (Perera, Pizzey et al, 2002) males raises
The induction of spermatogenesis in male anxiety about mutagenic risks in these
patients with thalassaemia is more difficult individuals, especially after ICSI, where natural
that the induction of ovulation in their protective barrier against gamete selection
female counterparts, with a success rate of during fertilisation is lost.
10-15% in moderate to severely iron loaded

FIGURE 2

IIN
NDDU
UCCTTIIO
ONNO
OFF SSP
PEER
RMMAATTO
OGGEEN
NEESSIISS

ñ Baseline testosterone and semen analysis


ñ HCG 2000 units twice-weekly for 6 months
ñ Monitor testosterone level
ñ Repeat semen analysis-no sperm
ñ Continue HCG with combined HMG 75 units three times weekly
for additional 6 months
ñ If semen analysis is satisfactory SSA
AV
VEE
ñ If azoospermia persists, stop treatment

72
before encouraging women with
Pre-pregnancy thalassaemia major to embark on pregnancy:
cardiac impairment, liver dysfunction and the
counselling vertical transmission of viruses.

Before embarking on fertility treatment, it is 1. The most important is cardiac function


important that patients and their partners because cardiac complications remain the
attend pre-pregnancy counselling, which has leading cause of death in both transfused
a three-fold purpose (a) evaluation of and untransfused patients. The cardiac
eligibility, (b) physicians to review load is increased during pregnancy by at
medications involved and (c) physician/s, least 25-30% due to increased heart rate
patient and partner to discuss the risks and stroke volume. This, along with iron
associated with induced fertility and load, has a real potential for premature
pregnancy. death from cardiac failure. Therefore it is
prudent that all patients with TM should
have cardiac assessment by ECHO (Left
Evaluation of ventricular ejection fraction >65%;
fractional shortening >30%), by ECG, both
eligibility ((FFiigguurree 33)) at rest and with exercise, and by 24 hr
tapes to check for rhythm disorders. If LV
Each patient should be assessed regarding dysfunction can be demonstrated in
suitability to embark on pregnancy with patients under stressful conditions or if
optimum outcome both for the mother and significant arrhythmias have occurred,
the fetus. There are at least 3 important then women should be strongly advised
factors that must be seriously considered against planning pregnancies (Hui et al,

Figure 3
EEV
VAALLU
UAATTIIO
ONNO
OFF EELLIIG
GIIB
BIILLIITTYY FFO
ORRP
PRREEG
GNNA
ANNC
CYY

ñ Heart: ECG, Echo, MRI


ñ Liver: LFT, ultrasound, biopsy
ñ Endocrine: diabetes, thyroid, parathyroid and
ñ Risk of thrombo-embolism: thrombophilia screen
ñ Viral infections: HBV, HCV, HIV, rubella
ñ Bone health: Vitamin D, calcium, DEXA, x-ray
ñ Iron overload: ferritin, liver and heart Fe
ñ Ascertain hemoglobinopathy status of partner
ñ Optimise lifestyle issues (smoking, etc).

73
2002). Most of the non-invasive cardiac Diagnosis and Management of
investigations are relatively insensitive for Osteoporosis in ‚-thalassaemia). Patients
detecting early cardiac loading. Modified should also be screened for diabetes,
MRI has recently been developed using thyroid function, and acquired red cell
gradient T2* measurements to quantify antibody. Both partners should be
iron levels, and can accurately relate screened for haemoglobinopathy.
these to LV dimensions assessed using
the same technique (Anderson et al,
2001). If the facility exists, cardiac MRI Review of
should be performed and the aim should
be to have T2* closer to 20 ms. medications ( F i g ure 4 )

2. Liver function should be evaluated by This is a good opportunity to review


biochemical test while iron overload medications and to give advice to patients
status by liver biopsy and MRI. Liver regarding diet, smoking and alcohol, and to
biopsy can also provide information on commence supplements of folic acid, calcium
fibrosis and cirrhosis. and vitamin D. Patients on oral chelators
(deferasirox or deferiprone) are
3. All patients should be screen for HIV, recommended to switch to desferrioxamine
Hepatitis B, Hepatitis C and rubella. The prior to induction of
opportunity should not be missed to ovulation/spermatogenesis (Singer and
ensure rubella immunity prior to Vichinsky, 1999). Hormone replacement
pregnancy. If the patient is HIV positive therapy should also be stopped at least 4-6
and wishes to have a family, she should weeks prior to induction of gametogenesis.
be advised of the usual recommendations Bisphosphonate is contraindicated during
for care which include appropriate pregnancy and breast-feeding, as both are
antiviral agents, delivery by CS and the states of considerable negative calcium
avoidance of breast feeding to reduce balance. It is therefore prudent to ensure
the risk of vertical transmission to <5% adequate calcium and vitamin D intake
(RCOG clinical Green Top Guidelines, before and throughout pregnancy. Other
2004). As regards Hepatitis C-positive medications that should be discontinued at
cases, these women should be given a least six months prior to fertility treatment
course of antiviral agents to attain include interferon, ribovarin and hydroxy
Hepatitis C RNA negative status. urea. Hypothyroid patients receiving thyroid
replacement therapy should receive
4. Before embarking on pregnancy, it is also increased doses, to ensure they are
important to establish bone heath by X- euthyroid. Hyperthyroidism is rare in patients
ray of spine and DEXA scan of hip and with thalassaemia. However, if a patient is
spines (BMD score) and correction of receiving an anti-thyroid drug such as
osteoporosis/osteopenia by institution of carbimazole, this should be replaced by
appropriate therapy (see Chapter 6: propyl thiouracil.

74
Figure 4

REEV
R VIIEEW
WOOFF M
MEED
DIIC
CAATTIIO
ONNSS P
PRRIIO
ORR TTO
OPPR
REEG
GNNAAN
NCCYY

ñ Stop HRT
ñ Stop interferon, ribovarin, hydroxy urea
ñ Stop bisphosphonates six months prior to fertility treatment
ñ Switch from warfarin to heparin
ñ Switch from oral hypoglycaemic to insulin
ñ Switch from oral iron chelation to DFO
ñ Review thyroid medication
ñ Give calcium and vitamin D supplements
ñ Start folic acid supplement to prevent neural tube defect

overloaded and that have adequate cardiac


Risks associated with function prior to pregnancy. Serum ferritin is
likely to alter by 10%, despite increase in
pregnancy ((FFiigguurree 55)) frequency of blood transfusion (Aessopos,
Karabatsos et al, 1999; Tuck, Jensen et al,
All patients should be made aware that 1998; Daskalakis, Papageorgiou et al, 1998;
pregnancy per se does not alter the natural Butwick, Findley and Wonke, 2005). The aim
history of thalassaemia. If pregnancy is during pregnancy is to maintain pre-
managed in a multidisciplinary setting, the transfusion haemoglobin concentration
foetal outcome is usually favourable with a above 10g/dL (Aessopos et al, 1999).
slight increase in incidence of growth
restriction (Aessopos, Karabatsos et al, 1999;
Ansari, Kivan and Tabaroki, 2006; Tuck,
Jensen et al, 1998). It has been shown that
Management of
the risks of pregnancy-specific complications
such as ante-partum haemorrhage and pre-
pregnancy ((FFiigguurree 66))
eclampsia in thalassaemia are similar to the Once pregnancy is confirmed, the patient
background population. It has also been should be managed in a multidisciplinary
shown that DFO is not required during team consisting of obstetrician, midwife,
pregnancy in patients that are not iron physician, haematologist and anaesthetist.

75
Figure 5

R i s ks a s s o c i a t e d w i t h p r e g n a n c y

ñ Pregnancy does not alter the natural history of the disease


ñ Requires intense/vigilant monitoring
ñ Cardiac complications
ñ Risk of pregnancy-specific complications same as background population
ñ Risk of miscarriage same as background population
ñ Risk of foetal malformation: no increase
ñ Risk of foetal growth restriction: two-fold increase
ñ Preterm labour risk: two-fold increase
ñ Risk of transmission to the fetus/baby of Hepatitis B/C, HIV
ñ Risk of iso-immunisation
ñ Risk of pre-maturity and growth restriction is increased in multiple births

The patient should be made aware that scans from 24-26 weeks onwards must be
although pregnancy is high risk, the outcome undertaken to monitor foetal growth. In
is usually favourable (Aessopos, Karabatsos et selected cases, particularly those with
al, 1999). thalassaemia intermedia, thromboprophylaxis
by low molecular weight heparin is required
The main risk to the mother is from mid-trimester (Nassar, Usta et al, 2006;
cardiac complications, which Eldor and Rachmilewitz, 2002). Although
there is a predisposition to venous
can be minimised by ensuring thrombosis in post-splenectomy patients, no
optimal cardiac function before reports of thrombotic episodes have been
embarking on pregnancy. reported in the literature (Tuck, Jensen et al,
1998; Daskalakis, Papageorgiou et al, 1998).
The key points include evaluation of cardiac Folate demand in pregnancy is normally
function by ECHO, and of liver and thyroid increased and this may be relevant in
functions, in each trimester. All patients patients with thalassaemia due to bone
should be screened for gestational diabetes overactivity. Regular folic acid
at 16 weeks and, if normal, this should be supplementation is recommended in mothers
repeated again at 28 weeks. Serial ultrasound with thalassaemia major to prevent

76
superimposed megaloblastic anaemia, Patients with osteoporosis usually have
although this has only been demonstrated vertebral bodies with reduced height and the
individuals with ß-thalassaemia minor segmental position of the conus may be
(carriers) (Leung, Lao and Chang, 1989). If lower than predicted (Borgna-Pignatti, 2006).
cardiac function deteriorates during It is therefore important to correct
pregnancy, DFO may be used, with caution, osteoporosis prenatally by hormone
as evidence regarding teratogenicity of DFO replacement (and premidronate therapy),
is equivocal (Singer and Vichinsky, 1999). As where required, to increase bone density so
regards the newer oral chelating agents, data that spinal anaesthesia at CS becomes
on fetotoxicity are lacking. However, the feasible.
manufacturer’s product information for DFO
includes risk of skeletal anomalies in animal After delivery, DFO can be recommenced but
pregnancies. Although there are currently no not oral chelating agents. Breastfeeding
reports regarding human foetal anomaly should be encouraged in all cases except in
from DFO, patients should be informed about those who are HIV and/or hepatitis C RNA-
this prior to its use during pregnancy. positive and/or HBsAg positive because of
the risk of transmission via breast milk.
As regards the management of labour, if
pregnancy is non-complicated, one could All patients should be counselled regarding
await the spontaneous onset of labour. But, contraception. Intrauterine devices should be
similar to reported data, it is the authors’ avoided because of risk of infection. Taking
experience that 80% of women with oestrogen-containing birth control pill is also
thalassaemia will require caesarean section not advisable because of the risk of
(CS) because of higher frequency of thrombo-embolism (Orr, 1967). In most
cephalopelvic disproportion, largely due to cases, progesterone-only pill or barrier
short stature and skeletal deformity in this methods are usually appropriate. Male
cohort, combined with normal foetal growth. patients with hypogonadotrophic
It is desirable to use epidural anaesthesia for hypogonadism are not fertile spontaneously
CS wherever feasible, to avoid the risk of and therefore contraception is not required.
difficult intubation associated with general Calcium and vitamin D supplements should
anaesthesias due to severe maxillo-facial be continued during breast-feeding, however
deformity in TM patients (Orr, 1967). bisphosphonate therapy for osteoporosis
Although most skeletal deformities are largely should only be resumed after cessation of
prevented by regular transfusion, spinal breastfeeding.
abnormalities associated with TM are relevant
to regional blockade. Osteoporosis and
scoliosis are common in TM, despite
transfusion therapy (Borgna-Pignatti, 2006).

77
Figure 6

K e y p o i n t s f or p r e g n a n c y c a r e

ñ Check cardiac, liver and thyroid function once each trimester


ñ Screen for gestational diabetes
ñ Increase frequency of blood transfusion to maintain pre-transfusion Hb
above 10 g/dL
ñ Serial ultrasound scans to monitor fetal growth
ñ Higher incidence of caesarean section
ñ Encourage breastfeeding unless HIV positive and/or ∏CV RNA and/or
HBsAg positive
ñ Resume DFO after delivery
ñ Discuss contraception, where appropriate
ñ POP, barrier method
ñ Avoid intrauterine device and oestrogen-containing preparations
ñ Resume bisphosphonate after breastfeeding has ceased

78
Diagnosis and
Management of
Osteoporosis in ‚-thalasaemia

Osstte
O eoop
poorro
ossiiss is a skeletal disease et al, 2004; Voskaridou et al, 2003; Lasco et
characterised by low bone mass and micro al, 2001). The diminished osteoblast function
architectural deterioration with a resulting with reduced osteocalcin (Morabito et al,
increase in bone fragility and hence 2004) is accompanied by a comparable or
susceptibility to fracture (Sambrook et al, even greater increase in osteoclast activity
2006). With increased life expectancy, through RANK/RANKL/osteoprotegerin
osteopenia-osteoporosis syndrome (OOS) is a pathway as the final, dominant mediator
major cause of bone pain of hip and spine (Voskaridou et al, 2003).
and fragility fractures especially of the
lumbar spine which may be found in 70-80%
adult patients with ‚-thalassaemia world- Diagnosis and
wide, accounting for significant bone
morbidity (Chatterjee et al, 2001). investigations
((FFiig
guurree 11 aan
ndd FFiig
guurree 22 ))
Aetiology and
The commonest presentation is bone pain
pathogenesis and backache with or without past history of
fractures. Patients may also be asymptomatic
Several studies have shown reduced bone in 20% cases.
mass in osteoporotic patients with
thalassaemia (Chatterjee et al, 2000; Borgna- ((A
A)) D
DEEXXA
A SSccaan
n
Pignatti 2006; Chan et al, 2002; Morabito et The diagnosis is best confirmed by bone
al, 2004; Voskaridou et al, 2003) but the mineral density (DEXA) according to WHO
underlying pathogenesis is still speculative. criteria (Figure 1). Although bone mineral
The causes of OOS in thalassaemia syndromes density remains the best available non-
are multifactorial (Chatterjee et al, 2000), invasive assessment of bone strength in
and include marrow expansion secondary to routine clinical practice, many other skeletal
ineffective erythropoiesis (Borgna-Pignatti, characteristics also contribute to bone
2006), anaemia , transfusional strength (Mahachoklertwattana 2006). These
haemosiderosis (Borgna-Pignatti 2006) , include bone macro architecture (shape and
delayed puberty (Chatterjee et al, 2000), use geometry), bone micro architecture (both
of deferioxamine (Voskaridou et al, 2003) or trabecular and cortical), matrix and mineral
oral chelation agents for iron overload (Chan composition, as well as the degree of
et al, 2002), multiple endocrinopathies such mineralisation, micro damage accumulation,
as hypogonadothrophic hypogonadism or and the rate of bone turnover, which can
primary hypogonadism (Chatterjee et al, affect the structural and material properties
2000), low IGF1 (Lasco et al, 2002), low of bone which are complicated and difficult
vitamin D levels due to aberrant vitamin D- to assess in routine clinical practice
PTH axis (Borgna-Pignatti, 2006). Genetic (Sambrook et al, 2006).
factors, for instance, polymorphism of the
VDR gene and COL 1 gene seem to play an
important role in the development of low
bone mass (Borgna-Pignatti, 2006; Morabito

79
Figure1

Woorrlldd HHeeaalltthh OOrrggaanniissaattiioonn ((W


W WHHOO)) ccrriitteerriiaa ffoorr ddiiaaggnnoossiiss ooff OOOOSS
Osstteeooppoorroossiiss
O
BMD > 2.5 SD below the young normal mean (T score) or
Standard deviations in relation to patient’s age (Z score)

Osstteeooppeenniiaa
O
BMD >1.5-2.5 SD below the young normal mean (T score)

Figure 2

LLiisstt o
off iinnvveessttiiggaattiioonnss
ñ Bone profile-serum Ca, PO4, 25(0H) vitamin D, PTH 24h urinary calcium.
ñ Endocrine profile FSH, LH, E2/T, TFT
ñ Liver function test
ñ Spinal X-ray
ñ DEXA-Spine-hip, radius, ulna-annually
ñ Markers of iron overload

((B
B)) BBiioocchheem
miiccaall patients who may have micro fractures.
All patients must have endocrine and bone
profile including 25 (OH) vitamin D3, PTH, ((D
D))M
MRRII
calcium, phosphate, liver function tests, MRI of spine, if available, must be undertaken
(alkaline phosphate, ALT, bilirubin, albumin) to determine extramedullary haematopoiesis,
FSH, LH, testosterone and oestradiol assays specially in TI patients and also to check for
(Chatterjee et al, 2001; Chatterjee et al, degenerative changes, skeletal dysplasia and
2000). disc prolapse.

((C
C)) RRaaddiioollooggyy ((EE)) AAsssseessssmmeenntt ooff iirroonn llooaadd aanndd
AP and lateral X-ray of the spine is important cchheellaattiioonn tthheerraappyy (see Chapter 3: Iron
to rule out fractures even in asymptomatic Overload).

80
((2
2)) CCaallcciim
miim
meettiiccss
MANAGEMENT Vitamin D deficiency must be corrected
(oral dose of 1000-1500 IU/day) and
Principles of management of OOS are the calcium supplementation (500 mg-1G
same as other patients with osteoporosis due orally/day) (Sambrook et al, 2006).
to other conditions (Sambrook et al, 2006).
The aim is to improve BMD score and ((3
3)) AAnnttii--rreessoorrppttiioonn aaggeennttss
prevent/reduce future risk or fracture Bisphosphonates represent the biggest
with/without offering pain relief in advance in the treatment of osteoporosis
thalassaemia patients. General guidelines in the past decade in non-thalassaemic
include assessment of other drugs, lifestyle patients (Sambrook et al, 2006), with
issues, exercise and diet. results of clinical trials showing reductions
((A
A)) TThheerraappeeuuttiicc OOppttiioonnss ((FFiigguurree 33)) in the risk of vertebral fractures (40–50%)
and non-vertebral fractures (20–40%),
Controversy exists regarding the best including hip fractures. Bisphosphonates,
therapeutic option for osteopenia- the potent inhibitors of osteoclast
osteoporosis. It is likely that the factors function, can be used as second line
contributing to OOS in thalassemia intermedia therapy in TM patients (non-responders
(TI), while overlapped with those of or poor responders) and those without
thalassaemia major (TM) have a different hypogonadism (TI) with encouraging
emphasis with intramedullary expansion results.
being more important and hypogonadism RRoouuttee ooff aaddm miin niissttrraattiio
onn aan
nddd
doosse
e:: They
less important than in TM. The choice of can be given as pamidronate 1-2 mg/kg
therapy depends on the age of the patient, body weight once a month as IV infusion
the type of thalassaemia including for 3-5 years (Chatterjee et al 2001),
transfusion dependence, symptoms and orally as alendronate 70 mg orally per
severity of clinical presentation, the past week (Borgna-Pignatti, 2006) or
history of type and number of fractures, zolandronic acid two–three times per year
previous therapy, presence of risk factors of (Mahachoklertwattana 2006).
nephrocalcinosis, associated hypogonadism, Daily alendronate and risedronate have
hyperparathyroidism. An ideal therapy should reduced the risk of single and multiple
be safe and effective, able to correct the spine fractures, asymptomatic
specific defect of bone remodelling unit, (morphometric) and symptomatic spine
strengthen the bone and offer symptomatic fractures in women with bone mineral
relief. density T scores of less than -2.5 and one
or more prevalent spine fractures
((1
1)) SSeexx sstteerrooiidd rreeppllaacceem
meenntt tthheerraappyy (Borgna-Pignatti 2006). Despite their
In symptomatic or asymptomatic TM impressive anti-fracture efficacy, several
patients with proven OOS (DEXA scan) and issues are now arising with respect to
hypogonadism, it is logical to correct bisphosphonates including the risk of jaw
hypogonadism first by sex hormone osteosclerosis in long-term users (Borgna-
replacement therapy for at least two Pignatti 2006).
years (Chatterjee et al, 2001; Chatterjee
et al, 2000; Lasco et al, 2001; Carmina et
al, 2004).

81
((4
4)) CCoom
mbbiinnaattiioonn tthheerraappyy treatment for >5 years is not recommended
Combination of pamidronate to HRT as it may induce osteosclerosis, specially of
regime in TM has been used with the jaw (Borgna-Pignatti, 2006) and may
successful results (Chattergee et al, even aggravate the existing problem.
2001). Biochemical correction of hypogonadism
must be confirmed from optimal peak and
((B
B)) M
Moonniittoorriinngg ooff TTrreeaattm
meenntt trough sex steroid levels. Caution must be
Treatment should be monitored with exercised in prescribing vitamin D
biochemical parameters (bone and sex replacement therapy patients with risk of
steroid profile) and annual DEXA scan of nephrocalcinosis and bisphosphonate is also
spine and femoral neck to determine the T given in caution (Borgna-Pignatti 2006).
scores. A rise of 1-2% per year is expected in Patients on thyroxine and corticosteroid
the femoral neck with or without change in replacement therapy must be monitored
femoral scores (Mahaklertwattana et al, carefully as excess replacement can
2003). After 3 years of pamidronate, usually aggravate osteoporosis.
the BMD effect plateaus. Also long-term

Figure 3

Reeccoom
R mmmeennddaattiioonnss
ñ Diet and exercise
ñ Vitamin D and calcium supplementation
ñ Sex hormones replacement in HH-HRT
ñ Anti-resorption agents-Bisphosphonate
ñ Combination therapy-Bisphosphonate+HRT

82
The Management
of Cardiac Complications in
Thalassaemia Major

The quality and duration of life of prompt intervention.


transfusion-dependent patients with Ideally, a quantitative assessment of the
thalassaemia has been transformed over the degree of myocardial iron overload is
last few years, with their life expectancy required in order to identify those patients at
increasing well into the third decade and risk of developing heart complications as well
beyond, with a good quality of life (Olivieri as, importantly, those where the risk may be
1995; Zurlo 1989). minimal. Establishing the best treatment
protocols requires co-operation between the
Nevertheless, cardiac symptoms and treating physician and cardiologists
premature death from cardiac causes are still experienced in dealing with
major problems. cardiomyopathies.

Iron related heart complications


are the leading cause of death
and one of the main causes of Clinical
morbidity. manifestations
In the absence of effective iron chelation
therapy, many patients sustain iron-induced Patients with considerable iron
myocardial damage resulting in cardiac overload of the heart may
failure, cardiac arrhythmia, progressive remain free of symptoms. Once
congestive cardiac failure or sudden death myocardial dysfunction
(Brittenham,1994).
develops, discernible symptoms
Even after significant effects on are related to the degree of
heart muscle, however, ventricular impairment. Subtle
including symptoms of heart early signs may be confused
failure, aggressive iron chelation with the effects of the
can restore myocardial function underlying condition.
to normality. For example, breathlessness during exercise
may be attributed to anaemia. In more
The unique capacity of the heart to recover advanced stages of heart failure, clinical
from the effects of iron overload only presentations are equivalent to those seen
emphasises the importance of early with any severe heart muscle disease and
detection and, ideally, prevention; once overt may include dyspnoea, peripheral oedema,
heart failure is manifest, acute survival may hepatic congestion and severe exercise
be as low as 50%. limitation. Signs and symptoms of right heart
failure may predominate, but bi-ventricular
The regular assessment of involvement is the norm. The development
cardiac status helps physicians of the signs of classical heart failure implies
to recognise the early stages of advanced disease with a poor prognosis, until
heart disease and allows for the acute situation is resolved.

83
As mentioned above, an important significant myocardial iron-overload.
distinguishing feature of heart failure due to Treatment is directed towards the relief of
iron overload is the capacity of heart iron overload, with a secondary strategy of
function to make a complete recovery with symptomatic treatment of the documented
appropriate chelation therapy—a fact that arrhythmia.
may not be widely appreciated by physicians
and cardiologists unaccustomed to dealing Chest pain is uncommon in thalassaemia, but
with patients with thalassaemia. It must be may accompany intercurrent illnesses
emphasised that the patient may require including pericarditis or myocarditis. The
support of failing circulation for a period of frequency of these complications appears to
several weeks in order to achieve a full differ between countries, being rare in the
recovery. UK but more prevalent elsewhere.

