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GUIDELINES
FOR THE
CLINICAL
MANAGEMENT OF

THALASSAEMIA
2 REVISED EDITION
ND

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.

3

Dipartimento di Scienze Pediatriche e dell’Adolescenza. MD – Professor Medicine . Susan Perrine. First Department of Internal Medicine.. Beirut Lebanon AUTHORS OF CHAPTERS: Athanasios Aessopos. Universita degli Studi di Torino. MD – Professor of Paediatrics.Hematology & Oncology. MD . USA Vicenzo De Sanctis.MBA 4 . University College. MD . Department of Internal Medicine. MD – Professor. Ph. Ph.Sc. – Ex-Director of the Virus Reference Laboratory. B. MD – Consultant/Senior Lecturer in Reproductive Health. Boston University School of Medicine. Ospedale Maggiore Policlinico IRCCS. Ospedaliera – Archispedale S. Boston. Massachusetts.D. London. UK Demetrios Farmakis. University College London Hospital.D.O."Laiko" General Hospital. Cagliari.Director of Haemoglobinopathy/Thalassaemia Research Unit. UK Ali Taher.D. Athens. Dipl. Greece Emanuel Angelucci.Thalassaemia International Federation Antonio Piga. Italy Malcolm John Walker. GKT School of Medicine.Division of Medical & Molecular Genetics. MD . M. London. Divisione Pediatrica Azienda.Professor of Haematology. Athens. MD . . MD . Department of Haematology. U. Anna. Centro Anemie Congenite. Ministry of Health Cyprus. Italy Michael Antoniou. Professor of Paediatrics – Medicine Pharmacology and Experimental Therapeutics Boston. MD. Executive Director . University of Milan.Professor of Paediatric Endocrinology. University of Athens .EDITORS AND AUTHORS: Maria-Domenica Cappellini. Ph. UK Ratna Chatterjee. University of Athens .Professor of Cardiology. MD – Professor."Laiko" General Hospital. MD – Professor. London. USA Androulla Eleftheriou.. UK CO-ORDINATING EDITOR: Androulla Eleftheriou. Ematologia Ospedale Oncologico "Armando Businco".Sc. University of Pennsylvania.. Ferrara.Consultant Cardiology – Hatter Institute. American University of Beirut Medical Center. Cecil Fleming House. University College London. Guy's Hospital. Italy Alan Cohen.First Department of Internal Medicine. London. Italy John Porter. Greece. School of Medicine.

5 . 'George Gennimatas' General Hospital. Projects’ Coordinator for their invaluable contribution to the completion of the book.American University of Beirut Medical CenterEndoscopy Unit. Greece Ala Sharara. MD – Professor. Cyprus. MD . Athens. Blood Transfusion Centre. MD – Associate Professor. Ministry of Health Cyprus. Geniko Laiko Nosokomio Athinon. Director of the 3rd Reg. Helen Perry – Editor.Director of the Thalassaemia Unit and WHO Collaborating Centre. MD .Consultant of Paediatric Endocrinology. Nicosia. Matheos Demetriades – Thalassaemia International Federation. Lebanon Nicos Skordis. Dr Michael Angastiniotis . Greece ACKNOWLEDGEMENTS: The Thalassaemia International Federation would like to express its most sincere appreciation and gratitude to Dr. Department of Paediatrics. Beirut.CONTRIBUTORS: Constantina Politis. Director of Division of Gastroenterology. Ersi Voskaridou. Makarios III Hospital. Thalassaemia Centre.Thalassaemia International Federation. Medical Advisor and Dr.

Contents Foreword 8 Introduction 11 CHAPTER 1 14 Genetic Basis and Pathophysiology CHAPTER 2 20 Blood Transfusion Therapy in ‚-Thalassaemia Major CHAPTER 3 33 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 6 .

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 Growth Charts 188 Index 192 About Thalassaemia International Federation 198 7 .