Symptoms of palpitations are common in Patients frequently present with epigastric


patients with thalassaemia, and are a pain due to liver congestion, diminution in
frequent cause for anxiety—both for patients exercise capacity and also dyspnoea and
and their physicians. In brief, the prognostic cough.
implications of arrhythmia are related to the
degree of myocardial iron-overload and any Clliinniiccaall eexxaam
C miinnaattiioonn
associated myocardial dysfunction. Thus in A thorough medical history and physical
the case of a non-iron overloaded patient, examination are required for a basic
the development of an arrhythmia such as cardiological assessment, which should also
atrial fibrillation (AF) deserves simple include: 12-lead electrocardiogram and a
investigation and possible pharmacological detailed echocardiogram, undertaken
treatment, but does not necessarily imply an according to published guidelines. Where
adverse outcome. The same arrhythmia in a available, cardiac magnetic resonance
heavily iron overloaded heart, particularly if imaging (CMR), used to quantitatively
cardiac dysfunction is present, may be the estimate cardiac iron overload, has become
harbinger of severe decompensation and an invaluable tool in the estimation of clinical
requires immediate response and probable risk for the development of heart
hospitalisation. complications in thalassaemia. Additional
tests may also be valuable for the detailed
PPaallppiittaattiioonnss must therefore be investigated assessment of individual clinical problems,
and treated in the context of the patient as a such as the investigation of cardiac
whole. Ectopic activity, usually supra- arrhythmia (Holter or 24-hour ECG) or
ventricular but occasionally ventricular, can functional assessment by exercise tests.
produce symptoms requiring prophylactic
drug treatment (often with beta-blockers), EElle
eccttrrooccaarrddiiooggrraam
m
especially as these transient events can The electrocardiogram is frequently
trigger more sustained arrhythmias, abnormal, but changes are typically non-
particularly AF. Arrhythmias that produce specific. These changes commonly include
symptoms of haemodynamic compromise depolarisation changes in the T-waves and ST
(dizziness, syncope or pre-syncope) pose a segments of the anterior chest leads, and
significant clinical risk and are associated with sometimes a preponderance of right

84
ventricular voltages. Occasionally P-waves are protocol. A minimum data set should include:
also affected, suggesting bi-atrial right and left heart dimensions, biventricular
enlargement. Conduction disturbance in the function (left ventricular fractional
forms of bundle branch block may be seen shortening and ejection fraction), estimated
but higher degrees of conduction intracardiac pressures (pulmonary artery
disturbance are rare. When new ECG pressure, systolic and mean) and Doppler
abnormalities appear during follow-up, analysis of intra-cardiac flows. Longitudinal
further investigation is required in order to follow-up assessments should be carried out
detect the cause. at approximately the same time in the
patient’s transfusion cycle, to minimise
Am
A mbbuullaattoorryy m
moonniittoorriinngg ooff EECCGG variability of clinical parameters.
The standard method for detecting and
investigating cardiac arrhythmia is via Holter Examination by echocardiography of the
ECG recording for 24 or more hours. There ventricular response to exercise may also be
are now many types of recorders suited to useful, highlighting individuals with sub-
the detection of intermittent cardiac clinical disease in whom the ejection fraction
arrhythmia. fails to rise, or even falls, in response to
exertion or simulated exercise using i.v.
EExxe
errcciissee EECCGG dobutamine.
Exercise testing, by treadmill or cycle
ergometer, may be of value in identifying R a d i oi s o t op e s t ud i e s :
Radioisotope studies: The use of MUGA
patients at risk for cardiac arrhythmias or for (Multiple Uptake Gated Acquisition) to
assessing functional capacity. Adequacy of determine the overall left-ventricular ejection
treatment of cardiac disease can also be fraction is an outmoded technique (both in
gauged by exercise test performance. requiring the use of radioactive isotopes and
its high cost). Greater accuracy can be
An exercise test with gas-exchange achieved by monitoring resting ejection
evaluation allows verification of: VO2 peak fraction and the response to a reproducible
(maximal O2 utilisation at the peak of the stress, in order to establish whether the
stress) and VO2 AT (anaerobic threshold), ejection fraction can rise from its basal level.
which are parameters closely related to the
functional status and prognosis of patients CCaarrddiiaacc M
Maaggnneettiicc RReessoonnaannccee IIm
maaggiinngg
with left-ventricular dysfunction. ((CCM
MRR))
The CMR scan provides a
EEcch
hooccaarrddiiooggrraapphhyy combination of morphological,
Echocardiography is widely available,
relatively inexpensive and easy to perform. A
functional information on the
large number of parameters can be obtained heart as well as—uniquely—
from the cardiac ultrasound investigation but quantitative estimates of tissue
even the simplest measurements of chamber iron overload.
size can provide immediate and valuable data As a result, CMR is rapidly becoming the tool
on cardiac status and clinical progress, as of choice in the clinical assessment of
long as they are obtained by a skilled patients with thalassaemia and is hampered
practitioner following a standardised only by the limitation in access to

85
appropriate scanners in some parts of the thalassaemia involves a number of general
world. Scan times have been progressively measures, along with particular cardiological
reduced with modern protocols and very few interventions. Such measures might include:
patients are unable to tolerate the procedure
due to claustrophobia. ñ Maintenance of pre-transfusional
haemoglobin level close to 9-10.5 g/dl in
Caarrddiioollooggiiccaall m
C maannaaggeem
meenntt pprroottooccoollss patients without heart disease, and 10-
The frequency of cardiological assessments 11 g/dl in patients with heart disease;
described above depends on the age of the ñ Regular iron-chelation therapy and, for
patient and a clinical assessment of the likely patients with high iron loads or cardiac
risk of significant myocardial iron overload, or disease, constant infusion regimens (s.c.
awareness of high total body iron burden. or i.v.); consideration of combined
chelation regimes using parenteral and
ñ Well-chelated patients: first assessment at oral chelators simultaneously.
puberty, with repeat examinations yearly. ñ Surveillance and adequate management
The timing of a first CMR is not of other causes of heart failure such as
determined but should probably wait hypothyroidism, hypoparathyroidism,
until the time of greatest actuarial risk, renal dysfunction, coincidental valve or
i.e. late teens to early 20s. structural heart disease, vitamin C
ñ Asymptomatic patients with any evidence deficiency. Avoidance of unhealthy life
of cardiac impairment: every three to six styles, including smoking, lack of physical
months. An initial CMR will give evidence exercise and excess alcohol consumption.
of specific myocardial iron burden, which
may then be followed by repeat Monitoring cardiac function can be a useful
examinations at six to 12 months to guide to a patient’s overall prospects.
ensure treatment strategies are Impaired myocardial function may require
associated with a fall in heart iron specific cardiac treatment, but it also calls
content (rise in CMR T2* parameter attention to the immediate need for much
towards 20 msec). stricter adherence to chelation protocol or
ñ Patients with symptoms of cardiac the initiation of a more intensive chelation
impairment: weekly to every one to four programme, in order to prevent an
months, depending on clinical condition. inexorable progression to severe cardiac
An immediate CMR will help guide failure.
management while subsequent scans
provide an indication of response to SSp
peecciiffiicc CCaarrddiioollooggiiccaall CCaarree
treatment. The essence of treatment of
cardiac disease should be
Overall Management aggressive chelation therapy to
rapidly counteract iron toxicity
Strategy and progressively remove
excessive iron deposits (Davis
The therapeutic strategy to diminish the risk and Porter 2000).
of heart complications in patients with

86
(see Chapter 3: Iron Overload for details on rates in patients with established atrial
designing an appropriate chelation fibrillation.
programme under these conditions).
Diiuurreettiiccss are the mainstay in producing
D
Over recent years there has been a trend symptomatic improvement in those
towards treating patients with thalassaemia individuals who develop pulmonary
exhibiting mild ventricular dysfunction with congestion or signs of right-sided heart
agents known to improve myocardial failure. Loop diuretics such as Frusemide and
function in other forms of cardiomyopathy. Bumetanide will produce a reduction in
Treatment of myocardial dysfunction is best circulating volume, which may considerably
undertaken using angiotensin converting decrease pre-load. These diuretics should
enzyme inhibitors (ACE inhibitors). In therefore be used with caution in patients
controlled trials, these agents have been with thalassaemia. The tendency for patients
shown to reduce mortality in patients with thalassaemia to have restrictive
without thalassaemia established physiology, with diastolic heart failure, means
cardiomyopathy and to reduce the rate of that the reduction in pre-load due to a loop
appearance of heart failure in those with diuretic can produce a sudden fall in cardiac
asymptomatic left-ventricular dysfunction. output. These effects may precipitate pre-
renal failure. To restate, loop diuretics should
These results are very promising, and while be used cautiously and mainly in the late
their extension to heart failure in stages of disease.
thalassaemia remains conjectural, it is widely
applied in clinical practice. The usual Recent evidence supports the use of
precautions for initiating treatment in spironolactone as adjunctive treatment in
patients who are well hydrated and starting non-thalassaemic patients with cardiac
at low doses are recommended. The dose failure. This and related agents reduce
should be increased to the maximum potassium depletion induced by loop
tolerated, limited by hypotension in patients diuretics and counteract hyperaldosteronism.
with thalassaemia. Certain patients are unable Potassium sparing agents can be used with
to tolerate ACE inhibitors due to the ACE inhibitors, but require careful monitoring
development of chronic cough. These of electrolytes.
individuals should be treated with
angiotensin II receptor antagonists, such as When dealing with severe congestive cardiac
losartan. Even though support for this drug failure in hospital, it is advantageous to use
in cardiac failure is not strong at present, the constant intravenous infusions of loop
haemodynamic profile approximates that of diuretics. This aids careful titration of the
ACE inhibitors. doses of diuretic on an hour-to-hour basis,
according to urine output, thus avoiding the
Diiggooxxiinn should not be used in the early
D dangerous situation of massive diuresis,
stages of cardiomyopathy but may have a volume depletion, fall in cardiac output and
role as an inotropic agent in patients with worsening of renal function that can follow
cardiac dilatation accompanied by low blood large i.v. bolus doses of loop diuretics.
pressure. Digoxin has a very specific role in Inotropic support may be indicated in severe
the maintenance of reasonable ventricular cases.

87
Managing such patients can be aided by may have advantages for the prophylactic
utilising biochemical markers of heart failure treatment of AF.
(BNP or pro-N-terminal BNP). Values are high
in decompensated heart failure and fall in A m i o d a ro ne
Amiodarone has a very wide spectrum of
response to treatment. Data support delaying effectiveness against supraventricular and
hospital discharge in decompensated heart ventricular arrhythmias and produces a
failure until BNP levels have reverted to survival benefit in non-thalassaemic
normal. individuals with life-threatening ventricular
dysrhythmias. However, Amiodarone does
A n t i -a r rh y t h m i c a g e n t s :
Anti-arrhythmic agents: In many have an enormous potential for side effects,
instances, the use of drugs to treat relatively one of which—disturbances of thyroid
benign but symptomatic arrhythmias may function—is of particular relevance in
produce greater morbidity and mortality than patients with thalassaemia.
in untreated individuals. The decision to treat
arrhythmias in patients with thalassaemia The role of other drugs, such as calcium-
must therefore be carefully considered, antagonists and class I antiarrhythmic agents,
bearing in mind that iron toxicity is the has yet to be established. Generally, these
primary cause of this complication. Intensive agents should be avoided, since they all have
chelation treatment has been demonstrated a tendency to produce negative inotropic
to reduce arrhythmias. In the majority of effect. Their use has not been widespread,
instances, the arrhythmias are since arrhythmias tend to be associated with
supraventricular, although ventricular more severe levels of myocardial impairment.
tachycardia may occur in seriously ill Without more formal study, the use of such
individuals. The development of arrhythmia drugs cannot yet be recommended for the
may be associated with a deteriorating treatment of patients with thalassaemia.
ventricular function, and can be improved by
addressing the latter problem. Overall, Cardioversion should be considered in
arrhythmias require very careful assessment. patients who fail to respond to iron chelation
For most supraventricular arrhythmias, therapy and pharmacological intervention. In
reassurance of the patient is generally the situation of acute heart failure,
appropriate, whereas patients with cardioversion from AF to normal rhythm
ventricular arrhythmias require urgent should be considered early on, as re-
attention to address associated high establishing synchronised cardiac conduction
myocardial iron load, via improves cardiac failure.
intensified chelation.
A n t i - c o a g ul a t i on :
Anti-coagulation: All patients with in
Beettaa--bblloocckkiinngg aaggeennttss can also be used to
B dwelling central venous lines require formal
control many arrhythmias, and are indicated anti-coagulation with warfarin or other
in patients with stabilised heart failure as suitable Coumadin derivatives, to prevent the
they improve the medium- to long-term potentially life-threatening complication of
prognosis. Dosages should be low at first intra-atrial thrombus formation with
with careful slow upward titration over days embolisation and the development of
and weeks. In heart failure, Carvidelol and pulmonary hypertension. Patients in AF also
Bisoprolol have a special role, while Sotalol should be considered for anti-coagulation, if

88
only as a temporary measure prior to C) For patients with cardiac impairment,
cardioversion. with or without symptoms:
ñ intensification of iron chelation: i.v.
Heart transplant: A few patients have desferrioxamine (24 hours x 7
undergone heart transplant for severe, days/week); consider combination
irreversible cardiac damage, and this treatment with oral deferiprone and s/c
procedure has also been combined with liver desferrioxamine
transplant (Olivieri, 1994). The outcome of ñ slow blood transfusion with diuretics
transplant in patients with thalassaemia ñ specific cardiac medications:
needs to be carefully studied to determine ñ ACE inhibitors, or ARII blockers where
the effectiveness of this approach. The ACE not tolerated
presence of iron-induced damage to other ñ beta-blockers: carefully introduce
organs may adversely affect the outcome of once acute heart failure stabilised;
heart transplant. If surgery is successful, bisoprolol or carvidelol remain first
intensive chelation therapy is still required to choice
remove iron from other organs and to ñ diuretics, for the symptomatic relief
prevent iron accumulation in the of fluid overload; use sparingly whilst
transplanted heart. monitoring renal function;
spironolactone should be introduced if
possible
Summary ñ digitalis, if in atrial fibrillation,
Warfarin: if central line in situ, or if in AF
A) For asymptomatic patients with a normal
heart and no myocardial iron content by
CMR (or, where no CMR is available,
patients with proven good chelation
records and an absence of iron-related Conclusion
complications):
ñ encourage continuation of current, The prospects for patients with thalassaemia
effective chelation have improved with a greater understanding
ñ encourage maintenance of a healthy of the disease and with better, individualised
lifestyle regimes of management. Close co-operation
between the medical disciplines is called for.
B) For patients with increased cardiac iron At the same time, the fundamental
content (measured by CMR) but normal treatment aim remains to provide regular,
cardiac function (or, where no CMR is effective iron chelation, in forms that
available, those with iron related encourage patients to comply with
complications and/or a poor chelation treatment—treatment that must be allied to
history): more precise definition of tissue-specific iron
ñ intensification of iron chelation: s.c. or loads, so that patient and physician alike have
i.v. desferrioxamine (24 hours x 7 a better idea of individualised risk.
days/week); consider combination
treatment with oral deferiprone and s/c
desferrioxamine
ñ as for group A

89
treatment in TI. According to this study,
The prevalence, moderate to severe PHT was observed only in
TI patients with a prevalence of 23%. Systolic
pathophysiology, left ventricular dysfunction, in contrast, was
present only in TM cases with a prevalence of
diagnosis and 8%. Heart failure was observed in 3% of TI
patients and 4% of TM ones.
management of
In terms of pathophysiology, it seems that
pulmonary PHT in ‚-thalassemia results from a rather
complex combination of mechanisms, which
hypertension in lead to the increase of both cardiac output
and pulmonary vascular resistance. Chronic
‚-thalassemia tissue hypoxia and chronic hemolysis are
believed to hold the central pathogenetic
Cardiac involvement represents the primary role, while individual mechanisms involved
cause of mortality in both thalassemia major include the prolonged anemic state, the
(TM) and thalassemia intermedia (TI). In this increased percentage of hemoglobin F, the
context, pulmonary hypertension (PHT) is hepatic abnormalities, the presence of a
part of the cardiopulmonary complications of hypercoagulabilable state, the thalassemia-
the disease. related elastic tissue defects, and the
coexistent endothelial dysfunction.
Pulmonary hypertension was initially
documented in a small group of 7 TI patients The diagnosis of PHT in patients with
with right heart failure. In a subsequent thalassaemia may be performed simply and
study of a large 110-patient series, age- non invasively using transthoracic Doppler
related PHT was found in nearly 60% of cases echocardiography. It has been shown that a
followed by right heart failure in 5% of peak systolic tricuspid pressure gradient in
patients. It should be noted that all those the presence of tricuspid regurgitation
patients had preserved left ventricular higher than 30 mmHg is indicative of the
systolic function and normal pulmonary presence of pulmonary hypertension. A
capillary wedge pressure. Thus, following follow-up strategy with clinical examination
those observations PHT is currently of the cardiovascular system,
considered to be the primary cause of heart electrocardiography, chest X-ray and
failure in TI patients. echocardiography, performed on an annual
basis, or in shorter intervals if clinically
In what concerns the development of PHT in indicated, should be applied in every patient
TM, a recent study (Aessopos Kefarmakis, with thalassaemia. A close collaboration
2007) compared cardiac disease between between attending physicians, hematologists
two large aged-matched groups of TM and cardiologists is required in this context.
(n=131) and TI (n=74) patients, both treated Although both forms of the disease share a
uniformly in the currently accepted manner, common molecular background, the diverse
namely regular transfusion and chelation severity of the genetic defect and of the
therapy in TM and absence of any particular resulting clinical phenotype impose a

90
different therapeutic approach. The currently
applied regular lifelong therapy in TM
patients eliminates chronic hypoxia and thus
prevents the development of PHT. On the
other hand, the absence of systematic
treatment in TI leads to a cascade of
reactions that compensate for chronic
anemia but at the same time allow the
development of PHT. The accumulated
experience indicates that a large number of
TI patients, if not the majority of them,
should be considered for regular transfusion
and chelation therapy. Two crucial points
that remain to be clarified are the patient
selection criteria and the timing of treatment
onset. Until research data becomes available,
the judgement should be based on individual
clinical and laboratory assessment of
patients. The applied treatment, once
started, should definetely aim at prevention
and not palliation of anaemia-induced
complications.

91
The Liver
in Thalassaemia

Under normal circumstances, about one-third overload (HIC in mg/g dry weight x 10.6 =
of storage iron (ferritin and haemosiderin) in whole body iron store in mg/kg) (Angelucci,
the body is found in the liver. Approximately 2000). Non-invasive techniques used to
98% of hepatic iron is found in hepatocytes, assess hepatic iron include computed
which make up 80% of total liver mass; the tomography, biomagnetic liver
remaining 1.5-2% of total liver iron is found susceptometry (SQUID) and magnetic
in reticuloendothelial cells, endothelial cells, resonance imaging (MRI). Of these, relaxation
bile ductular cells and fibroblasts. Iron that rates R2 (1/T2) and R2* (1/T2*) measured by
enters the cell in excess of that required MRI appear to be the most promising and
accumulates in the major storage forms of accurate (Wood, 2005).
iron, ferritin, and haemosiderin. Progressive
accumulation of storage iron is associated Hepatic iron stores are closely
with cellular toxicity, although the specific correlated with cumulative
pathophysiologic mechanisms for
hepatocytes injury and liver fibrosis are not
transfusional iron load and have
entirely understood. These include lipid been used as a marker for the
peroxidation of organelle membranes, effectiveness of chelation
increased lysosomal fragility and decreased therapy and prognosis. An
mitochondrial oxidative metabolism. Iron also increase in hepatic iron is
has a direct effect on collagen synthesis
and/or degradation, and alterations in
associated with an increased risk
microsomal enzymes. of impaired glucose tolerance,
diabetes mellitus, cardiac
The liver plays a central role in iron disease and death.
homeostasis. In addition to iron released
from transfused red cells, an enhanced rate
of gastrointestinal iron absorption has been Hepatitis C Virus
suggested. This excess iron is initially
confined to the Kupffer cells but when (HCV)
transfusion requirements produce massive
iron overload, spillover to hepatic This RNA virus was first characterised in 1989,
parenchyma cells quickly occurs, with the risk having previously been termed non-A non-B
of late development of fibrosis and cirrhosis. hepatitis. The majority of HCV isolates studied
In patients with ‚-thalassaemia, in absence of so far can be divided into six major groups,
co-factors, the threshold hepatic iron designated genotypes 1-6, with subdivisions
concentration for the development of in each (subtype a, b, c, etc.). Antibodies
fibrosis is about 16 mg/g dry weight liver that develop after infection are not
(Angelucci, 2002). Clinical studies suggest a protective but rather are indicative of
relationship between hepatic iron current or past infection. Active infection is
concentration and the development of iron- diagnosed by the presence of circulating HCV
induced hepatotoxicity. RNA in blood (Sharara, 1996)

Hepatic iron concentration (HIC) is the gold


standard for the measurement of body iron

92
Preventative measures to R e v e r s ib ili t y :
Reversibility: The reversibility of advanced
minimise the risk of post- fibrosis and even early cirrhosis (Child A –
compensated or well-compensated*) has
transfusional hepatitis C include been documented in thalassaemia once
careful selection of voluntary causes of liver injury (iron overload and HCV
donors and appropriate blood infection are removed) (Muretto, 2002).
donor screening.
E n d -s t a g e l i v e r d i s e a s e :
End-stage liver disease: should lead to
consideration of liver transplantation.
Natural history and Hepatitis C is currently the commonest
reason for liver transplantation worldwide.
complications of Recurrent hepatitis C infection occurs in >
90% of cases after transplant but is usually
infection mild. Long-term survival after liver
transplantation for hepatitis C is similar to
A c u t e i n fe c t i o n :
Acute infection: generally benign, with that for other diagnoses, averaging 65% after
>80% asymptomatic. Anicteric Fulminant 5 years (Gane, 1996).
Hepatitis is very rare.
Heeppaattoocceelllluullaarr ccaarrcciinnoom
H maa ((HHCCCC))::
Chhrroonniicc iinnffeeccttiioonn:: develops in 70-80% of
C develops in 1-5% of infected individuals after
cases, leading to chronic liver disease. 20 years, particularly after the development
However, the clinical outcome is highly of cirrhosis, increasing by 1-4% each year
variable, for reasons that are not completely thereafter (Colombo, 1991). Prevention and
understood. Determinants of disease severity early detection of HCC are more effective
or chronicity as well as response to therapy than attempted cure. Cirrhosis patients
include age at acquisition, as well as host- should undergo a regular six-monthly
specific (e.g. immunity) and virus-specific screening programme, including liver
(e.g. genotype) factors and, most important, ultrasound examination and alpha-feto-
co-morbidities. protein check, for the early detection of
hepatocellular carcinoma.
C i r rh os i s :
Cirrhosis: develops in a variable percentage
of HCV-infected patients, ranging from < 5% E xt r a - h e p a t i c
Extra-hepatic manifestations of HCV
in young, healthy people, to approximately infection include porphyria cutanea tarda,
25-35% of cases of patients with relevant co- essential mixed cryoglobulinemia,
morbidities. Age and co-morbidities appear glomerulonephritis, autoimmune thyroidits
to be the most important factors affecting and vasculitis (Sharara, 1996).
the risk of developing cirrhosis. Cirrhosis
usually takes as long as two to three decades
to develop from the time of acquisition. Five- * Liver cirrhosis is divided to 3 stages following the
year survival in patients with compensated Child-Pugh score, Score 5-6 (Score A) is
characterised by: No ascites, Bilirubin < 2mg/dl,
cirrhosis is 91%, with a 79% rate of 10-year Albumin>3.5g/dl. INR <1.7, no encephalopathy.
survival. When cirrhosis is decompensated Therefore, Child-Pugh stage A can be defined as
however, 5-year survival falls to just 50%. “well compensated disease”.

93
to guide decisions on therapy and anticipate
Special features of complications (Angelucci, 1995).

hepatitis C in
thalassaemia major Treatment
This is a rapidly changing field and the
The severity of chronic hepatitis C in patients treatment of hepatitis in patients with
with thalassaemia may be greater because of thalassaemia should therefore be undertaken
concomitant iron overload, other concurrent in close collaboration with a specialist in liver
viral infections (HBV, HIV) and possible disease.
infection with mixed hepatitis C genotypes. It
has been demonstrated that iron and HCV Similar to non-thalassaemia patients,
infection are independent but mutually treatment of HCV in patients with
reinforcing risk factors for the development thalassaemia is aimed at eradication of the
of liver fibrosis and cirrhosis, with a reciprocal virus, improvement in liver histology,
multiplicative effect (Angelucci, 2002). It reduction of the risk of liver cirrhosis and
appears therefore that patients with hepatocellular carcinoma.
thalassaemia, particularly those with poor
control of iron overload, face an increased SSe
elleeccttiioonn ooff ppaattiieennttss ffoorr tthheerraappyy
risk of developing cirrhosis. Patients diagnosed with acute HCV infection
and persistently positive serum HCV RNA
after 12 weeks of exposure or diagnosis
Diagnosis and should receive treatment (Sharara, 2006).

monitoring Initiation of treatment in chronic hepatitis C


Annttiibbooddyy tteessttiinngg
A
has traditionally been based on one or more
of the following:
This is most valuable for screening blood and ñ confirmed presence of HCV-RNA
blood products and as initial testing in ñ moderate to high serum ALT levels
patients with chronic unexplained elevation ñ abnormal liver histology
in serum transaminases or those suspected
of having chronic liver disease. Confirmatory Encouraging results for the treatment of HCV
testing is done using HCV RNA detection by in thalassaemia, combined with the above-
polymerase chain reaction (PCR), the current mentioned risks of greater severity of chronic
standard for the confirmation of viremia. hepatitis C in such patients, means that the
Ascertaining the genotype and quantity of presence of serum HCV-RNA alone is
HCV RNA in serum is useful only in sufficient to consider treatment in patients
determining the type and duration of with thalassaemia, where the patient has no
treatment (see below). other contraindications to treatment or other
LLiivve
err bbiiooppssyy iinn tthhaallaassssaaeem
miiaa m
maajjoorr significant co-morbidities.

Liver biopsy prior to treatment is helpful in


determining the extent of liver damage and
Reessppoonnssee ttoo ttrreeaattm
R meenntt
Depending on HCV genotype and viral load,

94
40-80% of patients with chronic hepatitis C ñ High baseline HCV-RNA level and the
will respond to the current standard absence of its early decay (4-12 weeks)
treatment of pegylated interferon and upon initiation of treatment
ribavirin. Response is defined on the basis of ñ HCV genotypes 1 or 4
a negative highly sensitive qualitative HCV ñ Presence of bridging fibrosis or cirrhosis
RNA PCR assay, carried out 24 weeks after ñ Co-existence of other viruses (HBV, HIV)
completion of therapy.
Controversial in this specific setting is the
Patient responses are classified as follows: role of iron overload.
E a r l y v i r a l r e s p on s e ( E V R ) :
ñ Early viral response (EVR): defined as
an undetectable HCV RNA or a > 2-log Since no baseline factor is specifically
reduction in viral load after 12 weeks of predictive of treatment success or failure,
treatment withholding therapy on the basis of factors
R e s p o n s e a t e nd o f t r e a t m e n t
ñ R e s p o n s e a t e nd o f t r e a t m e n t suggesting a poor response is unwarranted.
( ETR ) :
(ETR): defined as absence of HCV-RNA at Because of the possible role of iron overload
the end of treatment in reducing the likelihood of successful
Sustained viral response (SVR):
ñ Sustained viral response (SVR): treatment of hepatitis C and for general,
absence of HCV-RNA > 6 months after well-known clinical reasons, effective
concluding treatment. This is in practice chelation therapy should be strongly
equivalent to viral eradication of HCV considered before initiation of antiviral
N o n -r e s p o n d e r s :
ñ Non-responders: lack of significant therapy in patients with bad control of
decline (defined as > 2-log reduction transfusional iron.
from baseline) in HCV RNA after 12 weeks
of therapy
R e l a p s e rs :
ñ Relapsers: re-emergence of HCV-RNA Treatment regimens
after a satisfactory end of treatment
response The gold standard is combination therapy
with pegylated interferon and ribavirin. An
Moonniittoorriinngg rreessppoonnssee
M example of an algorithm used for Hepatitis C
Depending on HCV viral genotype, the managament is presented in Figure 1.
current recommendation is to measure the
biochemical (serum ALT) and virological (HCV- T y p e o f i n t e r f e r on :
Type of interferon: Pegylated interferon
RNA) response after 4 to 12 weeks of ·-2a or ·-2‚ given subcutaneously once
therapy, and to continue therapy for an weekly
additional 12 to 24 weeks in patients with
undetectable HCV-RNA. Because serum ALT Duurraattiioonn:: 24 to 48 weeks, depending on
D
may be raised for other reasons in patients genotype
with thalassaemia (iron overload,
concomitant infections), monitoring response S i d e e f fe c t s :
Side effects: Typical side effects in most
is based on viral HCV RNA. patients include flu-like symptoms, insomnia,
and cognitive and mood changes, especially
Prreeddiiccttiioonn ooff ppoooorr rreessppoonnssee
P in the first two weeks after starting
Negative predictors in all patients with interferon. Dose-dependent neutropenia and
hepatitis C are: thrombocytopenia commonly occur during

95
Figure 1

96
interferon therapy. Particular attention In thalassaemia major this may be associated
should be paid to this complication in with a more marked haemolysis and a 30%
patients with thalassaemia and increase in transfusion requirement, which
hypersplenism. Since both deferiprone and requires careful adjustment of the
interferon may cause neutropenia, there are transfusion interval and intensification of iron
theoretical risks associated with their chelation therapy (Li, 2002; Inati, 2005).
combined use, and this combination should
be initiated with caution and under careful It is important to note that dose-reduction of
monitoring. Hypothyroidism is an important ribavirin is associated with an inferior
complication of interferon treatment. sustained viral response and it is hence
recommended that transfusion-chelation
Some patients have experienced requirements be adjusted to compensate for
exacerbation of local reactions at the site of ribavirin-associated haemolysis rather than
desferrioxamine infusion during interferon altering the recommended ribavirin dose
treatment. Heart failure has been seen in a (Inati, 2005).
few patients with thalassaemia receiving
interferon, and special care should be given TTrreeaattmmeenntt dduurraattiioonn aanndd vviirraall llooaadd
if prescribing interferon for patients with m
mo onniittoorriinngg: Depends primarily on the HCV
pre-existing heart disease. genotype. For genotypes 1 or 4, treatment is
administered for 48 weeks provided there is
M on i t o ri ng f o r s i d e e f f e c t s :
Monitoring for side effects: Close a positive early viral response (EVR) at 12
monitoring for hypothyroidism is mandatory weeks. In the absence of EVR, treatment is
in patients receiving interferon, and testing usually discontinued and further treatment
for thyroid function and the presence of options considered.
anti-thyroid antibodies should precede
initiation of therapy. Regular monitoring of This approach has been validated in patients
blood counts is also necessary, to identify with thalassaemia where an SVR of 64% is
neutropenia or thrombocytopenia. Cessation seen in patients infected with genotype 1
of therapy should be considered if the and 4 and who have exhibited an
absolute neutrophil count falls below 1,000. undetectable HCV RNA at 12 weeks of
treatment (Inati, 2005). For genotypes 2 or
Ribavirin
Ribavirin is a nucleoside (guanosine) 3, treatment is limited to 24 weeks. Given the
analogue, well absorbed orally, and typically high rate of SVR for genotypes 2 and 3,
given in doses of 800-1200mg/d. Alone, it approaching 80%, a 12-week determination
has limited antiviral activity in hepatitis C but of viral load is not usually necessary.
in combination therapy with interferon has
been shown to significantly increase TTrreeaattmmeenntt ooppttiioonnss ffoorr nnoonn--
sustained response rates compared to rreessppoonnddeerrss
interferon alone. These have not been firmly established and
are currently considered experimental. An
Si de e f f e cts :
Side effects: Haemolysis occurs in most expedited second treatment option may
patients without thalassaemia, with a need to be considered in patients with
decrease in haemoglobin of 10-20% from advanced fibrosis on liver biopsy.
baseline levels.