TIF’s activities in achieving the above include: 1. health-related organisations. 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. 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. other treatment options and the long-awaited final cure. research institutes and medical centres of excellence. 2. families and friends. At the forefront of that fight. as well as offering a comprehensive assessment of groundbreaking advances in chelation therapy. comprehensive guide to the optimal treatment of thalassaemia. 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. and. pharmaceutical industries 3. including stem cell transplantation and gene therapy. including access to sufficient quantities of safe blood and iron chelation therapy. regional and international projects contributing to worldwide improvements in: ñ Epidemiology 8 . with major advances dramatically improving patient care. ñ ñ ñ ñ ñ The development of a collaborative network of national and international thalassaemia and other disease-specific patient organisations. As such. With the support of member associations. patients. ñ Dissemination of the knowledge. TIF focuses on three categories of projects. The coordination of or participation in national. it sets out to provide a full guide to the treatment to which every patient everywhere is entitled.Foreword The fight against thalassaemia has entered new and exciting territory. this second revised edition of Guidelines for the Clinical Management of Thalassaemia provides medical professionals with a clear. its prevention and its medical and other care. clinical studies and observations. ñ Research focused on the continuous improvement of medical care and on realising a total cure for thalassaemia. experience and expertise of countries with successful control programmes to countries in need. dedicated scientists and healthcare workers. based on scientific evidence. medical and scientific communities involved in the field. Written by some of the world’s leading authorities on haemoglobin disorders. The establishment of new and promotion of existing national patient organisations. and. This book is a key tool in achieving that goal.

including Antonio Cao. regional European and international workshops. would never have achieved the level of success it currently enjoys. The first edition of this book served for many years as the reference text for the treatment of thalassaemia. Annuziata di Palma.ñ Medical and other care ñ Social integration and quality of life ñ Extending knowledge of the disease. offered by University College London (UCL) and part-funded by TIF. translation and free distribution of educational and awarenessraising material. As a response to the rapid medical advancements achieved after 2000 in the field of management of thalassaemia. difficult years. The authors and all other contributors that have made this book possible deserve particular recognition for their work. health professionals. patients and parents considered its preparation essential. This new. Renzo Galanello. ñ The preparation. a new second edition of the Guidelines. was the first of its kind to be produced at a time when specialists. published in 2000. national. The establishment of programmes for the continuous education of health professionals. 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. its prevention and treatment to policy makers. one of its most important tools for the dissemination of knowledge and experience. when knowledge on this subject was very limited. dedicated work by scientists and medical professionals from around the world. conferences. patients and parents. Vilma Gabutti. The first edition of the Guidelines for the Clinical Management of Thalassaemia. TIF’s achievements are the result of voluntary. Calogero Vullo and Beatrix Wonke. and the community at large ñ Securing the rights of every patient for equal access to quality medical care. who led the way in the early. publication. without which TIF’s educational programme. The recent launch of a unique e-MSc in Haemoglobinopathies. seminars and meetings. including: ñ Organisation of local. Giuseppe Masera. Bernadette Modell. in view of the rapid achievements in the treatment of thalassaemia. is just one example of the scope and ambition of TIF’s educational programme. Special acknowledgement is also due to a number of other specialists. patients and parents. and the community. and ñ The safety and adequacy of blood 4. second edition is a timely response to the many further advances that have been made since then. Thalassaemia was published by TIF in 9 . 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. fully updated.

it is extremely important that the prevention of thalassaemia receives similar attention. unable to provide for an ever-increasing number of patients. including detailed advice on the structure of. even the best updated treatment programmes will eventually collapse. Only a year after its publication and distribution across the world. At the same time. 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. While outside the scope of this book.December 2007 offering an invaluable tool to medical staff involved in the treatment of thalassaemia. and whose support and guidance in promoting our mission have been multi-faceted and invaluable. Panos Englezos TIF President 10 . National Health Authorities. time and effort in producing this second revised edition of Guidelines to the Clinical Management of Thalassaemia. such programmes. Unless new births of affected children are prevented or minimized. TIF ran out of stock and in order to have a timely response to the needs of health professionals involved in the treatment of thalassaemia. Thalassaemia Centres and individual health professionals in the field are strongly encouraged to follow the recommendations of the panel of experts as presented in this book. I would like to express our most sincere appreciation to the Non-Communicable Diseases Genetics Department of the World Health Organisation (WHO). Governments. In this context. TIF. and challenges to implementing. based on its long-time experience. can offer considerable support to countries. with which TIF has been collaborating on an official basis since 1996. Last but by no means least. the prevention of thalassaemia remains a crucial objective for TIF. TIF in collaboration with the main authors and editors of the book have published this second revised edition in December 2008. the development of national prevention programmes is at the heart of TIF’s activities.

which account for a great proportion of births affected by a genetic disease. 11 . the United Kingdom and France. 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. 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. the most common types of clinical importance being ·-. genetic diseases consisting mainly of sickle cell disease and the thalassaemias. recent data indicate that about 7% of the world’s population is a carrier of a haemoglobin disorder. (World Bank 2006. as has been the case in some of the countries mentioned above. where large scale migration from affected countries had occurred much earlier. Although reliable data are still lacking for many regions of the world. Sub-Saharan Africa accounts for more than 70% of births affected by sickle cell disorders every year.000500. the proportion of births in ‘at-risk groups’ is predictive of the future genetic make-up of the population. the Middle East. more recently. to which there is currently large-scale migration. Hb disorders have spread through the migration of populations from endemic areas to countries where their prevalence in indigenous populations had been extremely low. 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. including HbE. South America. In some regions. the South Pacific and South China. 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. Thalassaemia. with the remainder occurring at various rates (from low to high) in other parts of the world. Canada.and ·-thalassaemia. Southern and Eastern Asia. 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. Scandinavia. is more prevalent in the Mediterranean basin. Belgium. the Netherlands and. including Germany. ‚‰.000 children are born each year with the severe homozygous states of these diseases. with reported carrier rates ranging from 2% to 25%. such as Scandinavia. occurring widely across the world and constituting a global public health problem. Several types of thalassaemia have been described and named according to the affected globin-chain. Australia.Introduction Haemoglobin (Hb) disorders are hereditary. Such countries include the USA. where migration occurred up to a century ago and where large ethnic minority groups are now entering their fourth and even fifth generation. and that 300.

Southern European countries with Hb disorders occurring in the indigenous population.Carrier prevalence will clearly continue to rise in Northern and Western Europe. able to respond effectively to public health requirements and to adopt effective policies. although these. constitute potential targets for increasing migration. Recognition of the problem in Northern and Western Europe has raised concerns and stirred up interest amongst national and EU health policy-makers who. significant progress has been achieved during the last few years. 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. 12 . have already taken significant steps in the context of their agenda on rare diseases. financial backing and certainly political commitment. and to raise strong health professional and patient/parent awareness—tasks that are essential in the promotion of effective control programmes. and Hb disorders are likely to become the leading recessive disorder throughout the region. especially in the area of clinical management. along with Spain and Portugal. in addition to and complementary to the work of World Health Organisation (WHO). posing a serious public health problem. which was traditionally involved in the promotion of control programmes for Hb disorders. effectively addressing the control of these disorders in these countries will require considerable work. The European countries need to address ethnic minorities. Hungary and the Czech Republic. Low prevalence European countries where haemoglobinopathies have not yet penetrated to a significant degree through migration include Poland. which are widely scattered geographically. these countries already have strong health care infrastructure and systems in place. the earlier classification of endemic and non-endemic countries for Hb disorders is no longer relevant. as a result of reproduction and inter-community marriages. However. Unlike affected countries of the developing world. however. such as the United Kingdom and France. which in some regions can reach very high carrier levels. Although appropriate services are still largely underdeveloped. Some countries in Europe. Albania is a separate example. The main difficulty is that the populations of these countries are not homogeneous. albeit at considerably lower prevalence rates. Clearly. even in the absence of further migration. and the resources and quality health services required. 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. 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. as was the case in the Mediterranean countries where the earliest control programmes were successfully established. Unfortunately data on the epidemiology and status of control programmes in Russia remains scanty. include Portugal and Spain—countries that are.