97
Maan
M naaggeem meenntt ooff ssppeecciiaall ppaattiieenntt HBsAg, and other public health
ppooppuullaattiioonnss measures, have led to a
Consultation with a physician experienced in
the management of liver disease is especially
significant reduction in
important in the clinical management of the hepatitis B infections in most
following patient populations: countries of Europe and North
ñ Children America, as well as other parts
ñ Patients with cirrhosis of the world. Hepatitis B
ñ Immunosuppressed patients nevertheless remains a
ñ Pregnant patients
ñ Patients with acute hepatitis C formidable medical problem,
mainly in developing
Prreevveennttiioonn
P countries.
There is currently no vaccine or
immunoglobulin to prevent hepatitis C. The Current HBsAg positivity in thalassaemia
following recommendations are made to major ranges from <1% to >20% and
reduce the risk of non-parenteral Hepatitis B infection remains a significant
transmission: cause of chronic liver disease and
hepatocellular carcinoma in patients with
Sexual transmission
Sexual transmission risk is generally low. thalassaemia in many regions of the
However, insufficient data exist to developing world.
recommend changes in current
recommendations: that patients encourage Clliinniiccaall ssiiggnniiffiiccaannccee ooff HHBBVV m
C maarrkkeerrss
their sexual partners to be tested for Despite the availability of good screening
hepatitis C, and that safe sexual practices tests for hepatitis B, the interpretation of
should be encouraged. results may be difficult or misleading.

G e ne r a l m e a s ur e s
General measures, such as avoiding ñ A
Accu
uttee iinnffeeccttiioonn.. HBsAg is a reliable marker
sharing toothbrushes, razors, etc. are (can be present for 4-5 months). HBeAg
advised, to avoid transmission to family is also transiently present (1-3 months).
members. However, the risk of transmission Anti-HBc IgM is the most reliable test for
is low, and special measures such as to the diagnosis of acute HBV infection.
segregate towels and eating utensils are
probably unnecessary. ñ C
Chhrroonniicc iinnffeeccttiioonn (overt carrier) is marked
by the presence of HBsAg and anti-HBc in
the blood (usually accompanied by HBeAg
or anti-HBe). In accordance with
Hepatitis B Virus international definitions, overt carriers
can be classified as:
(HBV)
ñ aaccttiivve
e ccaarrrriieerrss, identified by the
IIn
ncciiddeennccee presence of HBeAg or anti-HBe
Vaccination strategies, antibodies and a viral load ≥5 log10
screening of blood donors for copies/ml (although others cite a figure

98
of ≥4 log10 copies/ml), corresponding interpretations of screening results.
to about 17,200 IU/ml, according to
most recent standardisations. The great
majority of active carrier cases are Natural history
associated with the presence of hepatic
disease. A c u t e he p a t i t i s :
Acute hepatitis: This is the most common
presentation, with an incubation period of 4-
ñ iin
naaccttiivvee ccaarrrriieerrss, characterised by the 20 weeks. Severity is variable, with an icteric
persistent normality of transaminase in period often preceded by a prodromal illness
an anti-HBe-positive subject, associated with arthralgia and urticaria. Progression to
with levels of viremia below the fulminant hepatic failure is rare (≤1%). Acute
threshold (<5 Log10) and, eventually, hepatitis B is usually managed by supportive
with IgM anti-HBc <0.2 IMx Index. In the measures alone.
majority of such subjects, the
histological finding, when available, does Prrooggrreessssiioonn ttoo cchhrroonniicc hheeppaattiittiiss BB
P
not reveal significant liver disease occurs in 5-10% of otherwise healthy adults
(necroinflammatory activity <4 HAI), and in 90% of neonates. In acute icteric
while in a small minority of cases it is hepatitis B in adults, transition to chronicity
possible to observe effects of a chronic appears to be rare, probably occurring in less
(sometimes even cirrhotic) disease than 2% of cases. For patients with chronic
which have became silent spontaneously hepatitis B infection, co-infection with
or thanks to the effect of the antiviral hepatitis C may increase the severity and rate
treatment. of progression of liver disease.

ñ p re v i o u s i n fe c t i o n :
previous infection: the presence of C i rr ho s i s
Cirrhosis occurs at a rate of 1-2.2% per
anti-Hbc antibodies ± anti-Hbs indicates year. Iron loading in thalassaemia may
previous infection. In particular increase the risk, as may concomitant HCV
circumstances, such as deep infection.
immunosuppression (i.e. hemopoietic
stem cell transplantation), the possibility H e p a t oc e l l ul a r c a r c i n o m a
Hepatocellular carcinoma is a well-
of HBV reactivation after a previous recognised complication of chronic hepatitis
infection has been demonstrated. This B infection.
category of patients can therefore also
be defined as potential occult carriers
(Marzano, 2007).

ñ v ac c in at io n :
vaccination: the presence of HBsAg
antibodies (if anti-HBc is not present)
indicates vaccination.

Patients with thalassaemia should be


screened for all serological markers of
hepatitis B and classified according to
Table 1, which provides a list of possible

99
TTe
esstt Reessuullttss
R IIn
ntteerrpprreettaattiioonn Reeccoom
R mmmeennddaattiioonn
HBsAg - Susceptible to infection/never Consider vaccination
anti-HBc - exposed to virus
anti-HBs

HBsAg + Acute or chronic infection Further evaluation


anti-HBc + or -

HBsAg - Resolution of previous infection


anti-HBc +/-
anti-HBs +
anti-HBeAg -

HBsAg - Past infection*- potential


anti-HBc +/- occult carrier.
anti-HBs -
anti-HBeAg -

HBsAg + Carrier with chronic infection Further evaluation,


anti-HBc + (if HBsAg+ 6 months or more) including HBV-DNA
anti-HBs - Highly infectious levels
HBeAg +

HBsAg - Carrier with chronic infection Further evaluation,


anti-HBc - (if HBsAg+ 6 months or more) including HBV-DNA
anti-HBs + levels
HbeAg -
Anti-HBe -

HBsAg - Immunisation without infection


anti-HBc -
anti-HBs +
HBeAg -
Anti-HBeAg -

* Other interpretations include:


1. Recovering from acute HBV infection, with loss of HBsAg but anti-HBs has yet to appear
(“window period”).
2. Immune to HBV but anti-HBs never appeared or has fallen below the level of detection.
3. Chronic HBV infection with undetectable serum levels of HBsAg.
4. False positive anti-HBc, with susceptibility to HBV infection.
* Interpretations 2 and 4 are the most common explanations of this serologic pattern.

Table 1: Possible interpretations of Hepatitis B screening results

100
Prevention: HBV 2007 Treatment
Vaccination: All newly Overview
(Hepatitis Annual Update 2007
diagnosed patients with ‚- website:http://clinicaloptions.com/Hepatitis/AnnualUpdates)

thalassaemia should be The primary goal of therapy for Chronic


vaccinated against hepatitis B. Hepatitis B (CHB) is long-term suppression of
Three injections (at 0, 1 and 6 serum HBV-DNA which in turn will likely
reduce progression to cirrhosis, liver failure
months) are required to and hepatocellular carcinoma.
produce an antibody response
in 95% of normal individuals. The key endpoints in determining the
The vaccine is ineffective in efficacy of therapy include suppression of
those already exposed to serum HBV DNA to low and preferably
hepatitis B. undetectable levels, normalisation of ALT
levels, histologic improvements, HBeAg
In individuals acutely exposed to known seroconversion in HBeAg-positive patients,
contaminated blood, hyperimmune globulin and the relatively rare event of HBsAg
can limit the risk of acute infection. seroconversion.

Prreevveennttiioonn ooff vveerrttiiccaall ttrraannssm


P miissssiioonn:: The information provided below is derived
from US treatment algorithms, AASLD*,
Transmission of hepatitis B from mother to
infant occurs during the perinatal period. The EASL**, and APASL*** Guidelines, according
risk of infection is 26-40% if the mother is to which, the currently preferred first-line
HBeAg positive. Mothers with acute hepatitis monotherapy treatment options include the
B during pregnancy transmit the virus in up use of Adefovir, Entecavir and Pegylated
to 70% of pregnancies if infection occurs in Interferon, which has almost completely
the third trimester, and up to 90% if it occurs replaced standard interferon alfa-2b.
within 8 days of delivery.
Lamivudine and Telbivudine are not preferred
Measures to prevent vertical transmission first-line drugs in most populations, because
include administration of hepatitis B vaccine of high resistance rates.
and hepatitis B immuno-globulin (HBIG) to
neonates within 12 hours of delivery by a Recent trends include treatment of patients
carrier. This results in >90% reduction of the with any elevation of HBV-DNA with
risk of transmission. compensated or decompensated cirrhosis.
Combination therapy with nucleos(t)ide
Unlike hepatitis C, hepatitis B is highly analogues is also now widely used in cirrhotic
infectious through the sexual route and close patients as well as in patients with HBV and
personal contact. Detailed advice and HIV co-infection or in patients who have
immunisation need to be given to the undergone BMT after HBV infection.
patient’s immediate family and sexual *AAAASSLL:: American Association for the study of Liver Disease
** EEA
ASSLL:: European Association for the study of Liver Disease
partner(s). *** AAPPA ASSLL:: Asian Pacific Association for the study of Liver
Disease

101
SSuum mm maarryy:: IIm
mpplliiccaattiioonnss ffoorr CClliinniiccaall ñ The rates of genotypic resistance with
PPrraaccttiiccee long-term therapy are high with
The key recommendations based on updated lamivudine (70% at 4-5 years), somewhat
treatment guidelines for treatment of less with telbivudine (21.6% in HBe-Ag-
chronic Hepatitis B are as follows: positive and 8.6% in HBeAg-negative
ñ Patients with HBeAg-positive chronic patients at year 2), intermediate with
Hepatitis B should receive treatment adefovir (30% at 5 years of therapy in
when serum HBV DNA levels are ≥ 20,000 HBe-Ag-negative patients), and low with
IU/mL and ALT levels are elevated, entecavir in nucleoside-naïve patients
particularly 2-fold (<1% at year 4), but higher in lamivudine-
resistant patients (~42% at year 4). Oral
ñ Patients with HBeAg-negative chronic drugs with a high genetic barrier to
Hepatitis B should receive treatment resistance and/or high potency are
when serum HBV DNA levels are ≥2,000 generally preferred to reduce the
IU/mL and ALT levels are elevated likelihood of resistance. Interferon and
peginterferon therapy have not been
ñ Genotype testing should be used more associated with the development of
broadly. Knowledge of genotype may be resistance
useful in predicting natural history. For
example, genotype C HBV is associated ñ Potential future therapies for chronic
with more advanced disease and a higher Hepatitis B include pegylated interferon
rate of HCC than genotype B in Asians. and other nucleos(t)ide analogues,
For patients considering pegylated particularly tenofovir that is in late-stage
interferon therapy, genotype is useful in studies and shows promise of high
predicting response to therapy: HBV potency and low rates of resistance. The
genotype A responds much better than role of combination therapy is evolving,
genotype D (common genotypes in primarily to reduce the rate of resistance
whites), and genotype B responds with long-term therapy
somewhat better than genotype C
(common genotypes in Asia)

ñ All patients with chronic hepatitis B and


cirrhosis with HBV DNA levels ≥ 2,000
IU/mL should be treated. In addition, it
may be appropriate to treat all patients
with cirrhosis and viraemia regardless of
HBV DNA levels, particularly if ALT levels
are elevated. Preliminary evidence also
supports the use of combination
nucleos(t)ide agents in these patients,
and therapy should probably used be
long-term, even after HBeAg
seroconversion in HBeAg-positive patients

102
EExxaam
mpplleess ooff ttrreeaattm
meenntt aallggoorriitthhm
mss ffoorr ssppeecciiffiicc ggrroouuppss wwiitthh HHBBVV iinnffeeccttiioonn iinncclluuddee::
UUSS TTrreeaattm
meenntt AAllggoorriitthhm m RReeccoom mm meennddaattiioonnss ffoorr TTrreeaattm
meenntt ooff HHBBeeAAgg--PPoossiittiivvee
oorr HHBBeeAAgg--NNeeggaattiivvee CCiirrrrhhoottiicc PPaattiieennttss
ñ HBV DNA < 2,000 IU/mL and compensated cirrhosis
- May choose to treat or observe
- Adefovir or entecavir preferred; pegylated interferon alfa-2a may be option in early
well-compensated cirrhosis

ñ HBV DNA ≥ 2,000 IU/mL and compensated cirrhosis


- Treat; adefovir or entecavir are first-line options
- Long-term treatment required, and combination therapy may be preferred
(adefovir or tenofovir plus lamividine, telbivudine or entecavir)

ñ HBV DNA < 200 IU/mL or ≥ 200 IU/mL and decompensated cirrhosis
- Combination therapy preferred (adefovir or tenofovir plus lamivudine,
telbivudine or entecavir)
- Long-term treatment required
- Wait-list for liver transplantation

Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

22000077 AAAASSLLDD GGuuiiddeelliinneess oonn M


Maannaaggeem
meenntt ooff CChhrroonniicc HHeeppaattiittiiss BB PPaattiieennttss wwiitthh
CCoom
mppeennssaatteedd CCiirrrrhhoossiiss
ñ Who to treat
- Patients who are HBeAg positive or negative
- Patients with HBV DNA > 2,000 IU/mL; no ALT specified
- Consider treating if ALT elevated for patients with HBV DNA < 2,000 IU/mL
- Observe for patients who are HBV DNA negative

ñ Drugs of Choice
- Adefovir or entecavir preferred

Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

103
22000077 AAAASSLLDD GGuuiiddeelliinneess oonn M
Maannaaggeem
meenntt ooff CChhrroonniicc HHeeppaattiittiiss BB PPaattiieennttss wwiitthh
DDeeccoom
mppeennssaatteedd CCiirrrrhhoossiiss
ñ Who to treat
- HBeAg positive or negative at any HBV DNA level

ñ Drugs of choice
- Combination of lamivudine or telbivudine plus adefovir or entecavir
monotherapy is preferred (interferons contraindicated)

ñ Duration of therapy
- Long-term

ñ Other recommendations
- Refer for transpalntation
Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

Pootteennttiiaall M
P Maannaaggeem
meenntt ooff HHeeppaattiittiiss BB AAnnttiivviirraall DDrruugg RReessiissttaannccee
Reessiissttaannccee TTyyppee
R SSttrraatte
eggyy
Lamivudine Continue lamivudine and add adefovir (preferred over switch to
adefovir) or tenofovir
Switch to emtricitabine/ tenofovir*

Adefovir Continue adefovir and add lamivudine or telbivudine (preferred


over switch to lamivudine or telbivudine)
Switch to or add entecavir (if no prior lamivudine resistance)
Switch to emtricitabine/tenofovir*

Entecavir Switch to or add adefovir or tenofovir*

Telbivudine Continue telbivudine and add adefovir or tenofovir*


Switch to emtricitabine/tenofovir*

* Not approved by the FDA for the treatment of Hepatitis B


Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

104
Ad
A dvvaan
nttaag
geess aan
nddD
Diissaad
dvvaan
nttaag
geess o
off C
Cuurrrreen
ntt TTh
heerraap
piieess ffo
orr C
Chhrro
onniicc H
Heep
paattiittiiss B
B
Ag
A geen
ntt Ad
A dvvaan
nttaag
geess Diissaad
D dvvaan
nttaag
geess
Interferon alfa-2b ñ HBsAg loss rates ñ Parenteral administration
ñ Short treatment duration ñ Frequent adverse effects
ñ No drug resistance
Lamivudine ñ Oral administration ñDrug resistance common
ñ Excellent tolerance (~20%/yr and up to 70% with
ñ Use in ESLD* 4-5 yrs of therapy)
ñ Use in adefovir failures
Adefovir ñ Oral administration ñ 24-to 48-week HBV response less
ñ Excellent tolerance potent than entecavir and telbivudine
ñ Use in ESLD* ñ Drug resistance delayed and less
ñ Use in lamivudine failures common than with lamivudine, but
more common than with entecavir
with extended therapy (0% at Yr 1, 3%
at Yr 2, 11% at Yr 3, 19% at Yr 4, and
30% at Yr 5 of therapy in HBeAg-
negative patients)
Entecavir ñ Oral administration ñ Drug resistance: rare in nucleoside-
ñ Excellent tolerance naïve parents (estimated at < 1% at
ñ High potency in lowering Yr 4), but common in patients with
HBV DNA levels lamivudine resistance (estimated at
ñ Use in adefovir failures 6% at Yr 1, 14% at Yr 2, 33% at Yr 3,
and 42% at Yr 4)
Pegylated ñ HBsAg loss ñ Parenteral administration
Interferon ñ Fixed duration of treatment ñ Frequent adverse effects but
ñ No drug resistance less than recombinat standard
interferon
Telbivudine ñ Oral administration ñ Drug resistance: intermediate rates
ñ Excellent tolerance of drug resistance in treatment-naïve
ñ High potency in lowering patients (5.0% at Yr 1, and 21.6% at
HBV DNA levels Yr 2 in HBeAg-positive patients, and
8.6% at Yr 2 in HBeAg-negative
patients)

* ESLD, end-stage liver disease


Reference: Hepatitis Annual Update 2007-Emmet B. Keeffe, website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

The authors of this book have made an effort treatment of CHC/B, should be decided in
to provide readers with essential information consultation with and monitored by a
on CHC and CHB treatment. However, specialist hepatologist.

105
Infections
in Thalassaemia Major

Infections are the second commonest cause briefest interaction with patients with
of death in thalassaemia major. Clinicians thalassaemia, should have the same
involved in the care of thalassaemia will be awareness, as should patients themselves. A
fully aware of this risk and the importance of basic outline of the effects of infection in
any intervention that may limit it (Rahav, thalassaemia and their practical implications
Volach et al, 2006). However, all medical and are provided in Table 1 (see also Table 2 for
nursing staff, including those with the more blood-borne infections).

Blood
borne Relevance for severity Orientation for practical management
trans-
mission

Anaemia Splenectomy Iron Iron Vaccine Sensitive to broad Suspend Note


overload chelation available spectrum chelation
antibiotics if suspected

Parvovirus B19 ++ +++ - - - No - No Pregnancy


HIV +++ +- +? + - No - No
HBV +++ - - +? - Yes - No
HCV +++ - - ++ - No - No
CMV ++ + - ? - No - No Stem cell
transplant
Streptococcus - +? +++ - - Yes Yes Yes
pneumoniae
Meningococcus - - +++ - - Yes Yes Yes
Hemophilus - - +++ - - Yes Yes Yes
Influenzae
Klebsiella - + - + - No Yes Yes
Pseudomonas - + ++ + - No Yes Yes
Vibrio vulnificus - + - + - No Yes Yes
Escherichia coli - + - + - No Yes Yes
Salmonella - + + + - No Yes Yes
Yersinia + - - +++ +++ No No Yes deferrioxamine
enterocolitica
Mucor species - - - ++ ++ No No Yes Deferrioxamine-
Immunosup-
pression
Pythium - ++ +++ ++ - Yes No Yes? Farming
insidiosum

Table 1: A summary of the effects of infection in thalassaemia and their practical implications.

106
A patient with thalassaemia major must not The pathogens most commonly associated
be considered as immuno-compromised per with post-splenectomy sepsis are
se, particularly if the disease is well encapsulated organisms, particularly:
compensated by treatment. On the other
hand, many alterations to the body’s immune ñ Streptococcus pneumoniae (accounting
system have been described in thalassaemia, for more than 75% of documented
including reduction in neutrophil numbers, bacterial infections in asplenic patients);
changes in number and function of natural ñ Haemophilus influenzae, and;
killer cells, increase in number and function ñ Neisseria meningitides.
of CD8 suppress cells, occurrence of
macrophages, chemotaxis and phagocytosis IInnffeeccttiioonnss wwiitthh ggrraam
m--nneeggaattiivvee, rod-shaped
and interferon gamma production. bacteria, notably Escherichia coli, Klebsiella
species (e.g., pneumoniae) and Pseudomonas
Even in the absence of any evidence-based aeroginosa, occur with increased frequency
data on a direct relationship between these in asplenic patients and are often associated
alterations and the development of severe with high mortality. Other gram-negative
infections in thalassaemia, it is recognised by organisms have also been implicated in post-
treating physicians through clinical splenectomy sepsis.
observations and practice that several factors
linked to the disease, its complications and PPrroottoozzooaann iinnffeeccttiioonnss due to Babesia have
treatment may facilitate or aggravate the been implicated in a fulminant haemolytic
severity of infections. febrile state in splenectomised patients, and
Maallaarriiaa iiss rre
M eppe
eaatte
ed dllyy rre
eppo
orrtte
edd aass m
moorree sseevveerree
Where infection is suspected, the main in asplenic people with an increased risk of
causes to be considered include: death (Boone and Watters, 1995)
ñ Splenectomy; (for blood-borne infections see Table 2).
ñ Transmission of pathogens by blood
transfusion;
ñ Iron overload and
ñ Iron chelation. Iron overload
The role of iron load in
susceptibility to infection has
Splenectomy not yet been fully established in
The major long-term risk after clinical trials. It is clear, however,
splenectomy is overwhelming that a variety of micro-
sepsis. In older studies, the risk of post- organisms are more pathogenic
splenectomy sepsis in thalassaemia major is in the presence of iron
increased more than 30-fold in comparison
with the normal population (Singer, 1973).
overload.
Modern preventative measures (see below)
The best-described association between
have reduced this risk but the overall impact
bacterial infection, iron and iron chelators
of these measures is unclear.
involves Yersinia enterocolitica (see below).

107
Many other organisms, such as Klebsiella manifestations: erythema infectiosum or
species, Escherichia coli, Streptococcus fifth disease in children, mild to severe
pneumonia, Pseudomonas aeroginosa, aplastic crises and myocarditis. During
Legionella pneumophila and Listeria pregnancy severe foetal anaemia and
monocytogenes, have been shown to have myocarditis may lead to lethal non-immune
increased virulence in the presence of excess hydrops fetalis.
iron. On the other hand, phagocytic
efficiency, tested in vitro, is impaired in In patients with an already shortened red cell
patients with thalassaemia with iron overload lifespan (15-20 days) combined with anaemia
compared with individuals without due to haematological disorders such as
thalassaemia. spherocytosis, sickle-cell anaemia,
autoimmune haemolytic anaemia and
Several observations in vivo indicate that thalassaemia, B-19 infection may cause an
infections are more frequent or severe in acute, life-threatening red cell aplasia,
patients with iron overload either related to commonly referred to as “transient aplastic
genetic haemochromatosis or to crisis”. The cessation of erythropoiesis lasts
transfusions, as in thalassaemia. The role of for 5-7 days and haematologically
iron overload in aggrevating Mucormycosis in complicates chronic haemolytic anaemia. The
bone marrow transplanted patients has been condition is characterised by:
demonstrated.
ñ A variable fall in haemoglobin;
IIrro
onn cchheellaattoorrss ñ Disappearance of reticulocytes from
A potential risk of natural siderophores, as in peripheral blood (< 0.2%);
deferoxamine, is that they may be used by ñ A virtual absence of red blood cell
micro-organisms as a source of iron, and so precursors in the bone marrow at the
become more virulent. This has been beginning of the crisis and
demonstrated in vitro and in vivo for Yersinia ñ B-19 DNA viraemia.
enterocolitica, which has a receptor on the
outer membrane that efficiently binds Following recovery from an acute B-19
ferrioxamine. infection, patients are typically immune to
further infections by the agent. Where
A clear relationship between Mucormycosis patients are immunosuppressed (e.g.
and desferrioxamine has been reported in transplanted, HIV-infected) and fail to mount
dialysis patients but only sporadically in an effective antibody response to the virus,
thalassaemia. Similar observations have been the infection may be persistent and may
reported for Rhizopus infections. mimic or trigger autoimmune inflammatory
Specific infections disorders.

B-19 may be transmitted via the respiratory


Viral Infections system or blood derivates. The incidence of
B-19-infected individuals with persistently
Huum
H maann PPaarrvvoovviirruuss BB--1199 ((HHPPVV BB1199)) detectable levels of B-19 DNA, despite the
Parvovirus B-19 is a common pathogen that presence of specific IgG, is estimated at 1%
may cause a wide range of clinical of blood donors. The resulting risk of

108
infection is estimated at between 1/625 and policies addressing the problem, as well as on
1/50,000, depending on a number of factors the local prevalence of blood transmissible
(including detection methods, seasonal pathogens.
outbreaks, B-19 DNA load of the donor and
co-presence of B-19 IgG antibodies) (Lefrere, With the use of standard
Maniez-Montreuil et al, 2006). There is procedures for prevention, it is
currently no general rule on action to be possible to keep the risk of HIV
taken to prevent blood-borne transmission of transmission very low; with the
B-19 in high-risk populations, including use of the most sensitive
thalassaemia major patients. screening measures, it is
possible to lower this risk still
Management of acute B-19 crises includes further.
close monitoring and adequate blood
transfusion adjustment. Immunoglobulin Naattuurraall hhiissttoorryy
N
administration may be beneficial in chronic In the absence of treatment, the median
illness. time from HIV seroconversion to the onset of
AIDS in transfused patients is about 7-11
years. Factors affecting progression are
Human symptomatic primary infection, age at
infection and viral load (HIV1-RNA
Immunodeficiency concentration in plasma).
Virus (HIV) Maannaaggeem
M meenntt ooff HHIIVV iinn tthhaallaassssaaeem
miiaa
RRiisskk ooff ttrraannssffuussiioonn--aassssoocciiaatteedd A detailed account of the treatment and
iinnffeeccttiioonn monitoring of HIV patients is beyond the
scope of this book. Patients with
Although sensitive and specific laboratory
thalassaemia identified with HIV infection
serologic tests became available soon after
should be managed in collaboration with an
the discovery and description of HIV, a
infectious diseases’ unit with expertise in HIV.
number of patients with thalassaemia who
Advances in drug treatment have
received transfusions previous to HIV
revolutionised the care of patients from
screening have been infected. Many more
strategies aimed at preparing patients to die
are still being infected in countries where
to treatments that may fully control the
effective protective measures for blood
disease. However, accessing the best—and
safety, including blood donor selection and
most expensive—treatment will depend on
testing, have yet to be applied.
local conditions.
The prevalence of HIV infection SSp
peecciiaall ccoonnssiiddeerraattiioonnss iinn tthhaallaassssaaeem
miiaa
in thalassaemia varies greatly Although antiretroviral therapy should be
worldwide, from <1% to >20%. In Italy, administered to patients with thalassaemia
for example, the prevalence is currently 1.7%
major based on the same general guidelines
while in Cyprus it is 0.17%. The rate of HIV
used for other infected non-thalassaemic
infection as with other infections among
individuals, side effects such as endocrine
transfused patients depends on the timing of
dysfunction and diabetes could be more
introduction and quality of public health
significant.