Until the final goal of a complete cure for thalassaemia is found. using methods such as gene therapy and stem cell transplantation. and the right of patients to receive. We hope that these guidelines. 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. Professionals and support groups alike would benefit from forming wider partnerships with similar groups representing other disorders. 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.. It includes updated information on new approaches for more effective. and an overview of the progress achieved to date towards a total cure for thalassaemia. M. enabling all countries to benefit from each other’s experience. 50-80% of children with sickle cell disease and a significant number of children with ‚-thalassaemia die each year—undiagnosed or misdiagnosed. Ph. B. The difficulties encountered in service development for haemoglobin disorders apply equally to many other inherited disorders. will prove an indispensable tool for health professionals involved in this field. which constitute the authors’ consensus on the most effective treatment of ‚-thalassaemia major. An essential means of doing so is through global collaboration on Hb disorders. safe and less laborious treatment. Androulla Eleftheriou.Sc. parents and the community It is evident that all countries would benefit from the sharing of experience and expertise.In lower and middle-income countries on the other side of the world. the most complete and up-to-date systems of treatment available. The instruments required to support such policies include: ñ ñ ñ ñ Standards and guidelines for laboratory services National guidelines for the management of thalassaemia Epidemiological information and surveillance Establishment of an educational programme for health professionals. where haemoglobin disorders are most prevalent in the indigenous population.D. patients..MBA TIF Executive Director Coordinating Editor 13 . sub-optimally treated or not treated at all. it is the obligation of national health authorities and health professionals to provide.Sc.. Dipl. It is hoped that this book will offer valuablel information to all medical professionals involved in the treatment of patients with thalassaemia.

and. Globin Genes and Globin Synthesis The globin chains have an extremely precise structure. which are named with letters of the Greek alphabet and belong to two groups: the ·-globin cluster. Haemoglobin must have the correct structure and be trimmed in such a way that the number of ·-chains precisely matches that of the ‚-chains. which constitutes the predominant oxygen carrier during pregnancy . totalling about 30 picograms in weight per cell. which replaces HbF shortly after birth. comprising the globin chains Â. i. “upstream”) and following them (on the 3’ side of the DNA sequence. after pairing.e. i. d) a minor adult component. they determine which gene is to be turned on and which off. lie several nucleotide sequences which have a “regulatory” role. in front (on the 5’ side of the DNA sequence. ensuring their prompt loading with oxygen in the lung alveoli and its controlled gradual delivery into the tissues. ‚ and ‰. b) “fetal” haemoglobin (HbF ·2Á2). Each molecule of haemoglobin is formed by two pairs of identical sub-units. When the above conditions are not met. the red cells of the adult human contain approximately 98% HbA. ·2‚2).and ·-globin chains. and the ‚-globin cluster. ·2Â2 and ˙2Á2 tetramers. as well as how efficient its expression will be. Each red blood cell contains approximately 300 million molecules of this protein. Haemoglobin Types Oxygen is transported from the lungs to the tissues by a highly specialised protein molecule. The Thalassaemias: Definitions and Worldwide Distribution The term “thalassaemia” refers to a group of blood diseases characterised by decreased synthesis of one of the two types of polypeptide chains (· or ‚) that form the normal adult human haemoglobin molecule (HbA. Under normal conditions. resulting in decreased filling of the red cells with haemoglobin. c) “adult” haemoglobin (HbA ·2‚2). Flanking the structural genes. The precise Depending on which of the genes the defect occurs and the corresponding effect on the 14 . and anaemia.Genetic Basis and Pathophysiology structure of the globin chains is coded by genes contained in the DNA of chromosomes 16 (the · gene cluster) and 11 (the ‚ gene cluster).0% HbA2 and traces of HbF. most of the globin synthesis occurs in the erythroblasts in the bone marrow. haemoglobin. The globin chains appear sequentially during ontogeny and. In adult life. HbA2 (·2‰2). form the following four major types of haemoglobin: a) “embryonic” haemoglobins. the result is a complete or partial defect in one or both “allelic” globin genes. “downstream”). comprising the ˙. which are detectable from the 3rd to the 10th week of gestation and represent ˙2Â2.e. which is located in the red cells of the blood. the globin chains. Á. 2.