109
Viirruusseess
V
enveloped HIV-1, HIV-2, HTLV-I, HTLV-II
CMV, HHV-6, HHV-8, EBV
HBV, HCV, HGV
non-enveloped HAV; parvo B19, TTV

Baacctteerriiaa
B
Gram-positive Staphylococcus epidermidis
Staphulococcus aureus
Coagulase negative stachylococci
Streptococcus viridans
Enterococcal species
Bacillus cereus
Gram-negative Yersinia enterocolitica
Pseudomonas fluorescens
Salmonella enteritidis
Citrobacter freundii
Serratia marcescens
Enterobacter cloacae
Coliform bacteria
Flavobacterium species

Prroottoozzooaa
P
Plasmodium vivax Trypanosoma cruci
Plasmodium falciparum Babesia microti
Plasmodium malarias Toxoplasma gondii
Plasmodium ovale Leishmania donovani

Otthheerrss
O
Treponema pallidum
Prions

Abbreviations in Table 2:
HIV: human immunodeficiency virus, HTLV: human T-cell leykaemia/lymphoma virus; CMV: cytomegalovirus,
HHV: human herpes virus; EBV: Epstein-Barr virus; HBV: hepatitis B virus; HCV: hepatitis A virus; parvo B 19:
parvovirus B19;TTV: transfusion-transmitted virus. Ref. A. Modell, ZLB Central Laboratory Swiss Red Cross,
Bern, Switzerland 2000.

Table 2: Transfusion transmitted pathogens

110
There is general agreement that a patient’s organ transplant recipients, CMV infection
iron status influences the outcome of HIV-1 constitutes a major, if not one of the most
infection. In HIV-infected patients with important causes of morbidity and mortality.
thalassaemia major, the rate of progression
of HIV was significantly faster in patients with Unlike the case with other infectious agents,
low level of chelation with deferoxamine and the presence of serum CMV IgG antibodies
higher serum ferritin concentrations. Further does not preclude infectiousness. It is
to the capacity to remove iron, iron estimated that approximately 2-12% of anti-
chelators, mainly deferiprone, show CMV positive healthy donors are infectious,
interesting antiviral properties in vitro, but i.e. can transmit the virus.
there is so far no evidence of a direct
antiviral effect. Optimal control of iron The increasing use of bone marrow
overload with iron chelation is therefore transplantation as a treatment for
recommended in HIV-positive patients with thalassaemia demands special attention to
thalassaemia and the choice of chelator the serological status of CMV. Prevention of
should take into consideration the above transmission through blood products is
data as well as the individual’s needs. effectively achieved by the use of anti-CMV
Because of an increased risk of neutropenia, negative donation, but this policy may be
deferiprone should be used with caution in applied only in special conditions, such as
such cases. stem cell transplantation, because exclusion
of CMV positive donors (50-75% of the adult
While there is no direct evidence that population are anti-HCMV positive) will affect
splenectomy facilitates the progression of significantly the national pool of blood
HIV infection, a decision to perform supply. As CMV is WBC-associated virus, the
splenectomy in an HIV-positive patient with widespread use of leucocyte filtration, in
thalassaemia should be made with extreme recent years recommended for all patients
caution. Of particular concern is the removal with thalassaemia, no matter what their
of an important fraction of T cells and the condition, constitutes an effective
potential for overwhelming infection in preventative measure.
immuno-compromised patients.

Bacterial infections
Human
Yersinia enterocolitica
Cytomegalovirus
Mechanisms of infection
(HCMV) The Yersinia organism is most commonly
transmitted by the ingestion of
Transfusion-associated CMV has a wide contaminated food, meat, milk or water,
clinical spectrum. In the immuno-competent although it is commensal in healthy
patient-host, it is usually sub-clinical or may individuals. On rare occasions it becomes
appear as an infectious mononucleosis-like virulent, crossing the intestinal membrane
syndrome. In the immuno-compromised and provoking life-threatening infections. The
host, however, such as bone marrow or best known factor predisposing the organism

111
to virulence is the availability of a large Post-infection sequelae include erythema
amount of iron, as is the case in severe iron nodosum and reactive arthritis, mostly in
overloaded patients or in those undergoing adults.
iron chelation with desferrioxamine (Vento,
Cainelli and Cesario, 2006), as described LLaab
boorraattoorryy ddiiaaggnnoossiiss
above. Specific culture conditions (at 22oC for 48
hours) are necessary to identify Yersinia
Transfusion-associated transmission of species and in this context, the treating
Yersinia enterocolitica may occur from physician should inform the laboratory of
apparently healthy donors, albeit rarely, as his/her suspicions in order to enable it to
the organism can survive and multiply under proceed to the correct culture conditions for
normal storage conditions (4oC). The blood and stool samples.
mortality rate among recipients of
contaminated blood is >50%. Serologic tests for Yersinia are problematic
because of the likelihood of cross-reactivity.
Clliinniiccaall m
C maanniiffeessttaattiioonnss However, a four-fold rise in IgG titres in serial
The clinical manifestations of Yersinia samples obtained 15 days apart may be
infection depend on the age and health of suggestive of recent infection. Overall, the
the host. While variable, these manifestations pickup rate for stool, blood culture and
are severe in over 80% of cases involving seroconversion is low. In some cases
patients with thalassaemia. Fever is the most diagnosis may only be made after obtaining
common presenting feature, often samples of affected tissue (e.g. gut, lymph
associated with abdominal pain and diarrhoea node).
or vomiting. Extra gastrointestinal
manifestations, such as acute respiratory TTrre
eaattm
meenntt
distress syndrome, arthralgia and skin rashes, The basic but most important point is that
are also sometimes seen. anyone involved in the care of a patient with
thalassaemia with the above-described
The most typical clinical picture is an ‘acute symptoms must be aware of the risk of
abdomen’ that mimics and may even be Yersinia infection and its management.
indistinguishable from acute Simple information leaflets issued by the
appendicitis/peritonitis, caused by treating centre and carried by the patient or
mesenteric lymphadenitis. It is important to parents of children may be of help, especially
have this critical point in mind, as the two when travelling.
conditions require a very different
antimicrobial approach. In the absence of a quick reliable laboratory
diagnosis, treatment must begin on the basis
The most dangerous condition is septicaemia, of clinical suspicion. In such cases, the
which, in the absence of specific antibiotics, following measures should be taken:
may be fatal in more than 50% of cases.

Complications may include abdominal,


hepatic or splenic abscess, intussusception,
nephritis, ileo-psoas abscess and meningitis.

112
ñ Stop iron chelation therapy infection by Campylobacter and
Chryseobacterium meningosepticum. Despite
immediately the in vitro data for micro-organisms such as
ñ Obtain suitable laboratory Listeria monocytogenes and Salmonella,
samples there is no in vivo evidence that the
ñ Commence antibiotic prevalence and severity of related infections
treatment immediately in thalassaemia is higher than in the non-
thalassaemic population.
Yersinia species are typically intracellular and
therefore antibiotics with good intracellular Klebsiella species
penetration are recommended. In mild Klebsiella infections in thalassaemia major
suspected cases, oral ciprofloxacin is the and even more in HbE/b-thal are associated
recommended first line treatment. In with high mortality and morbidity rates are
severely unwell patients, immediate occasionally reported in the literature. In a
parenteral therapy is mandatory with the large retrospective study including 160
same drug. I.v. trimethoprim- patients, the prevalence was reported to be
sulfomethoxazole or cephalosporins may be 7.5%, with a clinical spectrum including
added or used as an alternative. sinusitis, intracranial infection, meningitis,
septicaemia and pyogenic abscesses of the
It is generally advisable to continue liver, lung and kidney. Mortality rate was 16%,
antibiotics for at least two weeks after and permanent neurological sequelae 25%.
proven infection. Iron chelation should not Predisposing factors seemed to be iron
be restarted until the patient has been overload and liver function derangement
asymptomatic for over a week. Some (Chung et al, 2003).
patients relapse after restarting
desferrioxamine. Whenever possible, an Pseudomonas aeruginosa in
alternative chelator should be prescribed. In thalassaemia constitutes the most common
contrast to deferoxamine, the synthetic pathogen-related infection to the central
chelators, deferiprone and deferasirox do not venous catheter. It may cause severe
seem to trigger Yersinia enterocolitica infections such as meningitis (Wang, Lin et al,
virulence. 2003). Splenectomy seems to be the main
predisposing factor.

Other bacterial Melioidosis of the musculoskeletal system


caused by Pseudomonas pseudomallei has
infections been sporadically reported in thalassaemia.

Other micro-organisms that may cause Vibrio vulnificus is sporadically reported as


severe infections and should be seriously the cause of severe infections, including
considered in the management of unwell septicaemia, wound infections and meningitis
patients with thalassaemia include Klebsiella in patients with thalassaemia in South-East
species, Pseudomonas species, Vibrio Asia. Iron overload is likely to be the most
vulnificus, Escherichia coli, Salmonella species important predisposing factor.
and Mucor species. Recent papers also report

113
Escherichia coli is not reported as a have been observed in patients with
significant pathogen in thalassaemia major, thalassaemia (Krajaejun et al, 2006).
being clinically significant in patients with
HbE/‚-thalassaemia, as for Klebsiella. The disease has high rates of morbidity and
mortality and early diagnosis and prompt
Salmonella species initiation of effective treatment are
Many in vitro data suggest that patients with extremely important. The organism does not
thalassaemia, particularly those that are respond to antifungal agents. A vaccine has
splenectomised, have a decreased opsonic been recently developed which has
activity and phagocytic efficiency against demonstrated at this preliminary stage
Salmonella species. Overall, however, in vivo effectiveness in patients with thalassaemia.
the prevalence of Salmonella infections does (Krajaejun et al, 2006)
not seem higher than in normal subjects.
Common infections
Haemophilus influenzae
Thalassaemics appear to have a lower natural not related to
immunity to this microorganism, however
vaccine-induced immunity seems to be thalassaemia
effective.
Dengue
Haemorragic fever due to d de
enng
guue
e vi r a l
Fungi iin
nffe
eccttiio
onn is endemic in Southeast Asian
countries where thalassaemias are also
Mucor species common. In an uncontrolled study from
Mucormycosis or Zygomycoses are Thailand, dengue was reported to be
opportunistic fungal infections caused by frequent and more severe than expected in
ubiquitous organisms of the Zygomycetes patients with thalassaemia, underscoring the
class. The relationship with conditions of iron need for providing special awareness of
overload and deferoxamine use is well proper diagnosis and management,
known. particularly in these regions of the world.

In thalassaemia, severe infections have been Helicobacter pylori


observed only in immunocompromised In one study of patients with thalassaemia
subjects after stem cell transplantation. with recurrent abdominal pain, the
prevalence of H. pylori infection was not
Pythiosum insidiosum statistically different from matched non-
Pythiosis is caused by the oomycete thalassaemic healthy subjects.
Pythium insidiosum. Human pythiosis has
been reported in Thailand among
farmers and their relatives although
zoonosis is prevalent in many other
parts of the world. The most
severe forms (cutaneous, vascular
and disseminated pythiosis)

114
Malaria and ∆ransfusion-related
thalassaemia Malaria and Chaga’s
There is evidence that in most cases, being a disease
healthy carrier of a haemoglobinopathy
provides protection against the clinical Post-transfusion malaria and Chaga’s disease
severity of malaria. have been known for more than 50 years.
Plasmodium species and Trypanosoma cruzii
However, the same is not true for the may remain viable for at least two weeks in
homozygous state. Patients with ‚- refrigerated blood components as well as in
frozen plasma, and in this context, there are
thalassaemia major or great concerns that increased tourism to and
intermedia are not protected from endemic countries might increase the
from severe malaria and may frequency of transfusion-transmission of
indeed be more prone to severe these pathogens. Both infections remain an
forms of the disease, depending important topic for blood transfusion
services, and national standards including
on their clinical condition donor selection have been drawn up based
(anaemia, splenomegaly, iron on WHO, Council of Europe, EU and North
overload and other American Authorities’ recommendations, in
complications). Patients must order to prevent or minimise the
therefore be provided with transmission of these diseases.
specific advice for the
prevention of malaria before
and during periods of travel in
endemic areas.

115
Splenectomy in
‚-thalassaemia

Many patients with thalassaemia major splenomegaly causes concern about


require splenectomy. However, optimal possible splenic rupture.
clinical management from the time of
diagnosis may delay or even prevent ñ Leucopenia or thrombocytopenia due to
hypersplenism, thereby increasing the hypersplenism causes clinical problems
efficiency of transfusion therapy and (e.g. recurrent bacterial infection or
reducing the need for splenectomy. bleeding).
Throughout the care of the patient with
thalassaemia, the size of the spleen should Splenomegaly due to periods of under-
be carefully monitored on physical transfusion with blood of inappropriately low
examination and, as needed, by haemoglobin may be reversible. Before
ultrasonography. considering splenectomy in this situation, the
patient should be placed on an adequate
Splenectomy should be considered when: transfusion programme for several months
and then re-evaluated.
ñ Annual blood requirements exceed 1.5
times those of splenectomised patients, It is generally advisable to delay
provided that they are on the same splenectomy until patients are
transfusion scheme and have no other
reasons for increased consumption. Such
at least five years old because
reasons include new alloantibodies, of the increased risk of
infection, and changes in the haematocrit overwhelming sepsis below this
of the transfused units. For patients age (see below).
maintaining a pre-transfusion Hb level of
about 10 g/dl, this increase in transfusion
requirements represents consumption of Surgery
more than 200-220 ml of red cells
(assuming haematocrit of transfused cells The two surgical techniques most commonly
is 75%)/kg/year (Modell, 1977; Cohen, employed for total splenectomy are the open
1980). The rate of iron overload should and laparoscopic approaches. The
also be taken into consideration. For laparoscopic approach requires a longer
patients who maintain effective chelation operative time and may not be practical for
therapy despite increased blood patients with very large spleens, but the
requirements, splenectomy may be recovery period is shorter and there is
unnecessary. For patients with increasing virtually no surgical scar. Many surgeons now
iron stores despite good chelation have extensive experience with this
therapy, reduction in the rate of approach.
transfusional iron loading by splenectomy
may be an important component of the In some centres, p
paarrttiiaall ssp
plle
enneeccttoom
myy is used
overall management of iron overload. to preserve some of the immune function of
the spleen while reducing the degree of
ñ Splenic enlargement is accompanied by hypersplenism (De Montalembert, 1990). The
symptoms such as left upper quadrant long-term success of this approach is still
pain or early satiety. Massive undergoing evaluation. In particular, the

116
likelihood of splenic re-growth and the thrombotic tendency, special consideration
volume of splenic tissue required to preserve should be given to the use of low-dose
immune function are two questions aspirin (80 mg/kg/d) for patients with high
outstanding. Any surgery on the spleen platelet counts, or the use of anticoagulation
should include a careful search for accessory for patients with a history of previous
spleens. thrombosis or other risk factors.

Reduction of splenic tissue by e


emmb
boolliissaattiio
onn is The major long-term risk after splenectomy is
a less invasive approach to hypersplenism overwhelming sepsis. In older studies, the risk
than complete or partial surgical of postsplenectomy sepsis in thalassaemia
splenectomy (Pringle, 1982). However, this major is increased more than 30-fold in
approach has not gained wide acceptance comparison with the normal population
and may be complicated by fever, significant (Singer, 1973). Modern preventative
pain and the possible need for a subsequent measures (see below) have reduced this risk
total splenectomy. Embolisation does not but the overall impact of these measures is
permit a search for accessory spleens. unclear. The pathogens most commonly
associated with postsplenectomy sepsis are
An evaluation for gallstones should be encapsulated organisms (Pedersen, 1983),
performed prior to surgery, especially if the particularly:
patient has experienced symptoms
suggestive of biliary tract disease. In some ñ Streptococcus pneumoniae (accounting
cases, positive findings will lead to for more than 75% of documented
cholecystectomy at the same time as bacterial infections in asplenic patients)
splenectomy. Removal of the appendix at the ñ Haemophilus influenzae
time of splenectomy may prevent later ñ Neisseria meningitidis
problems in distinguishing infection with
Yersinia enterocolitica from appendicitis. Infections with gram negative, rod-shaped
Splenectomy also provides a good bacteria, notably Escherichia coli, Klebsiella
opportunity for a liver biopsy to assess the and Pseudomonas aeroginosa, occur with
liver histology and iron concentration. increased frequency in asplenic patients and
are often associated with high mortality.
Appropriate immunisations Other gram-negative organisms have also
should be administered at least been implicated in postsplenectomy sepsis.
2 weeks before splenectomy Protozoan infections due to Babesia have
(see below). been implicated in a fulminant haemolytic

Coom
mpplliiccaattiioonnss ooff sspplleenneeccttoom
myy
febrile state in splenectomised patients.
C Malaria is reportedly more severe in asplenic
Peri-operative complications include people (Boone, 1995) and carries an
bleeding, atalectasis and subphrenic abscess. increased risk of death.
Postoperative thrombocytosis is common,
with platelet counts often reaching Characteristics of overwhelming post-
1,000,000-2,000,000/mm3. Because patients splenectomy sepsis include the sudden onset
with thalassaemia may have an increased of fever and chills, vomiting and headache.

117
The illness rapidly progresses to hypotensive (Landgren, Bjorkholm et al, 2004). The
shock, and is commonly accompanied by currently available pneumococcal vaccine is a
disseminated intravascular coagulation. 23-valent polysaccharide vaccine that can be
Postsplenectomy sepsis has many of the given subcutaneously or intramuscularly. A
features of adrenal haemorrhage conjugate vaccine will be available shortly.
(Waterhouse-Friederichsen syndrome). The The protection rate with the 23-valent
mortality rate for such infections is vaccine is 70-85%. Pneumococcal vaccine
approximately 50%, despite intensive should be given at least 2 weeks in advance
supportive measures. Therefore, early of a splenectomy and then in 3-5 years. The
intervention on the basis of clinical suspicion, immune response to this polysaccharide
even in the absence of many of the above vaccine is poor in children less than two years
findings, is critical. of age. Children vaccinated under the age of
two should be re-vaccinated at age two.
The risk of overwhelming postsplenectomy Patients who underwent splenectomy
infection varies with: without being given pneumococcal vaccine
may still benefit from vaccination post-
ñ Age—risk is very high in children <2 years splenectony.
of age. However, fulminant bacteraemia
has been reported in adults as much as If not administered as part of routine
25-40 years after splenectomy. childhood immunisations, Haemophilus
ñ Time since splenectomy—the greatest risk influenzae vaccine should be given to
appears to be in the period 1-4 years patients before they undergo splenectomy
after surgery and should also be given to splenectomised
ñ Immune status of patient patients (Spoulou, Tsoumas et al, 2006).

Meningococcal polysaccharide vaccine should


Preventative also be administered to patients who are
undergoing splenectomy and to non-
measures immunised, previously splenectomised
patients.
The three types of protective measures a
physician can utilise to prevent post- These vaccines can be given at the same
splenectomy sepsis include: time in different syringes at different sites.
Yearly administration of influenza virus
1. Immunoprophylaxis vaccine is recommended to prevent this
2. Chemoprophylaxis febrile illness that might otherwise require
3. Patient education intensive evaluation and management of a
febrile episode in the splenectomised host
with thalassaemia (see below).
Immunoprophylaxis
Vaccination against Streptococcus
pneumoniae is a critical step in preventing
overwhelming infection after splenectomy

118
febrile illnesses and seeking immediate
Chemoprophylaxis medical attention. For all febrile episodes,
the physician should strongly consider:
Chemoprophylaxis with oral penicillin, 125
mg b.i.d. for children under two years, and
Evaluating the patient, including a
250 mg b.i.d. for children two years and over
complete physical examination
is recommended to reduce the risk of post-
splenectomy sepsis. Alternative antibiotics for Obtaining blood and other cultures as
patients unable to take penicillin include indicated.
amoxicillin, trimethoprim-sulfomethoxazole Beginning treatment with an
and erythromycin. All splenectomised antimicrobial regimen effective against
children under five years of age should be Streptococcus pneumoniae and Neisseria
treated with prophylactic antibiotics. The meningitidis.
value of chemoprophylaxis after this age is
unproven. Some clinicians continuously treat If bacteraemia is suspected, the patient
all splenectomised patients with prophylactic should be treated with parenteral antibiotics
antibiotics, irrespective of age, while others and observed in a medical facility until the
treat patients whose spleens are removed cultures are evaluated.
after the age of five years only for the first
two years after splenectomy. The use of Patients also need to be made aware of the
prophylactic antibiotics will need to be potential for travel-related infections such as
regularly re-evaluated as improved vaccines babesiosis and malaria, as well as the risk
become available and as new data regarding inherent in travel to an area where medical
antibiotic-resistant bacteria are developed. care is not readily accessible. In the latter
case, an appropriate antibiotic should be
The importance of compliance with made available for the patient to carry with
prophylactic antibiotics should be stressed him/her.
repeatedly to patients and parents. However,
the limitations of antibiotic prophylaxis must Patients should be reminded always to alert
also be emphasised. Patients and parents consulting physicians about their
should recognise that chemoprophylaxis does splenectomised status.
not prevent all cases of post-splenectomy
sepsis: the risk of death from febrile illnesses Other complications which have been
remains, and rapid evaluation of febrile recognized in splenectomised patients
episode is essential (see below). include:
ñ Thrombophilia
ñ Pulmonary hypertension
Education
T hr om b o p h i l i a
Thrombophilia- this is a complication
Patient and parent education can be highly which occurs more frequently in thalassaemia
effective in preventing overwhelming post- intermedia (see relevant chapter), but a
splenectomy infection. Physicians should higher risk is seen in splenectomised patients.
emphasise to the patient and parents the The phenomenon of increased coagulability is
importance of recognising and reporting related to the fact that damaged red cells

119
normally removed by the spleen, persist in
the circulation and trigger mechanisms of
Thrombin generation (see Figure 2 Chapter
11: Thalassaemia Intermedia and HbE). In
postsplenectomy patients markers of
thrombin generation such as thrombin AT III
(TAT) complexes, prothrombin fragments
(F1,2) fibrinopeptide A (FPA) and D-dimer
should be assessed annually, and anti-
coagulant prophylaxis prescribed where
indicated.

P ul m on a r y h y p e r t e n s i on
Pulmonary hypertension – this
complication is more frequent in
thalassaemia intermedia, but it is also
increasingly identified in thalassaemia major,
especially in splenectomised patients.

120
Thalassaemia Intermedia
and HbE

Most TI patients are homozygotes or


Definition compound heterozygotes for ‚-thalassaemia,
meaning that both ‚-globin loci are affected.
The clinical phenotypes of thalassaemia The mild clinical characteristics of TI
intermedia (TI) lie between those of compared with thalassaemia major are
thalassaemia minor (heterozygous state) and primarily the result of the following three
major (homozygous state), although there is mechanisms:
substantial clinical overlap between the three
conditions. TI was first described in 1955 by ñ inheritance of a mild ‚+ mutation;
Rietti-Greppi-Micheli, who referred to ñ presence of a polymorphism for the
patients as being ‘too haematologically enzyme Xmn-I in the GÁ- promoter
severe to be called minor, but too mild to be region, associated with increased HbF;
called major’. and
ñ co-inheritance of ·-thalassaemia on the
Thalassaemia intermedia encompasses a wide ‚-globin locus.
clinical spectrum. Mildly affected patients are
completely asymptomatic until adult life, The phenotype of TI may also result from the
experiencing only mild anaemia and increased production of ·-globin chains,
maintaining haemoglobin levels between 7- occurring either by the triplication of ·
10g/dL. These patients require only genotype associated with ‚-heterozygosity,
occasional blood transfusions, if any. Patients or by the interaction of ‚- and ‰‚-
with more severe thalassaemia intermedia thalassaemia (Taher, Ismaeel and Cappellini,
generally present between the ages of 2 and 2006).
6 years, and although they are able to survive
without regular transfusion therapy, growth Analysis of the genotypes of patients with
and development can be retarded. The thalassaemia intermedia is important for an
clinical spectrum of thalassaemia intermedia early diagnosis of the milder disease, thus
indicates the need for an individualised avoiding unnecessary blood transfusions.
treatment approach. Despite the availability
of a number of treatment options, the lack Predicting phenotype from genotype in TI is
of clear guidelines can present a significant still difficult, due to the interaction of
clinical challenge (Taher, Ismaeel and genetic and environmental factors. Primary
Cappellini, 2006; Camaschella and Cappellini, genetic modifiers are the numerous genetic
1995). alleles at the ‚-chain locus, which can cause
either complete or marked reduction in ‚-
chain synthesis. Secondary genetic modifiers
Mechanism of TI are those that have a direct effect on
modifying the amount of excess ·-chains
The pathophysiology of thalassaemias is (inheritance of abnormal ·- or Á-chain
based on an imbalance of globin-chain genes). Tertiary modifiers are polymorphisms
synthesis. In the case of ‚-thalassaemia occurring at loci involved in bone, iron and
intermedia, the imbalance is greater than bilirubin metabolism that can affect clinical
that seen in ‚-thalassaemia trait and less than expression. Relevant environmental factors
that of ‚-thalassaemia major. include social conditions, nutrition and the

121
availability of medical care (Taher, Ismaeel preventing or delaying hypersplenism and
and Cappellini, 2006). reducing the risk of red cell antigen
sensitisation. Unfortunately, however, the
accurate identification of these two
Differential diagnosis phenotypes at the onset is remarkably
difficult. Nevertheless, a careful analysis of
Differentiation at presentation between clinical, haematological, genetic and
thalassaemia major and thalassaemia molecular data may allow a reasonable
intermedia is essential for designing conclusion for treatment (Taher, Ismaeel and
appropriate treatment for an individual Cappellini, 2006; Wainscoat, Thein and
patient. The accurate prediction of a mild Weatherall, 1987; Weatherall, 2001). (see
phenotype may avoid needless transfusions Table 1 for an outline of the major
and their complications, while the timely differences between thalassaemia intermedia
diagnosis of thalassaemia major will allow an and major).
early start to a transfusion programme, thus

Heellppffuull cclluueess iinn ddiiffffeerreennttiiaattiinngg bbeettwweeeenn tthhaallaassssaaeem


H miiaa m
maajjoorr aanndd
tthhaallaassssaaeemmiiaa iin
ntteerrm
meeddiiaa
Thalassaemia major Thalassaemia intermedia
more likely more likely
CClliinniiccaall
Presentation (years) <2 >2
Hb levels (g/dl) 6-7 8-10
Liver/ spleen enlargement Severe Moderate to severe

HHaaeem
maatto
ollooggiiccaall
HbF (%) >50 10-50 (may be up to 100%)
HbA2(%) <4 >4

GGeenneettiicc
Parents Both carriers of high One or both atypical carriers:
HbA2 ‚-thalassaemia - High HbF ‚-thalassaemia
- Borderline HbA2

Mo
M olle
eccu
ullaarr
Type of mutation Severe Mild/silent
Coinheritance of No Yes
·-thalassaemia.
Hereditary persistence of No Yes
fetal haemoglobin
‰‚ thalassaemia No Yes
GÁ XMN1 Polymorphism No Yes

Table 1

122
degree of ineffective erythropoiesis is the
Pathophysiology of primary determinant of the development of
anaemia, while peripheral haemolysis of
Thalassaemia mature red blood cells and an overall
reduction in haemoglobin synthesis are
Intermedia (TI) secondary determinants.

Three main factors are responsible for the


clinical sequelae of thalassaemia intermedia:
ineffective erythropoiesis, chronic anaemia
Complications and
and iron overload. The severity of clinical
sequelae depends primarily on the underlying
management of TI
molecular defects. a-chains are highly In addition to the defining symptoms of
unstable and precipitate into erythroid thalassaemia intermedia, which are seen to a
precursors in the bone marrow, causing lesser or greater extent in other forms of
membrane damage and cell death (i.e. thalassaemia, patients with thalassaemia
ineffective erythropoiesis). Hypertrophy of intermedia experience a number of specific
erythroid marrow in medullary and complications that are rare in thalassaemia
extramedullary sites, a consequence of major. Figure 1 highlights the multitude of
severe ineffective erythropoiesis, results in complications in untreated thalassaemia
characteristic deformities of the skull and (Taher, Ismaeel and Cappellini, 2006;
face and may also cause cortical thinning and Cappellini, Cerino et al, 2001).
pathological fractures of long bones. The

Figure 1: Pathophysiological sequelae of untreated thalassaemia and corresponding clinical


manifestations

123
Splenomegaly and Extramedullary
Splenectomy haematopoiesis
Splenectomy is now uncommon and is mainly Extramedullary haematopoiesis is a
performed late in life. The main indications compensatory mechanism where bone
for splenectomy in thalassaemia intermedia marrow activity increases in an attempt to
are a significant enlargement of the spleen overcome the chronic anaemia of
and a decrease in mean haemoglobin levels thalassaemia intermedia, leading to the
in the absence of other transient factors formation of erythropoietic tissue masses
such as infection (Taher, Ismaeel and that primarily affect the spleen, liver, lymph
Cappellini, 2006; Cappellini, Cerino et al, nodes, chest and spine. These masses can be
2001; Borgna-Pignatti, Rigon, Merlo et al, detected by magnetic resonance imaging
2003; Galanello, Piras, Barella et al, 2001). As (MRI). They may cause neurological problems
for the type of surgery, the laparoscopic such as spinal cord compression and
approach is safe and feasible and preferred paraplegia, and intra-thoracic masses.
over open surgery, as a minimally invasive
alternative that may become the treatment In case of spinal cord compression, clinical
of choice in ‚-thalassaemia patients who awareness is crucial for early diagnosis and
require concurrent operations. During prevention of irreversible neurological
splenectomy, surgeons should assess the complications. MRI is the radiological method
gallbladder for any stones and perform of choice for diagnosing extramedullary
cholecystectomy whenever gallstones are haematopoietic masses and for delineating
found (Leandros et al, 2006). the extent of spinal cord involvement.

Management includes transfusion therapy, as


Gall stones and well as radiotherapy and hydroxyurea (Taher,
Ismaeel and Cappellini, 2006; Chehal, Aoun,
cholecystectomy Koussa et al, 2003; Castelli, Graziadei, Karimi
and Cappellini, 2004; Saxon, Rees, Olivieri,
Gallstones are much more common in 1998). Hypertransfusion is a promising
thalassaemia intermedia than in thalassaemia treatment method, targeting at higher Hb
major as a result of ineffective erythropoiesis levels, involving many blood transfusions
and peripheral haemolysis. Similar to over a period of weeks to compensate for
laparoscopic splenectomy, laparoscopic the demands of erythropoiesis.
cholecystectomy has more favourable and
feasible outcome than open cholecystectomy
(Taher, Ismaeel and Cappellini, 2006; Kidney stones
Cappellini, Cerino et al, 2001; Borgna-
Pignatti, Rigon, Merlo et al, 2003; Galanello, As a result of ineffective erythropoiesis and
Piras, Barella et al, 2001; Leandros et al, peripheral haemolysis TI patients are
2006). susceptible to kidney stones, which can lead
to hydronephrosis and kidney failure. The

124
cause is associated with hypertrophic stones supplementation can help accelerate the
that block the renal tubules and even the healing of ulcers. Hydroxyurea also has some
calyces. The kidneys are frequently enlarged benefit, either alone or in combination with
in thalassaemia, due to the presence of erythropoietin or platelet-derived growth
extramedullary haematopoiesis. factor. In addition, the use of an oxygen
chamber can provide moderate relief since
tissue hypoxia may be an underlying cause of
Leg ulcers the ulceration (Taher, Ismaeel and Cappellini,
2006; Gimmon, Wexler and Rachmilewitz,
Leg ulcers are more common in older rather 1982).
than younger patients with thalassaemia
intermedia. It is unclear why ulcers develop.
However, once an ulcer has started to Thrombophilia
develop it is very painful and difficult to cure,
although regular blood transfusions may Patients with thalassaemia intermedia have
provide some relief in persistent cases. Zinc been shown to have an increased

Figure 2: Thrombotic mechanism in thalassaemia intermedia

125
predisposition to thrombosis compared with which is thought to be the primary cause of
thalassaemia major patients. Such events congestive heart failure in this patient
mainly occurred in the venous system and population (Aessopos, Farmakis, Karagiorga et
comprised deep vein thrombosis (40%), al, 2001). The mechanism underlying
portal vein thrombosis (19%), stroke (9%), pulmonary hypertension in thalassaemia
pulmonary embolism (12%) and others (20%). intermedia is unclear.
Moreover, splenectomised patients have
been shown to have a higher risk of As anaemia and iron overload are uncommon
thrombosis than non-splenectomised in well-transfused and chelated thalassaemia
patients (Cappellini, Robbiolo, Bottasso et al, major patients, the two conditions are likely
2000). (See Figure 2 for more on the to be at the root of the pathophysiology of
thrombotic mechanism in thalassaemia pulmonary hypertension. Regular transfusion
intermedia.) and iron chelation therapy is therefore
indicated in thalassaemia intermedia patients
Management of thrombophilia has two arms: who are well-stratified according to the early
prevention and treatment. Prevention detection of pulmonary hypertension indices.
consists of proper anticoagulation prior to Sildenafil has also been successfully used to
any surgical or other high-risk procedure. treat pulmonary hypertension, although data
Treatment entails the adequate use of from large patient numbers are lacking in
anticoagulation according to the thalassaemia intermedia (Taher, Ismaeel and
recommendations for hypercoagulable Cappellini, 2006; Aessopos, Farmakis,
states. Awareness is important since Karagiorga et al, 2001; Aessopos, Farmakis,
thromboembolism plays an important role in Deftereos et al, 2005).
pulmonary hypertension and right heart
failure (Taher, Ismaeel and Cappellini, 2006;
Taher, Ismaeel, Mehio, Bignamini et al, 2006; Hepatitis
Eldor, Rachmilewitz, 2002; Cappellini,
Robbiolo, Bottasso et al, 2000; Taher, Abou- Hepatitis due to viral (B and C) infection is
Mourad, Abchee et al, 2002). less frequent in thalassaemia intermedia than
in patients with thalassaemia major, since
blood transfusions are much less common in
Pulmonary thalassaemia intermedia. Abnormal liver
enzymes (increased alanine and aspartate
hypertension and aminotransferase) are frequently observed in
patients with thalassaemia intermedia,
congestive heart primarily due to hepatocyte damage resulting
from iron overload. Normalisation of liver
failure enzyme levels is often observed during
appropriate chelation therapy (Taher, Ismaeel
Pulmonary hypertension (PHT) is prevalent in and Cappellini, 2006; Cappellini, Cerino,
patients with thalassaemia intermedia. In a Marelli and Fiorelli, 2001).
study of 110 thalassaemia intermedia
patients (60.9% untransfused or minimally
transfused), 59.1% were shown to have PHT,

126
However, the mechanism involved in TI is
Endocrine function increased absorption from the gut rather
than blood transfusions. The resulting iron
Hypogonadism, hypothyroidism and diabetes overload can lead to a number of serious
mellitus are quite rare in thalassaemia complications, including cardiac failure and
intermedia. Although patients with endocrine abnormalities such as diabetes
thalassaemia intermedia generally experience mellitus and hypogonadism (Taher, Ismaeel
puberty late, they have normal sexual and Cappellini, 2006; Weatherall, 2001).
development and are usually fertile.
Hypothyroidism is sometimes observed late in Initiation of iron chelation depends on the
life (Taher, Ismaeel and Cappellini, 2006; amount of excess iron, rate of iron
Cappellini, Cerino, Marelli and Fiorelli, 2001). accumulation, and duration of exposure to
excess iron. Increased levels of liver iron
concentration (LIC) have been observed with
Pregnancy in TI small increases in serum ferritin (Fiorelli,
Fargion, Piperno et al, 1990). Thus, direct
Women with thalassaemia intermedia may assessment of LIC by biopsy or MRI is
have spontaneous successful pregnancies, recommended. Chelation therapy should be
although complications during pregnancy initiated if LIC ≥ 7 mg/g dry weight of liver
may occur. The chronic anaemia of (Taher, Ismaeel and Cappellini, 2006).
thalassaemia intermedia can cause an
increase in spontaneous abortions, pre-term
labour and intrauterine growth retardation,
while endocrine complications due to
Osteoporosis
( a l s o s e e c h a p t e r o n o s t e op o ro s i s )
haemosiderosis are common.
Folic acid deficiency is common in
There is a high incidence of osteoporosis of
thalassaemia intermedia and occurs due to
the spine and hip in both sexes in
poor absorption, low dietary intake or, most
thalassaemia intermedia. The severity
significantly, an increased demand for folic
increases with age and even young patients
acid from active bone marrow. During
exhibit a spinal bone mineral density far
pregnancy, women with thalassaemia
below that of age-matched controls.
intermedia should be given oral folic acid
Management consists of bisphosphonates
supplementation (around 1 mg/day), and
and calcium supplementation with follow up
should be carefully monitored in order to
bone-mass densitometries (Origa, Fiumana et
assess the need for transfusion therapy and
al, 2005).
to avoid haemodynamic compromises (Taher,
Ismaeel and Cappellini, 2006; Nassar,
Rechdan, Usta and Taher, 2006).
Pseudoxanthoma
Iron overload elasticum (PXE)
PXE is a rare hereditary connective tissue
Just as in thalassaemia major, TI patients are
disorder, characterised by generalised
susceptible to complications of iron overload.
degeneration of the elastic fibres with a

127
broad phenotypic expression. The clinical
picture consists mainly of cutaneous, ocular Transfusion therapy
and vascular manifestations; skin
histopathology involves swollen, irregularly and iron chelation
clumped and multiply-fragmented elastic
fibres in the middle and deep reticular Although transfusion therapy is not currently
dermis, with secondary calcium deposition. a routine treatment approach for patients
This condition has been described as with thalassaemia intermedia, it can afford
occurring in Ùhalassaemia. significant benefits. The decision to initiate
therapy should be based on the presence
and severity of signs and symptoms of
anaemia, including failure of growth and
Management of development. As the rate of iron loading is
variable in thalassaemia intermedia, an
thalassaemia assessment of liver iron concentration is
advisable before initiating transfusion
intermedia therapy. Patients with thalassaemia
intermedia may benefit from an individually
There are a number of options currently tailored transfusion regimen, compared with
available for managing patients with the regular transfusion regimens
thalassaemia intermedia, including implemented in thalassaemia major, to help
splenectomy, transfusion therapy, prevent transfusion-dependency.
modulation of fetal haemoglobin production Alloimmunisation is a relatively common
and bone marrow transplantation (Taher, observation in thalassaemia intermedia,
Ismaeel and Cappellini, 2006; Cappellini, although the risk is decreased if transfusion
Cerino, Marelli and Fiorelli, 2001). therapy is initiated before the age of 12
months (Pippard, Callender, Warner and
Weatherall, 1979; Mourad, Hoffbrand, Sheikh-
Splenectomy Taha et al, 2003; Cappellini, 2005).

Splenectomy is no longer a major mode of Transfusions are indicated where the


management. However, the main indications following are observed:
for splenectomy include growth retardation ñ failure to thrive in childhood in the
or poor health, leucopenia, presence of significant anaemia;
thrombocytopenia, increased transfusion ñ emergence of bone deformities;
demand and symptomatic splenomegaly. ñ increasing anaemia not attributable to
rectifiable factors;
Splenectomy before the age of 5 carries a ñ evidence of a clinically relevant tendency
high risk of infection and is therefore not to thrombosis;
generally recommended. ñ presence of leg ulcers;
ñ development of pulmonary hypertension;
ñ delayed or poor pubertal growth spurt
and
ñ progressive splenic enlargement.

128
eligible for transplantation is complex and is
Modulation of fetal related to both quality of life and expected
survival time of the transplanted patient. This
haemoglobin is particularly relevant in patients with
thalassaemia intermedia, especially in those
production who are only mildly affected. In stable
asymptomatic TI patients who do not require
Increasing the synthesis of fetal haemoglobin transfusions, bone marrow transplantation is
can help to alleviate anaemia and thereby not needed.
improve the clinical status of patients with
thalassaemia intermedia. Agents including
cytosine arabinoside and hydroxyurea may
alter the pattern of erythropoiesis and
Recommendations
increase the expression of Á-chain genes.
Erythropoietin has been shown to be
for the management
effective, with a possible additive effect in
combination with hydroxyurea. Butyrates are
of thalassaemia
a further experimental category, still
unlicensed and with difficult intake. Good
intermedia
responses have been reported; however, Two major issues regarding the management
most patients complain of the difficulty of of thalassaemia intermedia are 1) the
intake orally and intravenously. Further approach and management of complications
clinical evaluation is required to clarify the in adult thalassaemia intermedia patients and
value of this approach (Taher, Ismaeel and 2) preventing such complications in younger
Cappellini, 2006; Karimi, H. Darzi, M. Yavarian, patients. A stratification of the management
2005; Dettelbach and Aviado, 1985; Dixit, of TI between adults and young patients has
Chatterjee, Mishra et al, 2005; Perrine, therefore been established.
Ginder, Faller et al, 1993; Cappellini,
Graziadei, Ciceri et al, 2000; Olivieri, Rees, The scheme for adult thalassaemia
Ginder et al, 1997). (For more details, see intermedia patients is as follows:
Chapter 13: Alternative approaches to the ñ each patient to be reviewed separately
treatment of thalassaemia.) and stratified by risk;
ñ hydroxyurea introduced as a suitable
initial approach;
Bone marrow ñ transfusion and iron chelation therapy
with deferoxamine subcutaneous infusion
transplantation and concomitant steroids for protection
from alloimmunisation are essential;
Bone marrow transplantation is an ñ aspirin for stroke prevention, post-
established treatment for ‚-thalassaemia. splenectomy and life-long anticoagulation
Although marrow transplantation can lead to in patients with a history of thrombotic
cure, the degree of its success depends events is a must;
primarily on the health and age of the ñ liver MRI assessment of iron
patient. The decision as to which patients are concentration (or liver biopsy if MRI is

129
unavailable) is important to determine
liver iron status for future chelation. Definition of ‚-
There are no clear guidelines for the thalassaemia/HbE
management of thalassaemia intermedia in
the young. Thus, the authors recommend Haemoglobin E has the clinical phenotype of
the following: a mild form of ‚-thalassaemia, and is most
ñ a guarded approach to the need for frequent in southeast Asia, particularly
splenectomy and delay in initiating eastern Thailand and Laos. The combination
transfusion unless considered necessary of HbE with ‚-thalassaemia spans
based on the above mentioned thalassaemia phenotypes, from a condition
indications; indistinguishable from thalassaemia major to
ñ early initiation of transfusion and iron a mild form of thalassaemia intermedia (TIF,
chelation therapy if there is evidence of 2002; Premawardhena et al, 2005).
growth abnormalities, poor performance
at school or a psychological impact Clinically, ‚-thalassaemia/HbE may be
secondary to facial deformities; classified into three categories, each of
ñ regular follow-up with echocardiodoppler which has its own unique clinical
for cardiac complications and initiation of management requirements:
therapy at earlier disease onset to
prevent progression;
ñ regular follow up of liver iron Mild ‚-
concentration with MRI or liver biopsy;
ñ discourage smoking, prolonged thalassaemia/HbE
immobilisation and the use of oral
contraceptives or an intrauterine device. Mild ‚-thalassaemia/HbE patients do not
require treatment and rarely develop clinical
See Table 2 for indications for transfusion problems. Haemoglobin levels may be as high
and splenectomy. as 9-12 g/dl. Care should be taken not to

Indications for transfusion Indications for splenectomy


Growth failure or poor performance at school Growth retardation or poor health
Transient stressful conditions Leukopenia
(e.g.pregnancy, infection)
Symptomatic anaemia Thrombocytopenia
CHF+PHT Increased transfusion demand
Leg ulcers Symptomatic splenomegaly

(Taher, Ismaeel and Cappellini, 2006)

Table 2: Indications for transfusion and splenectomy in thalassaemia intermedia

130
confuse this group of patients with
individuals having iron deficiency or with Severe
carriers of ‚-thalassaemia, by careful
investigation of the red cell morphology, ‚-thalassaemia/HbE
including iron status and haemoglobin
electrophoresis (TIF, 2002; Premawardhena Patients present with the clinical symptoms
et al, 2005). of thalassaemia major, including defective
physical development, bone deformities
including facial changes, anaemia, jaundice
Moderately severe and hepatosplenomegaly. Haemoglobin levels
can be as low as 4-5 g/dl. The clinical
‚-thalassaemia/HbE management of this group of patients needs
to be addressed as in thalassaemia major
This group encompasses the majority of ‚- (TIF, 2002; Premawardhena et al, 2005).
thalassaemia/HbE patients. Most patients
have steady haemoglobin levels of 6-7 g/dl.
Clinically, these patients manifest symptoms Complications and
similar to thalassaemia intermedia and
normally do not require blood transfusions management of
unless they develop infections precipitating
further anaemia. Other complications such as ‚-thalassaemia/HbE
iron overload may occur in these patients.
Where this is the case, iron chelation therapy Complications in ‚-thalassaemia/HbE patients
should be initiated. Patients in this group depend on the category they belong to, as
often have a somewhat shortened lifespan, indicated above. The worst of the
but with careful monitoring and treatment complications occur in the severe group, in
can have an open-ended prognosis (TIF, which the clinical picture is similar to that ‚-
2002; Premawardhena et al, 2005). thalassaemia major. This includes the
multitude of problems brought about by iron
overload due to dependence on transfusions
(see sections on complications in ‚-
thalassaemia major for further explanation).

131
Stem Cell
Transplantation

Figure 1). Class II patients have an 87%


Outcome and patient probability of survival and an 83% chance of
disease-free survival, with a 3% risk of
selection rejection and a 15% risk of non-rejection
mortality (see Figure 2), while Class III
Bone marrow transplantation from HLA- patients have a 79% probability of survival
identical siblings has been increasingly and a 58% chance of disease-free survival,
adopted for the cure of with a 28% risk of rejection and a 19% risk of
haemoglobinopathies. Since 1981, a large non-rejection mortality (see Figure 3).
clinical experience has been gained with (Centres performing transplants in patients
more than 1,500 bone marrow transplants with broadly similar characteristics have
performed in centres around the world. Over shown comparable outcomes [Lucarelli
that time, a number of factors – the use of 1997].) In the case of Class III patients, the
cyclosporin, more effective treatment of introduction of conditioning regimens
cytomegalovirus infection, improved aseptic containing less than 200 mg/kg of
techniques and the evolution of systemic cyclophosphamide resulted in a significant
antibiotic therapy – have led to a remarkable decrease in transplant-related mortality, but
improvement in the outcome of bone with a concomitant increased risk of graft
marrow transplantation procedures (Lucarelli, rejection. Among adults (aged >16), the
1997). probability of surviving a bone marrow
transplant procedure is 66% with a 62%
Three patient classes have been probability of cure, a 35% chance of
identified on the basis of the transplant-related mortality and a 5% chance
following risk factors, which of returning to the pre-transplant
have been found to have a thalassaemic condition (see Figure 4).
significant influence on post- Based on these outcomes, bone
transplant outcome: marrow transplantation in
ñ inadequate iron chelation thalassaemia should be
therapy, considered for patients at an
ñ presence of liver fibrosis and early age or before
ñ hepatomegaly (Giardini, 1995) complications due to iron
overload have developed.
Patients in Class I have none of the above However, a final decision must
characteristics, patients in Class II have one or be based on an assessment of
two, and patients in Class III exhibit all three
characteristics.
the relative advantages and
disadvantages of bone marrow
Among Class I children with thalassaemia transplantation and
major transplanted early in the course of the conventional therapy, requiring
disease, the probabilities of survival and the physician, patient and family
disease-free survival are 93% and 91% to weigh the outcome and risks
respectively, with a 2% risk of rejection and of each.
an 8% risk of transplant-related mortality (see

132
There are several possible advantages to this
HLA-matched sibling approach. First, stem cells can be obtained
easily at birth, and often in sufficient
donors quantity for a successful donation – thus
avoiding the bone marrow harvest of a donor
The general applicability of bone marrow at a later age. Second, it has been suggested
transplantation is limited by the availability of that graft versus host disease (GVHD) may be
a related HLA-matched donor. There is a one- less severe when stem cells are obtained at
in-four chance that any given sibling will be this early point in life. Third, the routine
HLA identical, with the likelihood of a collection of cord blood stem cells from all
thalassaemic patient having an HLA identical births would provide a wider pool of donors
sibling donor varying according to family size. for BMT therapy.

However, the evidence of decreased GVHD


Matched unrelated using cord blood is not persuasive. And in
many cases, the quantity of stem cells
donor transplantation obtained is insufficient for engraftment in an
adult recipient. Thus, while cord blood
Because most patients with thalassaemia do transplantation has been successfully used to
not have a compatible sibling donor, there is treat some patients with thalassaemia
interest in using unrelated but otherwise (Miniero, 1998), its overall value in treating
matched donors. Unfortunately, the the condition has yet to be firmly
complication rates of transplants using established.
matched unrelated donors are generally
much higher than with sibling matched
transplants. It is hoped that with continuing
improvements in matching techniques,
Mixed chimerism
complication rates will be reduced to Persistence of residual host haematopoietic
acceptable levels. There has been some cells, normally termed mixed chimerism,
application of transplantation using matched frequently occurs after bone marrow
unrelated donors in thalassaemia, suggesting transplantation in ‚-thalassaemia (Andreani,
that if unrelated donors are from a closely 1996). Reduction of the dose of busulfan or
related genetic background the outcome cyclophosphamide in the conditioning
may be improved (Dini, 1999; Miano, 1998). regimens produced higher rates of mixed
Experience so far is limited, however. chimerism – a risk factor for graft failure.

None of the patients showing full donor


Cord blood engraftment rejected the transplant, while
29% of patients with mixed chimerism
transplantation rejected the graft within two years of
marrow infusion. Nevertheless, a condition of
The use of stem cells obtained from umbilical long-term (> 2 years) persistent mixed
cord blood collected at the time of delivery chimerism has been observed after
has recently received considerable interest. successful BMT in thalassaemia. This

133
observation may have a significant impact on
the design of future bone marrow transplant
strategies.

Post-transplant
follow-up
Post-transplant clinical follow-up
of BMT is particularly important.
Within the first year, careful
monitoring of haematological
and engraftment parameters,
infectious complications and
graft versus host disease is
essential.
Long-term follow-up is of particular interest
with respect to monitoring the evolution of
multi-system problems (iron overload,
pubertal development, growth, endocrine
deficiencies) related to the primary disease. A
number of reports indicate that iron
overload, chronic hepatitis, cardiac function
and endocrine deficiencies can be more
easily managed after transplant, sometimes
permitting the healing of damaged organs. It
is particularly important to remove excess
iron after transplant. This can usually be
achieved by repeated venesection (6 ml/kg
blood withdrawn at 14-day intervals)
(Angelucci 1997).

134
Figure 1: Kaplan and Meier probabilities of Figure 2: Kaplan and Meier probabilities of
survival, event-free survival, survival, event-free survival,
rejection and non-rejection rejection and non-rejection
mortality in 119 Class I thalassaemic mortality in 291 Class II
patients aged less than 17 years. thalassaemic patients aged less
than 17 years

Figure 3: Kaplan and Meier probabilities of Figure 4: Kaplan and Meier probabilities of
survival, event-free survival, rejection survival, event-free survival,
and non-rejection mortality in 126 rejection and non-rejection
Class III thalassaemic patients aged mortality in 115 adult thalassaemic
less than 17 years. patients (aged more than 16
years).

135
Alternative Approaches to the
Treatment of Thalassaemia

There is currently no definitive treatment for recovery from bone marrow suppression
any of the serious haemoglobin disorders, after the use of cytotoxic drugs, attention
other than bone marrow transplantation—an has focused on the possible role of cytotoxic
option available only to a small minority of agents as therapies in the treatment of
patients that have a suitable donor and are in serious haemoglobin disorders. Several
good clinical condition. Another, promising, cytotoxic agents that alter the pattern of
approach involves the use of therapeutics to erythropoiesis, favouring the expression of
definitively correct the globin chain foetal (Á)-globin genes and so increasing the
imbalance in ‚-thalassaemia, by re-activating number of red cells containing HbF (F-cells),
the foetal globin genes. have been explored over the past 20-25
years (Pace and Zei, 2006; Fathallah and
Atweh, 2006; Gambari and Fibach, 2007).
Modulation of fetal
TThhee ddeem meetthhyyllaattiinngg aaggeennttss 55--aazzaaccyyttiiddiinnee aanndd
haemoglobin ddeecciittaabbiinnee have been administered to a few
‚-thalassaemia patients with good responses,
Foetal haemoglobin is the predominant non- raising total haemoglobin levels by a mean of
· globin produced in humans until around six 2.5 g/dl above baseline and clearly
months of age, when it is typically prolonging the lives of end-stage patients
suppressed and the production of ‚-globin is (Lowrey, 1993; Dunbar, 1989; Ley, 1982). The
increased. This pattern is the norm even mutagenic potential and instability of
when the genes are mutated, as in ‚- formulations of 5-azacytidine have limited its
thalassaemia. investigation, but higher oral doses of
decitabine have been effective in baboons
Patients with ‚-thalassaemia who continue to (Lavelle, 2006), and studies are planned in
produce high levels of foetal globin, such as selected patients.
those with Hereditary Persistence of Foetal
Haemoglobin, have less globin imbalance and HHyyddrrooxxyyuurreeaa has been studied in HbE/ ‚-
less severe anaemia. thalassaemia patients, with lower responses
but reduced haemolysis (Fuchareon, 1996;
The therapeutic stimulation of Zeng, 1995). Hydroxyurea has been less
foetal globin could therefore beneficial in thalassaemia intermedia than in
sickle cell disease, in which the number of
benefit many patients, even painful crises was reduced and overall health
rendering some transfusion indicators improved. The lesser benefits in
independent. thalassaemia are perhaps due to the fact that
the cytostatic effects of hydroxyurea are
Several candidate therapies now offer the limited in the disease.
potential to correct or modulate the
underlying pathology. Otthheerr aaggeennttss
O
EErryytthhrrooppooeettiinnss ((EEPPOOss)) have increased
Cyyttoottooxxiicc aaggeennttss
C haemoglobin levels significantly in some
Following observations that foetal patients with thalassaemia intermedia, even
haemoglobin synthesis is reactivated during eliminating transfusion requirements in some

136
children. EPOs may thus be particularly (e.g. sodium 2,2-dimethybutyrate) (Boosalis,
helpful in patients with relatively low levels of 2001; review Perrine, 2005). Select
endogenous erythropoietin for their degree hydroxamic acid derivatives have had high
of anaemia (Bourantas, 1997; Nisli, 1996 and activity in transgenic mice (Cao and
1997; Rachmilevitz, 1998; Singer, 2003). EPO Stamatoyannopoulos, 2005).
promotes survival of red blood cells and may
counteract the rapid cell death (apoptosis) The mechanisms by which short chain fatty
caused by precipitation of excess ·-globin acids stimulate Á-globin production are being
chains in ‚-thalassaemia (review Silva, 1996; elucidated. Some new derivatives displace a
Perrine, 2005). repressor complex and cause acetylation
specifically of the foetal globin gene
SSh
hoorrtt cchhaaiinn ffaattttyy aacciidd ddeerriivvaattiivveess promoter (Mankidy et al, 2006).
Short chain fatty acid derivatives induce PPhheennyyllbbuuttyyrraattee aanndd bbuuttyyrraattee cause general
activity from the foetal globin gene histone hyperacetylation, which inhibits cell
promoter, resulting in two-to-six-fold higher proliferation, and are counter-productive in
foetal globin mRNA in some patients, thalassaemia, requiring limited exposure
especially those who have at least one ‚0- (Pulse therapy). Butyrates have induced fetal
thalassaemia mutation and EPO levels >140 globin production in approximately two-
mU/ml (review Collins and Perrine, 2005). thirds of patients with diverse molecular
Their acceptable toxicity profiles add to their mutations and raised total haemoglobin
potential as long-term therapeutic agents. levels an average of 2-3 g/dl above baseline
when given intermittently to avoid anti-
Several preliminary trials with intravenous proliferative effects (review Perrine, 2005).
butyrate and oral phenylbutyrate compounds As differences in drug metabolism contribute
have shown increases in foetal and total significantly to responsiveness to any drug,
haemoglobin levels in patients with these will certainly apply in the highly diverse
thalassaemia intermedia, while a few thalassaemia syndromes (Wilkerson, 2005).
previously transfusion-dependent New generation agents which promote
thalassaemia major patients have been erythroid survival, and can be given daily,
maintained transfusion-independent on offer significantly more potential benefit
home therapy for 5-7 years. Isobutyramide than the first generation prototypes.
has induced foetal globin and reduced
transfusion requirements in thalassaemia Coom
C mbbiinnaattiioonn tthheerraappyy
intermedia and major (Cappellini, 2000; Although pharmacological induction of fetal
Reich, 2000). haemoglobin in transfusion-dependent
patients with thalassaemia will require high-
The most effective compound thus far is potency induction of foetal globin, weaning
arginine butyrate, although this has the of transfusions to allow renewal of patients’
disadvantage of requiring intravenous own erythropoiesis, adequately high EPO
infusion due to its rapid metabolism. Oral levels to promote eyrthroid cell survival and
derivatives that persist for many hours after iron availability for erythropoiesis, there is
a single dose and which also stimulate expectation that some of the agents, used in
erythroid cell proliferation and survival, combination or properly scheduled, could
similar to EPO, will enter clinical trials soon result in complimentary effects and render

137
even severe patients transfusion-
independent. For example, a demethylating
agent and butyrate had synergistic activity,
much higher than additive effects, in
experimental studies (Constantoulakis, 1989).
Such combinations offer excellent potential
for patients with diverse syndromes.

An approach to rational
combinations can now be based
on a patient’s baseline HbF,
total haemoglobin and EPO
levels (review Perrine, 2005).
Clinical trials should be planned
to find optimal drug
combinations for different
patient subsets.

138
Gene Therapy: Current
Status and Future Prospects

The idea of using gene therapy to treat the vector. The corrected cells are then returned
haemoglobinopathies (thalassaemia and sickle to the patient, who in the meantime has
cell disease) is, in principle, straightforward. undergone chemotherapy (as in a donor-
Red blood cells (RBC) are continuously derived bone marrow transplant) to partially
replenished by bone marrow haematopoietic or completely destroy their diseased bone
stem cells (HSC). Therefore, the stable marrow (Persons and Tisdale, 2004).
transfer of a normal functioning copy of a ‚-
globin therapy gene unit into the patient’s Early studies with LCR-‚-globin gene
own HSC would result in the generation of retroviral vectors based on the mouse MoLV
normal rather than diseased RBC for life. virus and using an ex vivo procedure in
(Note: no donor bone marrow is needed). animal models, provided good proof of
principle. However, it proved very difficult to
A number of major discoveries accommodate LCR-‚-globin gene units within
and technical advances in gene MoLV retroviral vectors and manufacture
them. In addition, the LCR-‚-globin therapy
therapy over the last 20 years, gene units that could be incorporated into
particularly since 2000, mean this vector system were ineffective at
that, at long last, gene therapy producing a consistent and sufficiently high
for the haemoglobinopathies level of ‚-globin protein to be of therapeutic
looks a serious possibility in the value (Antoniou and Grosveld, 1999).
However, a major breakthrough occurred in
not too distant future. 2000, when the laboratory of Prof Michel
Sadelain reported work involving the testing
In 1987, a group led by Prof Frank Grosveld
of an LCR-‚-globin therapy gene unit within a
discovered the master regulator of the ‚-
class of retrovirus known as an HIV lentiviral
globin gene family, known as the ‘locus
(LV) vector (Figure 1; May et al, 2000). Prof
control region’ (LCR). It was found that
Sadelain showed for the first time that the LV
linking the LCR to a ‚-globin gene unit
vector can readily accommodate a larger and
enables the gene to be efficiently and
more efficient version of the ‚-globin
reproducibly switched on, and to produce a
therapy gene linked to the three most
sufficiently high level of ‚-globin protein to
powerful LCR elements (HS2, HS3, HS4), and
be of therapeutic benefit, if reproduced in a
that application of this vector in an ex vivo
gene therapy context (Levings and Bungert,
bone marrow transplant procedure could
2002; Stamatoyannopoulos, 2005).
completely cure or rescue the ‚-thalassaemia
condition in mouse models of this disease
The stable introduction of the LCR-‚-globin
(May et al, 2000; Rivella et al, 2003).
therapy gene unit into the patient’s HSC is
via a retrovirus delivery vector, resulting in
Since then, a number of groups in the US
the permanent splicing or integration of the
and Europe have built their own versions of
therapy gene into the HSC DNA, which is
the LCR-‚-globin gene LV vector (Persons and
then retained for life. Overall, the gene
Tisdale, 2004; von Kalle C et al, 2004;
therapy protocol employs an ‘ex vivo’
Sadelain et al, 2006). The smallest version of
procedure. HSC are isolated from the
the LCR-‚-globin gene LV vector has included
patient’s bone marrow and infected or
only LCR elements HS2 and HS3 in its design,
transduced with the LCR-‚-globin retroviral

139
Figure 1: IIlllluussttrraattiioonn ooff hhooww aa lleennttiivviirraall vveeccttoorr ccoonnttaaiinniinngg aa bb--gglloobbiinn tthheerraappyy ggeennee uunniitt iiss ccoonnssttrruucctteedd ffrroom
m
tthhee nnoorrm maall ((wwiilldd--ttyyppee)) HHIIVV vviirruuss..
AA.. Structure and gene organisation of wild-type HIV virus.
BB.. Replacement of the normal genes of the wild-type HIV virus with the Locus Control Region-‚-
globin therapy gene unit produces the lentiviral vector.
NNoottee:: combinations of locus control region elements HS2/HS3/HS4 or HS2/HS3 have been
employed.

which has significantly improved the ease of gene LV vector include: (i) reproducibility of
vector manufacture (Miccio et al, 2006). function of the vector; at present there is
significant variability in the expression of the
In all these cases, researchers have shown LCR-‚-globin therapy gene (including its
good efficacy in rescuing disease in mouse complete switching off), which is dependent
models of ‚-thalassaemia or of sickle cell upon the site where the LV vector has
disease. In addition, some groups have integrated within the HSC DNA (e.g. see May
shown that, under laboratory conditions, et al, 2000; Miccio et al, 2006; Han et al,
transduction of human HSC derived from 2007); (ii) insertional mutagenesis: the
bone marrow of severe ‚-thalassaemia major integration of the LCR-‚-globin gene LV
patients with the LCR-‚-globin gene LV vector into the HSC DNA has the potential to
vector can correct the globin chain disrupt host cell gene function causing, in
imbalance in resulting RBC (Persons and the extreme situation, a leukaemia-type
Tisdale, 2004; Sadelain et al, 2006; von Kalle condition (von Kalle C et al, 2004), as has
C et al, 2004; Roselli et al, 2006). been observed in clinical trials using retroviral
vectors for gene therapy of X-linked severe
Remaining problems that need to be combined immune deficiency (SCID-X1; see
addressed in order to improve both the Nienhuis et al, 2006), which also targets the
effectiveness and safety of the LCR-‚-globin HSC of the patient. Some researchers have

140
therefore included the chicken b-globin LCR al, 2005). Up to the end of 2006, two
element cHS4 in their LV vector design to try patients with ‚-thalassaemia had been
and ‘insulate’ the LCR-‚-globin gene unit, treated. It is too early in the trial to know if
which has led to some improvement in the any benefit has been derived.
reproducibility of functioning (Persons and
Tisdale, 2004; von Kalle C et al, 2004; The trial has not been without controversy,
Sadelain et al, 2006). In addition, it has been mainly related to the use of a high-risk full
suggested that the cHS4 element may act to chemotherapy-conditioning programme as
shield host genes within the HSC from part of a protocol whose success is still far
interference by the LCR-‚-globin therapy from certain, let alone in relation to what is
gene unit and therefore promote safety, currently achievable with a sibling-donor
although this has yet to be formally bone marrow transplant.
demonstrated.
We eagerly await the outcome
These studies led to the commencement of of these studies, as well as the
the first Phase I/II gene therapy clinical trial
for the haemoglobinopathies in 2006. The
commencement of future trials
trial is led by Prof Philippe Leboulch in Paris with LV vector designs with
and aims to treat five ‚-thalassaemia and five higher efficacy and safety
sickle cell disease patients within the age profiles.
range of 5-35 years. The protocol, as
expected, involves an ‘ex vivo’ approach,
with patients receiving a full chemotherapy-
conditioning programme with Busulfex to
destroy their diseased bone marrow (Bank et

141
Psychological Support
in Thalassaemia

The success of management of thalassaemia


Why is psychological is based, to a great extent on the
establishment of a therapeutic alliance
support so between caring staff and the patient
throughout the course of the disease.
important? Because of the disease-oriented emphasis of
medical education, many health professionals
find it difficult to come to terms with the
It is now universally recognised that psychological demands of treating chronic
thalassaemia, like other chronic diseases, has inherited diseases. This can be made more
important psychological implications. The way difficult in thalassaemia because patients
in which the family and the patient come to often express strong negative feelings, which
terms with the disease and its treatment will can hamper communication. Furthermore,
have a critical effect on the patient’s survival after many years of treatment, patients and
and quality of life. Without an understanding family may be better informed about the
and acceptance of the disease and its illness than non-skilled health professionals—
implications, the difficulties of lifelong a factor that can undermine the health
transfusion and chelation therapy will not be professionals’ perceived role. Taken together,
faced, leading to an increased risk of disease these factors can make honest, in-depth
complications and poorer survival. A key role communication, which is vital to successfully
for treating physicians and other health care coping with thalassaemia, extremely difficult
professionals is to help patients and families to maintain.
to face up to the difficult demands of
treatment, while maintaining a positive role.

Adherence to treatment is a basic goal, but a


The psychology of
general acceptance by the patient of his/her
own condition constitutes the key to normal
inherited chronic
development from childhood to adulthood. disease
Monthly contact with a local thalassaemia Every genetic disease, regardless of its
centre from the first years of life allows aetiology, implies a sense of guilt that may
doctors and other members of the team to interfere with the primary parent-infant
act as a reference point for the patient’s relationship. As its clinical manifestations
overall state of health, including general develop in the first year of life, the disease
attitude and well-being. In addition, this can have also a negative impact on the
regular interaction provides to the whole parent-child relationship. Moreover, the
staff, and in particular to the treating treatment is emotionally demanding, as
physician a good opportunity to promote the transfusion and chelation therapy require
patient’s physical, emotional and social repeated invasive procedures and hospital
development, taking on several visits.
characteristics of the traditional ‘family
doctor’ as guardian of the patient’s overall Chronicity is a powerful source of emotional
wellness. problems that intensify at each significant

142
developmental stage of the patient’s life. balance. It can also be extremely rewarding
Patients can feel that they are different, for the healthcare professional, both in
limited or isolated. Their state of mind can medical and emotional terms. Where a
shift rapidly from depression to anger and healthcare professional manages to maintain
vice versa. Health workers must be prepared a constant dialogue with his/her patients,
to accept this shift and to help patients deal s/he will often discover in patients with
with these feelings, finding a way to their thalassaemia skills that greatly surpass those
own ‘normalisation’ that implies different of their peers when facing the great
individual styles in adult life. challenges of life such as birth/death,
love/loneliness, opportunities/limits.
Overall, good treatment facilitates personal
development and achievement of targets in
life, while poor care makes such Caring for a ‘normal’
development difficult or unpredictable.
development
Communication: Settings and methodology for discussion are
important all along the course of the disease,
healthcare but are mandatory at crucial milestones in
the patient’s and parents’ experience:
professionals with At the onset and during the first period,
communication work is carried out with
patients parents, but the child has to be included as
soon as possible. From as early as three to
five years of age, young patients begin to ask
H e a l t h c a re p r o f e s s i on a l s s h o ul d s e e k ,
H crucial questions about the duration of care
ass far as possible, to:
a and possibilities of a cure. These should be
ñ Listen – to be interested in the patient’s dealt with sensitively and honestly. Separate
emotional and real experiences interviews with patient and with parents are
ñ Accept – to respect the patient’s point of recommended in the approach to
view and be sensitive to the timing of adolescence, while in adulthood individual
personal communication interviews with the patient are essential.
ñ Share – to be consistently close to the
patient’s positive and negative feelings
ñ Understand – at an emotional and not Communication of
simply an intellectual level
ñ Maintain boundaries – to give help and diagnosis
relief, but keeping in mind his/her role as
a physician As exemplification, it is useful to focus on
communication of diagnosis, because it is the
Good communication with healthcare natural starting point of the whole course of
professionals can be extremely beneficial for disease and may mark permanently
the patient, helping him/her to cope better (positively or negatively) the therapeutic
with thalassaemia and to maintain a sense of relationship.

143
In trying to establish an ideal setting, the transfusion interval may allow these
following points should be considered: symptoms to recur. This gives the patient the
experience of instability and doubt about
ñ The room chosen and time allocated aim his/her physical capabilities. Moreover,
to provide an atmosphere that will sustain because of the risk of transfusion-
hope and optimism; and not make the transmitted diseases, fears of being
patient feel depressed or misled. contaminated are ever-present and may be
ñ The diagnosis should be discussed with intense for real reasons (high risk of
both parents together, allowing ample transmission) or due to the patient’s
time to listen to their concerns and to emotional state. This fact helps to sustain
respond to their questions, worries and ambivalence towards therapy.
concerns.
ñ Information must be sincere, complete In any case, the need for periodic
and repeated as often as needed. The transfusions testifies that vital energy comes
weight of negative emotions may be so from other people, implying a dependence at
great that parents may appear confused the physical level that can invade the mental
even after complete information has level, limiting personal development. In
been given more than once. addition, transfusion therapy does not cure;
ñ In the months following diagnosis, the it merely provides a monthly “patch” for the
discussion must be renewed, with the anaemia, giving life and well-being but also
same attention given to the setting, and (even if safe from infection) causing iron
preferably with the same doctor to overload, which necessitates additional
preserve continuity. treatment that is also lifelong.

The same attention to setting must be This combination of advantages and


provided at any significant step, in order to disadvantages of transfusion finds a parallel
better support patient/parents in coping with in patients’ psychological reactions to their
distressing information. treatment.

Regularly transfused patients


Psychological impact can experience positive feelings,
such as gratitude for receiving
of anaemia and life, and negative ones such as
fear and anger at being ‘ruined’.
transfusion
Serious anaemia will cause the patient to feel
weak and vulnerable. Maintaining an
Psychological aspects
adequate haemoglobin level through optimal
transfusion therapy (see Chapter 2: Blood
of chelation therapy
Tranfusion Therapy in ‚-thalassaemia Major) Treating staff should be very familiar with the
eliminates these symptoms and reduces the emotional aspects of chelation, as
patient’s anxiety about death. However, the compliance with therapy determines
decrease in haemoglobin during the prognosis (see Table 1).

144
P s y c h o l o g i c a l a s p e c ts S u b c u t a n e o u s c h e l a ti o n O ra l c h e l a t i o n
Aggression + -
‘Patch’ + +
Body image damage + -
Daily reminder + +
Feeling different ++ +
Lack of check + +
Constant commitment + +

Table 1

In general, chelation is a psychologically Time and movement restrictions related to


demanding therapy, because: the use of the pump generate feelings of
being different and restricted.
ñ Iron chelation does not cure but rather
treats the main complication of the basic Parents may:
therapy (transfusion), as ‘the patch of ñ Not yet have overcome the shock of
another patch’. diagnosis. Administering the infusion can
ñ Like transfusion, it is a reminder of one’s be painful since they feel responsible for
illness, and even more on a daily basis. their child’s discomfort.
ñ Optimal chelation starts during the first ñ Use chelation as a control tool when the
years of life. child reaches adolescence.
ñ Effectiveness of the drug cannot be
checked quickly and directly by the Patients may:
patient. So compliance is a function of ñ Adopt attitudes of out-and-out refusal,
trust; that is to say, it reflects the quality feeling ‘tortured’ instead of cared for.
of the treating staff-patient relationship ñ Exploit any opportunity or excuse to skip
and a belief in long-term benefits. a day’s infusion.
ñ Repeatedly select the same sites for
S ub c ut a n e o us c h e l a t i on needle insertion, so trying to reduce the
Parenteral treatment implies a small act of body image damage.
aggression, either self-directed or inflicted by
the patient’s loved ones. Skin punctures from Physicians may:
the needles cause body image damage. The ñ ‘Bargain’ with the patient, under-
patient may feel ‘as full of holes as a prescribing desferrioxamine, more for
colander’. psychological reasons than on the
rationale of iron balance.

145
ñ Tacitly encourage non-compliers to ñ Promote the shift from parent to patient
treatment in order to avoid the management as early as possible. Many
development of negative psychological patients with thalassaemia can begin to
states. take control of their medication regimen
from six years of age. The early initiation
While the underlying motivation for all the of self-management limits overprotection
above reactions or attitudes is generally a and stimulates autonomy in the young
desire to provide relief from the patient’s patient. It also gives relief to parents and
discomfort and to make him/her feel better, ultimately improves the quality of life of
the long-term effects of such behaviour are the whole family.
harmful for the patient’s physical health and ñ Encourage patients to feel a sense of
emotional well-being. reward for achieving mutually agreed
therapeutic goals.
Orraall cchheellaattiioonn
O ñ Remember that long-term high
Oral administration simplifies significantly compliance fosters good capability and
many practical aspects of chelation self-reliance and is a key positive factor in
management with Deferrioxamine. maintaining emotional well-being.
For some patients (and some healthcare
professionals), a shift to oral chelation may
seem ‘the solution to every problem’. In fact, Psychological impact
however, oral chelation only helps with the
issues of daily ‘holes’ to the skin and of complications
consequent damage to body image. Patients
taking oral chelators must still face the daily During adolescence or young adulthood
feeling of being different and will still lack various complications may occur. The
the means to immediately and quickly assess psychological implications of such
the impact of treatment and in this context complications lie in their degree rather than
it will remain difficult for some patients even their onset. In general, asymptomatic
on oral chelation to maintain adequate complications do not require medication and
compliance. do not interfere heavily with quality of life.
However, when a serious complication such
Reeccoom
R mmmeennddaattiioonnss:: as heart disease or diabetes appears, the
ñ Define and resolve the practical aspects patient undergoes a period of psychological
of optimal chelation (see Chapter 3: Iron readjustment. S/he has to integrate the
Overload). hopes, enthusiasm and wishes typical of
ñ Avoid judging, reprimanding or youth with a damaged physical state and
threatening the patient. medical features typical of old age. In such a
ñ Pay due attention to the psychological situation, the inadequately supported patient
aspects of the disease, as may feel ‘hopelessly ruined’, giving up on
underestimating these undermines the health and continued therapy.
effectiveness of the treating staff-patient
relationship with an increased risk of Table 2 outlines the impact of the most
treatment failure. common complications (at moderate/severe
ñ Be involved in supporting, instead of stage) on patient emotional balance.
simply insisting or prescribing.

146
Coom
C mpplliiccaattiioonn TTrreeaattmmeenntt IIn
nfflluueennccee FFeeeelliinngg ooff Deeppeennddeennccee
D FFeeeelliinngg ooff Deeaatthh
D
bbuurrddeenn oonn ddaaiillyy lliiffee ddiiffffeerreennccee ddaam
maaggee aannxxiieettyy
Hypogonadism +++ ++ +++ + ++ -
Hypothyroidism + - + - ++ -
Hypoparathyroidism ++ ++ + + ++ -
Osteoporosis ++ ++ ++ + ++ -
Diabetes +++ +++ +++ +++ ++ +
Heart disease +++ +++ +++ ++ +++ +++
Hepatitis -/+++ ++ ++ + +++ +

Table 2

In contrast to the past, recent advances in Beginning a new job or an important loving
iron chelation therapy have led to a dramatic relationship can increase feelings of
progress in survival, in saving patients from inadequacy and fragility. Sometimes an
acute life-threatening heart failure, and emotional crisis occurs and psychological
generally in improving quality of life. support may be required.
Treating staff must maintain a positive
perspective and support a patient’s sense of Treating staff should accompany the patient
hope. along his/her life path, while respecting
Even in very serious cases, it is still possible his/her fragilities, sensitivity, and supporting
to deal with suffering by sharing and working resources. The most common mistakes on
together to find ways of accepting new limits the part of healthcare professionals is that
inherent to a given situation. they are being overprotective or
disinterested. On the other hand, special care
should be taken in preventing intrusions into
Challenges for the the patient’s privacy.

adult patient
Summary of
If the disease is fully compensated, physical
conditions allow the patient with psychological goals
thalassaemia to make his/her choices of adult
life without any restrictions or limitations. In terms of the psychological care of the
Even in this ideal state, however, at a patient, healthcare professionals should aim
psychological level young adults with to:
thalassaemia can run into more difficulties ñ Provide information that promotes
than peers in coping with the tasks of adult understanding of the illness
life, particularly those implying independence ñ Help patient and parents to talk and to
and responsibility. express feelings about the illness

147
ñ Help the patient to accept the illness and It is clearly not possible for a health
to take care of him/herself professional to provide all the above support
ñ Maintain realistic hopes if the organisation of his/her healthcare
ñ Facilitate a ‘normal’ lifestyle and system does not provide him or her with the
encourage self-esteem opportunity to work with patients on a long-
ñ Support the full development of an adult term basis. The ‘rotation’ of experienced
life professionals to different wards can seriously
undermine a patient’s psychological well-
Putting these goals into practice requires being, treatment and prognosis. Appropriate
health professionals to be: psychological support therefore not only
ñ Open-minded about psychological aspects requires motivated and able clinicians, but
of having and treating inherited disease also presupposes an organisational structure
ñ Trained in normal psychosocial that allows for the successful delivery of
development from childhood to optimal and comprehensive care.
adulthood
ñ Sensitised to the special issues of this
chronic hereditary disease
ñ Available to accompany and support the
patient throughout his/her life path

148
General Health Care and
Lifestyle in Thalassaemia

This right should be considered before other


Lifestyle points of view (i.e. those of parents,
relatives, school, hospital and official bodies).
If the disease is fully
compensated by ideal Staff should:
treatment, an individual with ñ Assure confidentiality of patient identity
thalassaemia major can enjoy a and data in all circumstances, trying to be
near-normal lifestyle and compliant with local, International laws
experience regular physical and and rules on privacy, if not against
emotional development from patient’s rights.
childhood to adulthood, ñ Help parents to be aware of disease-
including parenthood. related issues early on in the patient’s life
(e.g. teaching parents to decide with the
Treating staff should promote such a child, from the age of 6, if and how to
progression by trying to reduce as far as communicate with the school about
possible the degree to which the disease thalassaemia)
interferes with the patient’s personal and ñ Help the patient to build up a realistic
social life. Where the disease cannot be fully and balanced position between being
compensated with proper transfusional open and being secretive about the
schemes, the obstacles to a normal lifestyle disease
should be taken into account with a realistic
but positive approach, based on informing
and encouraging the patient, and reviewing
limitations on time and treatment schedule.
School
If the patient’s haemoglobin levels are
From a practical point of view, treating staff maintained close to the values recommended
should: in this book, no relevant interference with
ñ Manage treatment and monitoring academic performance should be seen.
schedules so as to minimise any Where the haemoglobin level is allowed to
unnecessary impact on normal daily fall too low, the patient may have difficulty in
activity school. However, individual variability is wide.
ñ Be aware of the particular psychological
aspects of health care for this chronic Although normal transfusion and follow up
condition (see Chapter 15: Psychological schedules many require a number of
Support in Thalassaemia) absences, these should not be to the extent
where the patients’ school performance is
negatively affected.
Confidentiality vs.
openness Home
Splenectomised patients should be warned
The patient should have the about the risk of having pets at home, due
right to decide if, when and to the possibility of bites and this increased
with whom to talk about the risk of septicaemia (Capnocytophaga
disease.

149
canimorsus-associated). Additional care in
preventive measures may be required in Sexual and
some areas due to specific infection risk (see
the example of Pythiosis in Thailand in reproductive life
Chapter on Infections). Patients with active
viral hepatitis or other viral infections should Differences in appearance (facial
take general measures to minimize or features, height, and skin
prevent the risk of transmission to the family. colour) may affect self-
confidence and participation in
Work social life. In adolescence, the
absence or delay of sexual
In general, it is important for development is regarded by
patients to have a positive patients as particularly
attitude towards their ability to stigmatising. Timely optimal
work. treatment of hypogonadism
In chronic diseases a shift to overprotection limits these effects. Carriers of a
is a frequent problem for all people involved viral infection must also address
(parents, treating staff, patient association additional uncertainties as
and patients themselves). This may be regards safe sexual behaviour.
partially useful when treatment possibilities
are scarce and the physical conditions of the The general improvement in the health of
patient are poor. However, well-treated patients with thalassaemia, particularly in
patients generally do not face difficulties in industrilized high income (HDI) countries,
performing work as a direct result of their means it is now possible for them to have
disease. children spontaneously or by induction of
pregnancy. Patient attitudes to parenthood
Depending on the country, thalassaemia may may range from unnecessary feelings of
be recognised as causing a certain degree of psychophysical inadequacy to an
disability, with resulting benefits and special underestimation of the risks and difficulties
employment facilities. While these may help involved. Treating staff should help the
the family and the patient from a practical patient and his/her partner to achieve a
viewpoint, care should be taken that these balanced position. The decision as to whether
entitlements do not interfere with a positive to induce pregnancy medically can be
attitude to normality, self-esteem and the difficult, and the patient’s and partner’s
ability to work (see Chapter 15: Psychological expectations, the risks of pregnancy and the
Support in Thalassaemia). long-term prognosis of the patient must be
seriously taken into consideration. Exhaustive
Symptomatic heart disease and osteoporosis counselling is necessary to explore these
may cause difficulties for patients in issues in a sensitive but thorough manner.
performing certain physical tasks and specific
advice in limiting at-risk activities should be
provided.

150
in the country to be visited should be
Routine Health Care obtained, and appropriate vaccination and
Vaacccciinnaattiioonnss
V
prophylaxis obtained in advance. Particular
attention should be paid to the prevalence of
There is no reason for patients malaria (see below).
with thalassaemia to skip or
delay standard recommended
vaccinations.
Blloooodd
B
Ideally, a patient should always receive blood
transfusions at the same place. Travel plans
Additional vaccinations for patients with should be coordinated with the patient’s
thalassaemia are discussed in the Chapter on transfusion schedule, in order to avoid
Infections. receiving transfusions elsewhere, particularly
Deennttaall ccaarree
D
if visiting areas where blood supplies carry a
high risk of infection.
Patients who are untransfused, under-
transfused or who begin transfusion at a
later stage in the disease may have some
Chheellaattiioonn
C
Travelling and holidays should be organised
malformations of the facial bones due to so as not to interfere with regular chelation
marrow expansion. This can affect growth of and treating staff should not indulge the
the teeth and cause malocclusion. ‘poor guy’ attitude. However, requests to
Orthodontic care may be successful in comply with adjustments in the chelation
improving masticatory function and/or schedule to minimise interruptions must also
correcting unaesthetic dental appearances. take into account some practical aspects
Orthodontic schedule must take account of (e.g. an adolescent planning the first camp
the peculiar characteristics of bone disease in holidays with peers), and relational aspects
thalassaemia in order, to prevent tooth (i.e. secrecy or open communication about
instability or loss. The degree of osteoporosis the disease).
of maxillary bone should guide the treatment
schedule. SSp
plleenneeccttoom
myy
TTrraavve
elllliinngg The splenectomised patient should always
travel with antibiotics, to assure prompt
Travel carries a degree of risk, which medication in case of fever, sepsis or animal
increases if the patient cannot receive expert bites. Treating staff should discourage travel
local treatment. If a patient is travelling to a where the risk of malaria is significant, as this
remote country, it is vital that adequate disease may be more serious in
travel insurance is obtained so that if serious splenectomised subjects.
complications develop, s/he can be flown
home immediately, with provision of any
necessary medical assistance. If the patient
plans a trip, treating staff should, as far as
Nutrition
possible, give information about the closest
hospital with services and experience in the
Geenneerraall
G
Patients with thalassaemia do
management of thalassaemia. As for any not have specific dietary
traveller, detailed advice about infection risks requirements, unless they have special

151
prescriptions. In general, a restrictive diet is Caallcciiuum
C m
easy to be prescribed but difficult to be Many factors in thalassaemia
maintained over the long term. In
thalassaemia, the patient already has a heavy
promote calcium depletion. A
treatment schedule and it is diet containing adequate
counterproductive to add further restrictions calcium (e.g. milk, cheese, dairy
without the likelihood of clear benefit. products and kale) is always
recommended.
During growth, a normal energy intake with
normal fat and sugar content is However, nephrolithiasis is seen in some
recommended. During adolescence and adult adults with thalassaemia major, and calcium
life, a diet low in highly refined supplements should not be given unless
carbohydrates (sugar, soft drinks, snacks) there is a clear indication, instead a low
may be useful in preventing or delaying the oxalate diet should be considered.
onset of impaired glucose tolerance or
diabetes. Vitamin D may also be required to stabilise
calcium balance, particularly if
There is no clear evidence that a diet is hypoparathyroidism is present. In case of
beneficial in preventing or managing liver liver disease, the activated form should be
disease, unless at late stages. preferred. However, if supplements are used,
careful monitoring is required in order to
IIrro
onn prevent toxicity.
Increased iron absorption from the intestinal
tract is characteristic of thalassaemia. The Patients with thalassaemia should not take
amount depends on the degree of additional calcium or vitamin D unless
erythropoiesis, the haemoglobin level and prescribed by their medical practitioner.
other potential independent factors. Drinking
a glass of black tea with meals reduces iron FFo
olliicc aacciidd
absorption from food, particularly in Patients with thalassaemia who remain
thalassaemia intermedia (de Alarcon, 1979). untransfused or are on low transfusion
However, there is no evidence that iron-poor regimens have increased folate consumption
diets are useful in thalassaemia major; only and may develop a relative folate deficiency.
foods very rich in iron (such as liver and Supplements (1mg/day) may be given if this
some ‘health drinks’ or health vitamin occurs. Patients on high transfusion regimens
cocktails) should be avoided. Patients with rarely develop this condition, and usually
thalassaemia should never be given iron have no need for supplements.
supplements. Many baby foods, breakfast
cereals and multivitamin preparations contain Viittaam
V miinn CC
added iron, along with other vitamin Iron overload causes vitamin C to be oxidised
supplements. The patient should therefore at an increased rate, leading to vitamin C
make a habit of reading labels carefully, deficiency in some patients. Vitamin C may
seeking expert advice if necessary. increase the ‘chelatable iron’ available in the
body, thus increasing the efficacy of
chelation with desferrioxamine. However,

152
there is currently no evidence supporting the hepatocarcinoma is significantly raised.
use of vitamin C supplements in patients on Excessive alcohol consumption also results in
deferiprone, deferasirox or combination decreased bone formation and is a risk factor
treatment. Indeed, vitamin C ingestion may for osteoporosis. In addition, alcoholic drinks
increase iron absorption from the gut, labile may have unexpected interactions with
iron and hence iron toxicity. Therefore, medication.
supplements should only be considered for
patients on desferrioxamine (see Chapter on SSm
mookkiinngg
Iron Overload). Cigarette smoking may directly affect bone
remodelling which is associated with
Some drugs, such as aspirin and throat osteoporosis and is related to adverse effects
lozenges, as well as certain ‘health foods’, on the general health.
may contain vitamin C and should be
avoided. A diet rich in fresh fruits, including Drruugg aabbuussee
D
citrus fruits and vegetables, is recommended. In many countries, drug abuse is common
among adolescents and young adults. For an
Viittaam
V miinn EE individual with a chronic disease, drug abuse
Vitamin E requirement is high in can be a serious threat to an already
thalassaemia. Treating staff should challenging condition, upsetting the delicate
recommend a regular intake of vegetable oils balance of factors affecting physical and
as part of a balanced diet. However, the mental health. Treating staff should aim to
effectiveness and safety of vitamin E help the patient maintain such a position,
supplementation in thalassaemia major has bearing in mind the challenges an adolescent
not been formally assessed and it is not patient is likely to face. A key danger is that—
possible to give recommendations about its as with many adolescents—drug abuse may
use at this time. be seen as a compensatory way to be
popular among peers or to ‘fit in’. For young
ZZiin
ncc people with thalassaemia, feelings of
Zinc deficiency may occur during chelation, dependence, difference and anxiety can
depending on the chelator, dose and push patients to seek ‘normality’ through an
duration. Zinc supplementation requires close abuse habit.
monitoring.
A transparent discussion of
these issues may help the
Substance abuse patient to gain insight into the
Allccoohhooll
A associated risks.
Patients with thalassaemia
should be discouraged from
consuming alcohol, as it can facilitate Recreational activities
Phhyyssiiccaall aaccttiivviittyy
the oxidative damage of iron and aggravates
the effect of HBV and HCV on liver tissue. P
Where all three factors are present, the In general, physical activity must always be
probability of developing cirrhosis and encouraged in patients with a chronic

153
disease. Patients with thalassaemia should
have a quality of life and range of life
experiences as much like those of others as
possible. There is no reason to prevent
patients from engaging in physical activity to
the limits of what they are capable of and
interested in doing, unless there is a precise
secondary medical condition.

Conditions requiring special attention


include:
S p l e n om e g a l y :
ñ Splenomegaly: the more enlarged the
spleen, the more rigorous treating staff
must be in recommending avoidance of
those sports and physical activities with
significant risk of abdominal trauma.
H e ar t d i s e as e :
ñ Heart disease: moderate physical
activity is beneficial, if is matched to the
clinical condition and its treatment.
O s t e op or os i s
ñ Osteoporosis or back pain in adults may
limit physical activity. Osteoporosis carries
an increased fracture risk and contact
sports should therefore be avoided if
osteoporosis is present.

Drriivviinngg
D
No special attention is needed. In some
countries, the presence of diabetes mellitus
requires special checks and limitations.

154
Organisation and
Programming of a
Thalassaemia Centre

as possible, in order to provide continuity of


The importance of a care. The staff must include a charge
nurse/nurse practitioner who supervises the
dedicated nursing staff.

thalassaemia unit The thalassaemia unit should operate on an


outpatient basis: facilities for evening, night,
Unless the number of patients is minimal, and overnight transfusion help minimise
organisation of a thalassaemia unit is useful inconvenience to the patient’s social life.
both in terms of functionality and cost.
Attempting to manage many patients with P a e d i at r i c v s . ad u l t c ar e
thalassaemia in big multi-purpose units (such The choice between a paediatric or adult
as paediatrics, oncohaematology and medicine setting may be crucial. Paediatric
transfusion centres) without dedicated centres, mainly in thalassaemia major,
facilities is often counterproductive, as most accumulate more experience and are closer
resources are used for the main activity of to prevention of genetic disease. As
the unit (acute patient, oncology patients, treatment opportunities improve, more
transfusion, etc). patients reach adulthood (Figure 1), with a
growing number of risk factors and
In a dedicated thalassaemia unit, a treating complications. This requires an approach
physician specially trained in thalassaemia more like that of adult internal medicine.
oversees all aspects of treatment, referring
to specialists when indicated. Staff most Each patient’s transition from paediatric to
commonly involved are: adult care must be accurate and smooth:
ñ Nurse specialist(s) ñ transmission of complete clinical records
ñ Cardiologist ñ shared discussion of past and current
ñ Endocrinologist clinical problems
ñ Diabetes specialist ñ Ideally, a clinician with continued care as
ñ Reproduction endocrinologist patients progress from paediatric to adult
ñ Andrologist or gynaecologist stages
ñ Psychiatrist/psychologist
ñ Social worker
ñ Hepatologist
ñ Transplant specialist
Programming of
The unit should be dedicated but not
treatment
isolated. The staff requires a career structure Transfusion therapy is ideally conducted
with promotion possibilities and regular according to the procedure outlined in
contact with other branches of medicine; Chapter 2: Blood Tranfusion Therapy in ‚-
otherwise, doctors and nurses can be afraid Thalassaemia Major. The day of transfusion
of losing skills and missing promotion should be utilised as effectively as possible –
opportunities, and as a result they may be ideally providing all treatment and other
unwilling to work in the unit. It is essential medical services the patient needs during
that staff turnover of the unit is kept as low one visit. This often includes:

155
Figure 1: Changing pattern of age distribution in patients with thalassaemia

ñ Physical examination
ñ Clinical and laboratory tests, scheduled by Interaction of the
the treating physician on the basis of
guidelines and individual need. thalassaemia unit
ñ Clinical discussion of the case record
ñ Individual conversation to set goals, with other hospital
renew critical information, and listen to
the patient (see Chapter 15: Psychological facilities
Support in Thalassaemia)
ñ Ideally the patient should leave the The unit must be closely connected with:
hospital after every transfusional event ñ A blood bank
with updated documentation. ñ A general laboratory
ñ If available, a special laboratory unit,
Several programmes for thalassaemia patient which runs all specific procedures used in
data have been set up. Some of them have the diagnosis, follow-up and monitoring
been computerised and can be distributed to treatment of thalassaemia,
the interested centres upon request (TIF’s ñ The clinical resources of the departments
website: www.thalassaemia.org.cy). of paediatrics, internal medicine and
haematology/oncology critical for
thalassaemia (see specialists).

156
Figure 2: An example of organisational interaction of the thalassaemia unit with other hospital
facilities [Kattamis 1989]

The well-functioning blood bank is of primary ñ Updating staff on new aspects of


importance for the management of thalassaemia and its treatment
thalassaemia. Its functions are not only to ñ Discussing and resolving organisational
find the huge amount of blood needed for aspects of the unit’s activities
the treatment of thalassaemia, but also to ñ Renewing staff motivation to work in the
secure the ideal blood for the patient, in field of thalassaemia, so as to prevent
order to minimise the risks involved in professional burnout
transfusion (e.g. alloimmunisation and
infections). The doctor from the Thalassaemia
Unit must keep blood bank staff sensitised to The organisation of a
the needs of chronically transfused patients
Thalassaemia Unit
The supervising physician should schedule
regular meetings of the staff for the purpose The organisation of the Thalassaemia Unit in
of: this fashion optimises treatment, while

157
ensuring the greatest possible level of ñ Capacity for expert diagnosis
comfort and convenience for patients with ñ Expert clinical management
thalassaemia and their families. It is essential ñ The use of outcome measures and quality
that patients with thalassaemia feel that the control, including survival and
unit is their own place, and that the medical complication rates, quality of life
staff have the patients’ best interests as top measures and other measures of patient
priority. Long-term management implies interest
collaboration of the patient and the family ñ Sufficient activity – which means a
with the well-organised thalassaemia unit minimum number of patients to ensure
team, to ensure continuous, appropriate adequate staff experience for quality care
treatment and a long and productive life for ñ High level expertise and experience of
the patient with thalassaemia. staff
ñ Epidemiological surveillance, including
A Thalassaemia Unit is expected to be a patient registers
centre of expertise for the management of a ñ Collaboration with national and
chronic disorder. As such, it should be in a international centres
position to provide multidisciplinary ñ Close links with patient associations
knowledge, as described above, with the aim
of improving both survival and quality of life. In such a system, the patient is fully
In addition, the centre will provide support to supported for self-management and is
local physicians treating patients with limited considered a partner in the decisions
access to expert centres, mainly due to affecting his/her treatment, a fact that may
distance. assist in patient adherence to long-term
treatment protocols.
The European Union has established criteria
for such centres of expertise (Rare Disease
Task Force Criteria), which could be used as a
standard in organising or running an expert
or Reference Centre, such as:

158
Outline of Diagnostic
Dilemmas in Thalassaemia

II -- IIn
nccrreeaasseedd ttrraannssffuussiioonn rreeqquuiirreem
meennttss VIIII -- W
V Woorrsseenniinngg jjaauunnddiiccee
A - Hypersplenism A - Gilberts
B - Alloantibody B - Increased haemolysis
C - Autoantibody C - Drug Reaction
D - Infection with HPV-B19 virus D - Liver failure

IIII -- FFe
evveerr VIIIIII -- LLeegg ccrraam
V mppss
A - Infection due to Bacterial A - Hypocalcaemia
B - Yersinia B - Hypoparathyroidism
C - Klebsiella
D - Delayed transfusion reaction
Diagnostic Dilemmas
IIIIII -- B
Baacckk PPaaiinn
in Thalassaemia
A - Osteoporosis and microfractures
B - Prolapse in disc Thalassaemia is an extremely demanding
C - End plate degeneration disease. Patients must commit themselves to
D - Prolapse a lifetime of transfusion and chelation
therapy, with all its attendant side effects. At
IIV
V -- UUnneexxppllaaiinneedd AAbbddoom
miinnaall PPaaiinn the same time, thalassaemia poses
considerable challenges to treating
A - Cholelythiasis physicians, who often struggle to resolve
B - Pancreatitis competing complaints that together pose
C - Portal vein thrombosis diagnostic dilemmas. The following chapter
D - Renal stones addresses some of those dilemmas, including
E - Hepatic capsule distension increased transfusion requirements, fever,
F - Yersinia back pain, abdominal pain, chest pain,
dyspnoea, worsening jaundice and leg
V -- CChheesstt PPaaiinn
V cramps.

II.. IInnccrreeaasseedd ttrraannssffuussiioonn


A - Pericarditis and myocarditis

rreeqquuiirreemmeennttss
B - Rib fracture (extramedullary expansion)
C - Pulmonary embolism

VII -- DDyyssppnnooeeaa
V The recommended treatment for
A - Dysrhythmia thalassaemia major involves regular blood
B - Delayed Transfusion reaction transfusions, usually administered every two
G - Pump failure to five weeks, to maintain the pre-
D - Pulmonary hypertension transfusion haemoglobin level above 9-10.5
g/dl. This transfusion regimen promotes
normal growth, allows normal physical
activities, adequately suppresses bone
marrow activity and minimises transfusional
iron accumulation. While shorter intervals
between transfusions may reduce overall

159
blood requirements, the choice of interval anti-Kell alloantibodies are most common.
must take into account other factors, such as However, 5-10% of patients present with
the patient’s work or school schedule. alloantibodies against rare erythrocyte
Reasons for increased consumption include antigens or with warm or cold antibodies of
hypersplenism, new alloantibodies, infection unidentified specificity.
and changes in the haematocrit of
transfused units. Autoimmune haemolytic anaemia is a very

II--A
A.. HHyyppeerrsspplleennssiissm
m
serious complication of transfusion therapy
usually combined with underlying
alloimmunisation. Even red cells from
Throughout the care of the patient with seemingly compatible units may have
thalassaemia, the size of the spleen should markedly shortened survival, and
be carefully monitored on physical haemoglobin concentration may fall well
examination and, as needed, by below the usual pre-transfusion level.
ultrasonography. Physicians should be on the Destruction both of the donor red cells and
look out for hypersplenism with stasis, of the recipient’s red cells occurs. Steroids,
trapping and destruction of red blood cells in immunosuppressive drugs and intravenous
an enlarged spleen. immunoglobulin are used for the clinical
management of this situation, although they
Splenectomy should be considered when may give little benefit. Autoimmune
annual blood requirements exceed 1.5 times haemolytic anaemia may occur more
those of splenectomised patients, provided frequently in patients beginning transfusion
that they are on the same transfusion therapy later in life.

II--C
C.. AAuuttooaannttiibbooddyy
scheme and have no other reasons for
increased consumption. (Reasons for
increased blood requirements include new
alloantibodies, infection and changes in the Autoimmune haemolytic anaemia (AIHA)
haematocrit of transfused units.) refers to a collection of disorders
characterised by the presence of
Enlargement of the spleen is accompanied by autoantibodies that bind to the patient's own
symptoms such as left upper quadrant pain erythrocytes, leading to the premature
or early satiety, or when massive destruction of red cells. Specific
splenomegaly causes concern about possible characteristics of the autoantibodies
splenic rupture. (especially the type of antibody), its optimal

II--B
B.. AAllllooaannttiibbooddyy
binding temperature, and whether
complement is fixed, constitute factors that
influence the clinical picture. However, in all
The development of one or more specific red cases of AIHA the autoantibody leads to a
cell antibodies (alloimmunisation) is a shortened red blood cell survival (i.e.,
common complication of chronic transfusion haemolysis) and, when the rate of haemolysis
therapy. Thus it is important to carefully exceeds the ability of the bone marrow to
monitor patients for the development of replace the destroyed red cells, to anaemia
new antibodies and to eliminate donors with and its attendant signs and symptoms.
corresponding antigens. Anti-E, anti-C and

160
II--D
D.. IIn
nffeeccttiio
onnw
wiitth
hHHP
PVV--B
B1199 IIII--B
B.. YYeerrssiin
niiaa
Parvovirus B 19 - In patients with an already Unlike most other bacteria, Yersinia
shortened red cell lifespan (15-20 days) and a enterocolitica makes no siderophores of its
low haemoglobin level due to haematological own and therefore lives most efficiently in an
disorders such as spherocytosis, sickle-cell iron-rich environment such as that found in
anaemia, autoimmune haemolytic anaemia unchelated patients with thalassaemia or
and thalassaemia, B 19 infection may cause uses the DFO in chelating patients which is a
an acute, life-threatening red cell aplasia, siderophore to obtain iron and thrive. The
commonly referred to as “transient aplastic Yersinia organism is most commonly
crisis”. The cessation of erythropoiesis lasts transmitted by the ingestion of
for 5-7 days and haematologically contaminated food, meat, milk or water,
complicates chronic haemolytic anaemia. although it is commensal in healthy
Attention must thus be given not only to individuals. It can also be transmitted
aplastic crises, but also to other clinical through blood.
problems such as myocarditis, which may
indicate infection with the virus. Fever is the most common presenting
feature, often associated with abdominal
IIII.. FFe
evveerr pain and diarrhoea or vomiting. Extra
gastrointestinal manifestations, such as
Fever is an elevation of body temperature arthralgia and skin rashes, are sometimes
that exceeds the normal daily variation. A seen. Complications may include abdominal
wide differential exists, spanning all types of abscess (right iliac fossa), nephritis or splenic
infections from bacterial to viral to fungal, abscess.
along with a multitude of syndromes and
organic diseases leading to fever. Generally antibiotics are continued for at
least two weeks after proven infection. Iron
IIII--AA.. IIN
NFFEEC
CTTIIO
ONND
DUUEE TTO
O chelation should not be restarted until the
B
BA AC CTTEERRIIA
A patient has been asymptomatic for over a
week. Relapse after restarting
In patients with thalassaemia, the causes may desferrioxamine has been noted in some
include other infections with Klebsiella and cases. If this occurs, a longer period of oral
Yersinia, or other bacterial pathogens and antibiotics may be necessary to eradicate the
delayed transfusion reactions. Iron overload infection. Iron chelation can be
and infection are common causes of death. recommenced after the infection has been
Hence clinical experience mandates that eliminated.
fever and infection, even in the non-
splenectomised patient, be thorough;y IIII--C
C.. KKlleeb
bssiieellllaa
investigated and treated swiftly and
aggressively. It is recommended that iron Of the multitude of bacteria described in
chelation be stopped while the cause of association with iron overload, Klebsiella
unidentified fever is investigated. species should be addressed as a potential
pathogen. In vitro Klebsiella species have
been shown to have increased virulence in

161
the presence of excess iron. Infection with IIIIII--A
A.. O
Osstteeo
oppo
orro
ossiiss
Klebsiella can be fatal in patients with
thalassaemia. There is a high incidence of osteoporosis of
the spine and hip in both sexes in
Although there is evidence of altered host thalassaemia, with severity increasing with
immunity in thalassaemia syndromes, only age. Even young patients exhibit a spinal
limited information is available regarding the bone mineral density far below that of age-
effects or functions of mononuclear matched controls.
phagocytes in relation to micro-organisms
and the influence of iron overload and iron
IIIIII--B
B,, IIIIII--C
C&& IIIIII--D
D..
Miiccrro
M offrraaccttuurreess,, ddiisscc p
prro
ollaap pssee
chelation on their activity and pathogenicity.

IIII--D
D.. DDeellaayyeed
d ttrraan
nssffu
ussiio
onn aan nd de en nd dp pllaatte
ed de eg
geen neerraattiio
onn
rreeaaccttiio
onn
Patients with thalassaemia may exhibit
Delayed transfusion reactions occur 5-10 dramatic skeletal abnormalities, frequently
days after transfusion and are characterised leading to marked changes in the facial
by anaemia, malaise and jaundice. These structure and body habitus and delayed
reactions may be due to an alloantibody that skeletal maturation. Skeletal changes are due
was not detectable at the time of transfusion largely to the expansion and invasion of
or to the development of a new antibody. A erythroid bone marrow, which widen the
sample should be sent to the blood bank to marrow spaces, attenuate the cortex and
look for a new antibody and to re- produce osteoporosis.
crossmatch the last administered units.
The skull and facial bones are often strikingly
IIIIII.. B
Baacckk P
Paaiin
n abnormal. Marrow expansion causes dramatic
widening of the diploic spaces and produces
Back symptoms are the most common cause a characteristic ‘hair-on-end’ radiographic
of disability in patients and account for a appearance of the skull. In addition, there is
huge portion of primary care physician visits. prominent frontal bossing, delayed
The differential spans congenital anomalies pneumatisation of the sinuses and marked
of the lumbar spine (spondylolysis, overgrowth of the maxillae. As a result, the
spondylolisthesis), trauma with sprains and upper incisors are ‘jumbled’ and the malar
strains, lumbar disk disease and organic eminences are especially prominent,
causes such as osteoporosis. producing malocclusion and the
characteristic faces. The ribs and bones of
Patients with thalassaemia experience myriad the extremities become box-like and
bone complications. The differential diagnosis eventually convex, due to expansion of the
includes osteoporosis, microfarctures, disc bone marrow. Premature fusion of the
prolapse and end plate degeneration. epiphyses can result in characteristic
shortening of the limbs, particularly the
arms. Of equal concern is the thinning of the
cortices due to marrow expansion, which
often results in pathologic fractures.

162
Compression fractures of the spine, often IIV
V--BB.. PPaannccrreeaattiittiiss
with spinal cord compression and neurologic
deficits, have been reported in children with Acute pancreatitis is an inflammatory
thalassaemia. Compression fractures and condition of the pancreas characterised
paravertebral expansion of extramedullary clinically by abdominal pain and elevated
masses often become particularly prominent levels of pancreatic enzymes in the blood. A
in the second decade of life. number of conditions are known to induce
IIVV.. UUnneexxppllaaiinneedd aabbddoom
miinnaall this disorder with varying degrees of
ppaaiinn certainty. However, the pathogenesis of this
disorder is not fully understood.
Correctly interpreting abdominal pain Although a number of situations can
constitutes a particular challenge in precipitate acute pancreatitis in humans, only
thalassaemia. The list includes pain a small fraction of patients with these
originating in the abdomen (peritoneal, predisposing factors develop the diseases—3
mechanical obstruction, vascular, abdominal to 7 percent with gallstone, 10 percent of
wall), pain referred from extra abdominal alcoholics and a few patients with
sites (thorax, spine, genitalia), metabolic hypercalcemia.
causes (uremia, porphyria) and neurogenic
causes. With regard to patients with thalassaemia,
pancreatitis is caused by myriad factors. First
Of the multiple complaints patients with and foremost is increased transfusion
thalassaemia present with, unexplained requirement, leading to increased turnover
abdominal pain spans a wide differential of red blood cells and hence further
diagnosis including chloelythiasis, precipitation of gallstones.
pancreatitis, portal vein thrombosis, hepatic
capsule distention and kidney stones. IIV
V--CC.. PPoorrttaall vveeiinn tthhrroom
mbboossiiss
IIV
V--AA.. CChhoolleellyytthhiiaassiiss Venous thrombo-embolism (VTE) is
increasingly recognised in paediatrics as a
A prominent feature of children with chronic complication of improved treatment
haemolytic anaemia is the development of strategies for previously lethal childhood
premature bilirubin gallstone disease and diseases. The basic pathological process
biliary tract inflammation. This is particularly underlying VTE is Virchow's triad (stasis,
true of children with ‚-thalassaemia, two- endothelial injury and hypercoagulability).
thirds of which have multiple calcified
bilirubin stones by the age of 15. Central venous catheters (CVCs), which
Fortunately, true episodes of cholecystitis or present a foreign intravascular surface,
cholangitis are rare. In the absence of clear- damage vessel walls and disrupt blood flow,
cut symptoms, gall bladder removal is thus are responsible for approximately 60 percent
rarely indicated. of VTEs in children. In patients with
thalassaemia, CVCs are resorted to when
frequent transfusions are required.

163
Thrombosis of the hepatic venous system absence of transfusion, the accelerated rate
usually occurs within the portal venous of iron turnover enhances dietary iron
system. Older children may develop portal absorption from the gut, resulting in a
vein thrombosis (PVT) secondary to liver chronic state of iron overload. In the liver,
transplantation, infections, splenectomy, iron first infiltrates Kupffer cells and then
sickle cell disease or the presence of engorges hepatocytes, ultimately provoking
antiphospholipid antibodies. PVT may fibrosis and, potentially, end-stage liver
manifest acutely with symptoms of an acute disease, in a manner analogous to that seen
abdomen, particularly in adolescents, or be in idiopathic haemochromatosis.

V.. CChheesstt ppaaiinn


asymptomatic for long periods of time until
symptoms reflecting chronic vascular V
obstruction (portal hypertension) occur (e.g.,
splenomegaly or gastrointestinal bleeding Chest discomfort is one of the most common
secondary to oesophageal varices). In challenges faced by physicians treating
addition, the debris released from thalassaemia patients. The differential
intravascular destruction of red blood cells diagnosis includes conditions affecting
may accumulate and plug the portal vein, organs throughout the thorax and abdomen,
particularly after spelenctomy. with prognostic implications that vary from

IIV
V--DD.. RReennaall ssttoonneess
benign to life-threatening. Failure to
recognise potentially serious conditions such
as acute ischemic heart disease, aortic
The kidneys are frequently enlarged in dissection, tension pneumothorax or
thalassaemia, due to the presence of pulmonary embolism can lead to serious
extramedullary haematopoiesis. Less well complications, including death. In
understood is the tendency for the renal thalassaemics, the differential diagnosis spans
tubules to be dilated. The urine is frequently pericarditis and myocarditis, extramedullary
dark, due to increased concentrations of bile causes and pulmonary embolism.

VV--AA.. PPeerriiccaarrddiittiiss aanndd


pigments; large amounts of urate, uric acid

myyo
m occaarrddiittiiss
and oxalate are also seen.

IIVV--EE.. HHeeppaattiicc ccaappssuullee


ddiisstteennssiioonn Cardiac symptoms and premature death from
cardiac causes are still major problems in
Hepatomegaly is prominent early on in thalassaemia. Heart complications are the
thalassaemia, due to increased red cell leading causes of death and one of the main
destruction as well as extramedullary causes of morbidity. In the absence of
erythropoiesis in the liver. Liver enlargement effective iron chelation therapy, many
tends to be somewhat more prominent in patients develop evidence of iron-induced
children with thalassaemia than in those with myocardial damage with cardiac failure,
congenital haemolytic anaemia. Later in the cardiac arrhythmia, sudden death or a
first decade of life, hepatomegaly becomes distressing slow death from progressive
fixed and non-reducible by blood transfusion, congestive cardiac failure.
due to development of cirrhosis secondary to
increased iron deposition. Even in the

164
The regular assessment of cardiac status can pulmonary embolism occurs as part of the
identify the early stages of heart disease, full picture of thrombosis. Data indicate that
enabling prompt intervention. thrombotic events primarily occur in the
venous system, comprising deep vein
The characteristic lesion in the heart is thrombosis (DVT) (40%), portal vein
caused by iron deposition in the myofibres, thrombosis (19%), stroke (9%), pulmonary
with associated myofibrillar fragmentation embolism (12%) and others (20%). Moreover,
and diminished mitochondrial volume per splenectomised patients have been shown to
myocyte. Classically, it has been suggested have a higher risk of thrombosis than non-
that there is a poor correlation between splenectomised patients. There are several
myocardial iron content, fibrosis and cardiac possible reasons for this, including the
functional impairment. Iron distribution in procoagulant activity of circulating damaged
the heart is relatively uneven. It has also red blood cells, as it is thought that RBC
been suggested that viral myocarditis is a remnants expose negatively charged
contributing factor to acute cardiac phosphatidyl-serine through the ‘flip-flop’
deterioration. phenomenon and subsequently initiate

VV--BB.. RRiibb ffrraaccttuurree


thrombosis.

((eexxttrraam
meedduullllaarryy eexxppaannssiioonn))
Deep vein thrombosis, pulmonary
thromboembolism and recurrent arterial
occlusion have been described in patients
Extramedullary haematopoiesis (EMH) is a with TI, mostly occurring without any other
compensatory mechanism where bone risk factors. It is important to be aware of
marrow activity increases in an attempt to these complications since thromboembolism
overcome the chronic anaemia of plays an important role in cardiac failure.

VII.. DDyyssppnnooeeaa
thalassaemia intermedia (TI), leading to the
formation of erythropoietic tissue masses V
that primarily affect the spleen, liver and
lymph nodes. These masses can be detected A cardinal symptom of diseases affecting the
by magnetic resonance imaging (MRI). They cardiorespiratory system is dyspnoea, defined
may cause neurological problems such as as an abnormally uncomfortable awareness
spinal cord compression and paraplegia, and of breathing. The differential covers general
intrathoracic masses. Extramedullary topics of obstructive disease of airways,
haematopoiesis can be managed by diffuse parenchymal lung diseases,
radiotherapy, since haematopoietic tissue is pulmonary vascular occlusive diseases,
highly radiosensitive, as well as transfusion diseases of the chest wall or respiratory
therapy and hydroxyurea. muscles, and heart diseases. Such an

V--CC.. PPuullm
moonnaarryy eem
mbboolliissm
m
extensive differential necessitates meticulous
V work up to reach a diagnosis. However,
dysrhythmia, pump failure, pulmonary
Patients with TI have an increased risk of hypertension and delayed transfusion
thrombosis compared with a normal age and reaction lead the list of probable causes of
sex-matched population and with dyspnoea in thalassaemia.
thalassaemia major patients, especially
following splenectomy. In TI patients,

165
VII--AA.. DDyyssrrhhyytthhm
V miiaa response occurring after re-exposure to a
foreign red cell antigen previously
Significant cardiac disease from iron overload encountered by transfusion, transplantation
typically occurs in the absence of symptoms. or pregnancy. The antibody, often of the
However, when symptoms do occur, they Kidd or Rh system, is undetectable on
include palpitations, syncopes, shortness of pretransfusion testing but increases rapidly in
breath, epigastric pain, decreased exercise titer following the transfusion.
tolerance and peripheral oedema. The These delayed reactions are seen generally
development of symptoms of heart failure within 2 to 10 days after transfusion.
implies advanced disease with a poor Haemolysis is usually extravascular, gradual
prognosis. and less severe than in the case of acute
Once the ventricles have enlarged, cardiac reactions, but rapid haemolysis can occur. A
arrhythmias are more common. These tend falling hematocrit, slight fever, mild increase
to be of atrial origin, but ventricular in serum unconjugated bilirubin, and
tachycardia is also occasionally seen. Sudden spherocytosis on the blood smear may be
death is likely to be arrhythmic in origin and noted. The diagnosis is often made by the
is more likely to be due to ventricular blood bank when ordering more blood for
arrhythmia than atrial. another transfusion, the direct antiglobulin
test and antibody screen which were
The decision to treat arrhythmias in patients previously negative, now have become
with thalassaemia must be carefully positive.
considered, bearing in mind that iron toxicity
is the primary cause of this complication. VII--CC.. PPuum
V mpp ffaaiilluurree
Intensive chelation treatment has been
demonstrated to reduce arrhythmias. In the The characteristic lesion in the heart is
majority of instances, the arrhythmias are caused by iron deposition in the myofibres,
supraventricular, although ventricular with associated myofibrillar fragmentation
tachycardia may occur in seriously ill and diminished mitochondrial volume per
individuals. The development of arrhythmia myocyte. Classically, it has been suggested
may be associated with a deteriorating that there is a poor correlation between
ventricular function and can be improved by myocardial iron content, fibrosis and cardiac
addressing the latter problem. Arrhythmias functional impairment. Iron distribution in
require very careful assessment. For most the heart is relatively uneven. It has also
supraventricular arrhythmias, reassurance of been suggested that viral myocarditis is a
the patient is generally appropriate, whereas contributing factor to acute cardiac
patients with ventricular arrhythmias should deterioration.
be warned as to the potential severity of
their condition. An important distinguishing feature of
cardiac dysfunction due to iron overload is
VVII--BB.. DDeellaayyeedd ttrraannssffuussiioonn the capacity of patients, if detected early, to
rreeaaccttiioonn make a complete recovery with appropriate
chelation therapy. This fact may not be
Delayed haemolytic transfusion reactions widely appreciated by physicians and
(DHTRs) are due to an anamnestic antibody cardiologists unaccustomed to dealing with

166
patients with thalassaemia. It must be deposition of bilirubin. Tissue deposition of
emphasised that supporting the failing bilirubin occurs only in the presence of
circulation in these patients for several weeks serum hyperbilirubinemia and is a sign of
may be required in order to achieve liver disease or, less frequently, a haemolytic
recovery. disorder. Of the many diseases presenting

VII--DD.. PPuullm
moonnaarryy hhyyppeerrtteennssiioonn
with icterus, physicians should suspect any of
V the following: unconjugated
hyperbilirubinemia, haemolytic, Crigler-Najjar
Pulmonary hypertension (PHT) is prevalent in type II, Gilbert's syndrome, conjugated
patients with TI (59.1%), and is thought to be hyperbilirubinemia, hepatocellular conditions,
the primary cause of congestive heart failure cholestatic conditions and drugs. Malignant
(CHF) in this patient population. The causes should not be missed, including
mechanism underlying PHT in TI is unclear, pancreatic, gallbladder, ampullary and
although evidence indicates a local cholangiocarcinoma.
pathophysiological response in the In patients with thalassaemia, worsening
pulmonary vascular bed that is independent jaundice is another way of presenting to the
of thromboembolism due to DVT. Suggested clinic. Hence the following discussion will
mechanisms include endothelial dysfunction shed light on the differential of worsening
with increased inflammation and apoptosis, jaundice in thalassaemics.

VIIII--AA.. GGiillbbeerrtt’’ss ssyynnddrroom


mee
decreased nitric oxide and nitric oxide
synthase production, pulmonary V
haemosiderosis and local thrombosis. Several
echocardiographic studies have confirmed The most common inherited disorder of
that cardiac ejection fraction is rarely bilirubin glucuronidation is Gilbert's
affected in TI. Nevertheless, patients with TI syndrome, which has also been called
often have an increased cardiac output and "constitutional hepatic dysfunction" and
left ventricular wall dimensions proportional "familial nonhaemolytic jaundice". Although
to the dilutional volume overload secondary many patients present as isolated cases, the
to chronic anaemia. condition is known to run in families.
As anaemia and iron overload are uncommon
in well-transfused and chelated patients with Gilbert's syndrome is usually diagnosed in
thalassaemia major, they are likely to be at young adults who present with mild,
the heart of the pathophysiology of PHT. predominantly unconjugated
Regular transfusion and iron chelation hyperbilirubinemia. It is rarely diagnosed prior
therapy is, therefore, indicated in TI patients to puberty when alterations in sex steroid
who are well-stratified according to the early concentrations affect bilirubin metabolism,
detection of PHT indices. Sildenafil has also leading to increased plasma bilirubin
been successfully used to treat PHT, although concentrations. The disorder is more
large-scale data for TI patients are lacking. commonly diagnosed in males, possibly due

VIIII.. W
Woorrsseenniinngg jjaauunnddiiccee
to their relatively higher level of daily
V bilirubin production.

Jaundice, or icterus, is a yellowish The physical examination is usually


discoloration of tissue resulting from the unrevealing, except for icterus. However

167
situations that exaggerate hyperbilirubinemia haemolysis even in normal subjects, usually
may bring the patient to medical attention within hours to days after the onset of
and have corresponding physical findings. exposure to the agent.
Thalassaemia patients with inherited Gilbert’s Amyl nitrite and butyl nitrite, primarily via
syndrome are at increased risk for haemolysis inhalation, have been used to increase sexual
and, as a result, would present with clinical arousal. Nitrites bind to haemoglobin,
manifestations of icterus and elevated producing methemoglobinemia that may be
bilirubin. so profound as to induce coma. The resulting

VIIII--BB.. IInnccrreeaasseedd hhaaeem


moollyyssiiss
methemoglobinemia and haemolysis may be
V more pronounced in patients who are G6PD
deficient. The possible presence of the latter
Patients with thalassaemia are more disorder should be suspected if methylene
susceptible to haemolysis, whether blue infusion does not quickly turn the
intracorpuscular (intrinsic) or chocolate colour of blood back to normal.

VIIII--DD.. LLiivveerr ffaaiilluurree


extracorpuscular (a distinction made here
because the causes of intrinsic RBC defects V
are all hereditary). Injury to the RBC
membrane due to the production of excess Hepatitis due to viral (B and C) infections is
·- or ‚-globin genes in thalassaemia is an less frequent in TI than in patients with
example of an intrinsic defect leading to thalassaemia major, since blood transfusions
haemolysis. Extracorpuscular causes of are much less common in TI. Abnormal liver
haemolysis, on the other hand, are almost enzymes (e.g., increased alanine and
always acquired conditions that lead to the aspartate aminotransferase) are frequently
accelerated destruction of otherwise normal observed in TI patients, primarily due to
RBCs. Examples include antibodies directed hepatocyte damage resulting from iron
against RBC membrane components, such as overload. Normalisation of liver enzyme levels
autoimmune haemolytic anaemia, is often observed during appropriate
alloimmune haemolytic anaemia, delayed chelation therapy.

VIIIIII.. LLeegg ccrraam


mppss
(haemolytic) transfusion reaction, and some
drug-induced haemolytic anaemias. V
Hypersplenism, which includes stasis,
trapping and destruction of RBC in an Electrolyte disturbances such as
enlarged spleen, is also part of hypocalcemia, endocrine deficiencies and
extracorpuscular haemolysis. neuromuscular and vascular issues may all

VIIII--CC.. DDrruugg rreeaaccttiioonnss


result in leg cramps.
V One-third of patients with thalassaemia major
suffer from leg cramps, muscle wasting and
A variety of drugs have been implicated as weakness. The differential diagnosis includes
causes of drug-induced oxidant haemolysis. hypocalcemia and hypoparathyroidism.

VIIIIII--AA.. HHyyppooccaallccaaeem
miiaa
Although any defect in the antioxidant
defence mechanisms, such as G6PD V
deficiency, substantially increases
susceptibility to haemolysis, the drugs Several acquired causes of
referred to below can produce oxidative hypoparathyroidism have been identified in

168
children, including thyroid surgery and iron
deposition in the parathyroid gland as a
result of frequent transfusions (as in ‚-
thalassaemia major).

VIIIIII--BB.. HHyyppooppaarraatthhyyrrooiiddiissm
V m
In the past two decades, several cases of
hypoparathyroidism (HPT) in ‚-thalassemia
major have been observed. HPT is thought to
be mainly the consequence of iron
deposition in the parathyroid glands. The
onset of HPT was preceded or followed in
most patients by other endocrine and/or
cardiac complications. No clear relationship
between HPT and serum ferritin levels was
established, suggesting either an individual
sensitivity to iron toxicity or early damage of
the parathyroid gland before chelation.
Furthermore, the fact that no new cases of
HPT have been diagnosed at a time when
improved chelation therapy regimes have
been introduced suggests that chelation may
have helped to prevent the development of
HPT.

169
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activity relationships on phenylalanine-
containing inhibitors of histone deacetylase: Z
in vitro enzyme inhibition, induction of
differentiation, and inhibition of proliferation Zurlo MG, De SP, Borgna-Pignatti C et al.
in Friend leukaemic cells. J Med Chem. Survival and causes of death in thalassaemia
2002;45:3296-3309 major. Lancet. 1989 July 1;2(8653):27-30

Wolfe, L., Olivieri, N., Sallan, D., Colan, S.,


Rose, V., Propper, R., Freedman, M.H. &

189
WEBSITES
National Evidence-Based Clinical Guidelines
Fertility: assessment and treatment for
people with fertility problems_. February
2004. http://www.rcog.org.uk

RCOG Clinical Green Top Guidelines.


Management of HIV in Pregnancy (39) - April
2004. http://www.rcog.org.uk

190
191
APPENDIX A

192
193
194
195
Index

Description Page Number

A
Adefovir 101, 105
Adult Haemoglobin (Hb A) 12
Alendronate 81
Assisted reproduction techniques ART 70
Arrhythmias 84, 88, 166
Alloimmunisation 19, 20, 24, 128, 160
Allergic transfusion reactions 28
Acute haemolytic reactions 28
Autoimmune haemolytic anaemia 28, 160
Arrested pubity 65
Amenorrhoea 66
Acarbose 69
5 - Azacytidine 136
Alchohol consumption 153
Aplastic crisis 108, 161
Antioxidants 37
Agranulocytosis 50
Arthropathy 50
Anticoagulants 21, 88, 126
ACE inhibitors 87
Amiodarone 88
Abdominal pain 163

B
Blood donation 18, 93, 98
Bone marrow expansion 79, 123, 162
Back pain 162
Bisphosphonates 74, 81
Butyrates 136
Bumetanide 87
BMP 88
Beta blocking agents 88

C
Chimerism 134
Cirrhosis 93, 99
Chelaton 38, 108, 127, 144, 151
Cardiac disease 73, 76, 83, 154

196
Calcium 69, 81, 152
Circulatory overload (transfusion) 29
Calcitriol 69
Cytotoxic agents 136
Confidentiality 149
Cytomegolovirus (CMV) 111
Chagas disease 30, 115
Chemoprophylaxis 118

D
Diabetes mellitus 68, 92
Deferiprone 48, 74
DNA 12
Delayed pubity 65
Desferioxamine DFO 39, 65, 77, 108, 112
DEXA scan 74, 79
Disc prolapse 162
Diet 151-153
Deferasirox 55
Delayed transfusion reactions 28, 162, 166
Decitabine 136
Dental care 151
Drug abuse 153
Driving 154
Dengue fever 114
Digoxine 87
Diuretics 87

E
Entecavir 101, 105
Extramedullary haemopoiesis 124, 165
Echocardiography 85
Ejection fraction (LVEF) 36, 49, 54, 73
Electrocardiogram (ECG) 84
Erythropoietin (EPO) 129, 136

F
Ferritin 33, 48, 53, 55, 75
Fetal haemoglobin (Hb F) 12, 129, 136
Fractures 81, 162, 165
Fertility 70

197
Folic acid 127, 152
Filtration (Leukoreduction) 19, 20, 29
Frozen red cells 20

G
GVHD 29, 133
Growth 43, 64
Growth velocity 64
Glucose tolerance 69
Gene therapy 139
Gallstones (cholelithiasis) 124
Gilbert's syndrome 167
GM CSF 50

H
HLA 133
Hepatitis C (HCV) 74, 92, 94, 126
Hepatocellular carcinoma 93, 99
Hepatitis B (HBV) 74, 98, 128
HIV 74, 109
Hypersplenism 116, 160
Hypothyrodism 67
Heart failure 36, 126, 166
Haemoglobin E (Hb E) 16,130
Haemoglobin Lepore 16
Haemoglobin S (Hb S) 16
Haemoglobin H (Hb H) 17
Hb Constant Spring 17
Hb Bart's Hydrops Fetalis 17
Hypogonadic hypogonadism 67, 70, 78
Hormone replacement therapy (HRT) 74, 81
Hydroxyurea 121, 124, 129, 136
Hypoparathyroidism 69, 169
Hypocalcaemia 69, 169
Heart function 36, 40, 49, 54, 56, 73

I
Iron load (haemosiderosis) 26, 31, 107, 127
Interferon (pegylated) 95, 101, 105
Iron absorption 31, 151
Insulin 69

198
Insurance (travel) 150
Immune function 107
Influenza virus vaccine 118
Indwelling intravenous lines 47
Intensive chelation 46
Immunoprophilaxis 118

J
Jaundice 117

K
Klebsiella 113, 161

L
Liver fibrosis 50, 92, 132
Liver failure 93, 168
Liver biopsy 35, 94
Lamivudine 101, 105
Lifestyle 149
Liver iron concentration (LIC) 33, 39, 48, 53, 55, 92
Labile plasma iron (LPI) 37
Leg cramps 168
Leg ulcers 125

M
Matched unrelated donors (MUD) 133
MRI 36, 92
MRI cardiac 36, 40, 49, 74, 85
Malaria 114, 115
Myocarditis 36, 164

N
Neutropenia 50
Neocytes 21
Nonhaemolytic febrile transfusion reactions 27
Nephrolithiasis (kidney or renal stones) 123, 164
Non transferring bound iron (NTBI) 37

199
O
Osteoporosis 74, 79, 127, 162, 154
Ovulation 70, 71
Oxidative damage 37

P
Puberty 65
Pregnancy 45, 51, 70, 127
Pre pregnancy counselling 70, 73
Preimplantation genetic diagnosis (PGD) 71
Pubertal staging 66
Physical activity 153
Parvovirus B19 108, 161
Palpitations 84
Pericarditis 164
Pancreatitis 163
Portal vein thrombosis 163
Pulmonary embolism 165
Pulmonary hypertension 90, 120, 126, 166
Pseudoxanthoma elasticum 127
Pamidronate 81

S
Survival 40, 49
SQUID 35
Skeletal dysplasia 43
Spermatogenesis 70, 72
Splenectomy 107, 116, 124, 128
Short chain fatty acids 137
School 149
Smoking 153
Splenomegaly 124, 154
Splenic embolisation 117

T
Thrombocytopenia 50, 97, 116
Transfusion requirement 23, 25, 26, 97
Transplantation (Stem cells) 129, 132
Transfusion related acute lung injury (TRALI) 29

200
V
Vaccinations 99, 101, 118, 151
Vitamin D 69, 81
Vitamin C 33, 39, 45, 52, 152
Vitamin E 153
Vision 43, 50

W
Washed red cells 20
Work 150

Y
Yersinia enterocolitica 42, 111, 161

Z
Zolandronic acid 81
Zinc deficiency 51, 153

201
About Thalassaemia
International Federation

The Thalassaemia International Federation (TIF) was established in 1987 with the mission to
promote the establishment of national control programmes for the effective prevention and
appropriate clinical management of thalassaemia, in every affected country of the world. TIF, a
Federation “umbrella”, is comprised of 98 national thalassaemia associations from 60 countries,
representing hundreds of thousands of patients worldwide.

TIF has been in official relations with the World Health Organisation (WHO) since 1996, and has
developed an extensive network of collaboration with scientific and medical professionals from
more than 60 countries around the world, as well as with other national and international health
bodies, pharmaceutical companies and other disease-orientated patients’ organisations.

TIF’s educational programme is one of its most important and successful activities. It includes
the organisation of local, national, regional and international workshops, conferences and
seminars, and the preparation, publication, translation and free distribution of leaflets,
magazines and books for health professionals and patients/parents, to more than 60 countries.

MIISSSSIIO
M ONN:: ““EEQ
QUUAALL AAC
CCCEESSSS TTO
OQQUUAALLIITTYY H
HEEA
ALLTTH
H SSEER
RVVIIC
CEESS FFO
ORRA
ALLLL
WIITTH
W H TTH
HAALLAASSSSAAEEM
MIIA
A””

MO
M OTTTTO
O:: ““U
UNNIITTYY IISS O
OUUR
R SSTTR
REEN
NGGTTH
H””

WORLD HEALTH ORGANIZATION (WHO) RESOLUTION:


no. EB118.R1 (29 May 2006)
““TTH
HAALLA
ASSSSA
AEEM
MIIA
AAANND
DOOTTH
HEER
RHHA
AEEM
MOOG
GLLO
OBBIIN
NOOP
PAATTH
HIIEESS””

202
1. ““BBlloooodd SSaaffeettyy KKiitt”” (1999) - 8. ““AA gguuiiddee ttoo tthhee
In English eessttaabblliisshhm meenntt aanndd
pprroom mo ottiioon no off n
noonn--
ggoovveerrnnm me en ntt
ppaattiieennttss//ppaarreennttss’’
2. “GGuuiiddeelliinneess ttoo tthhee CClliinniiccaall oorrggaanniizzaattiioonn”” 2007 - In
Maan
M naaggeem meenntt ooff English
TThhaallaassssaaeem
miiaa”” 2000 -
Translated into 6 languages
9. ““GGuuiiddeelliinneess ttoo tthhee CClliinniiccaall
Maan
M naaggeem meenntt ooff
3. ““CCoom mpplliiaannccee ttoo IIrroonn TThhaallaassssaaeem
miiaa”” Second
CChheellaattiioonn tthheerraappyy wwiitthh Edition - 2007 - In English
DDeessffeerrrriiooxxaam
miin
ne e”” 2000 –
Reprint 2005 - Translated
into 4 languages 10. ““TThhaallaassssaaeem
miiaa M
Maajjoorr aanndd
Me
M e”” – Children’s Book –
2007 - In English
4. ““AAbboouutt TThhaallaassssaaeem
miiaa”” -
2003 - Translated into 11
languages
11. ““AAbboouutt -- ‚‚ -- tthhaallaassssaaeem
miiaa”” –
2007 - In English, Italian,
5. ““PPrreevveennttiioonn ooff French
TThhaallaassssaaeem
miiaass aanndd OOtthheerr
HHaaeemmo og gllo
obbiin
nooppaatthhiieess””
Volume I (2003) - 12. ““AAbboouutt -- ·· -- tthhaallaassssaaeem
miiaa””
Translated into 2 languages – 2007 - In English, Italian,
French

6. ““PPrreevveennttiioonn ooff
TThhaallaassssaaeem
miiaass aanndd OOtthheerr 13. ““AAbboouutt ssiicckkllee cceellll ddiisseeaassee”” –
HHaaeemmo og gllo
obbiio
oppaatth
hiieess”” 2007 - In English, Italian,
Volume II (2005) - In French
English

7. ““PPaattiieennttss’’ RRiigghhttss”” 2007 - In 14. EEdduuccaattiioonnaall FFoollddeerr --


English Information for the
community, the carrier of
and the patient with a
Haemoglobin disorder.

203