mainly because the activity of the normal ‚ gene on the allelic chromosome makes enough stable globin. and a low ‚/·. countries around the Mediterranean Basin. the thalassaemia trait is not related to any significant clinical effects.alterations of their red cells. heterozygous carriers of ‚thalassaemia (one affected allele). ·-thalassaemia or ‚-thalassaemia results. the Middle East. ‚-Thalassaemia Phenotypic heterogeneity As a rule. which is occasionally associated with low normal or slightly subnormal haemoglobin levels. Trans-Caucasus and India for ‚. display a low mean cellular haemoglobin (MCH). The present book mainly addresses the latter group of thalassaemias. which are now recognised to occur widely across the world well beyond the countries where these were originally thought to be endemic i. low mean cell volume (MCV). Under normal circumstances. Molecular studies may reveal a large array of abnormalities underlying the above phenotypes and may assist in their identification.e.globin chain ratio on biosynthesis. mild morphological CELL TYPE SITE OF ERYTHROPOIESIS PERCENTAGE OF TOTAL GLOBIN SYNTHESIS Figure 1: Globin synthesis at various stages of embryonic and fetal development 15 . an increased level of HbA2. inheritance of two defective ‚-globin genes results in a wide spectrum of clinical conditions. In contrast.and the Far East for ·-thalassaemia (see Figure 1). ranging from transfusion dependence (thalassaemia major) to mild or moderate anaemia (thalassaemia intermedia). production of globin chains.

below outlines the pathophysiology of ‚thalassaemia and describes the chain of events following globin chain imbalance and the accumulation of excess ·-chains – that is. skeletal deformities and increased GI iron absorption. Pathophysiology of ‚-thalassaemia Advances in the management of thalassaemia were achieved only after the pathophysiology of the disease was elucidated and clearly understood by the scientific and medical community involved in the field. ineffective erythropoiesis leading to anaemia. bone marrow expansion. Figure 2 The degree of globin chain imbalance is determined by the nature of the mutation of PATHOPHYSIOLOGY OF ‚-THALASSAEMIA MAJOR Figure 2: Effects of excess production of free ·-globin chains 16 .

cse. Population ‚-gene Mutation Severity Indian -619 del ‚Ô Mediterranean -101 ‚++ Black -88 ‚++ Mediterranean.edu/globin/html/huisman . ‚o refers to the complete absence of production of ‚-globin on the affected allele. A more comprehensive list of ‚ mutations can be found on the internet at the ‚-gene. In ‚++ the reduction in ‚-globin production is very mild. African -87 ‚++ Japanese -31 ‚++ African -29 ‚++ Southeast Asian -28 ‚++ Black -26 ‚++ Mediterranean. Asian Indian IVS1-nt1 ‚o Mediterranean. ‚+ refers to alleles with some residual production of ‚-globin (around 10%).psu. 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.Table 1 includes the common types of ‚-thalassaemia mutations according to ethnic distribution and severity. http://globin. More than 200 thalassaemic mutations have been reported to date. their severity and ethnic distribution 17 .

The human ·globin genes are duplicated and located in the telomeric end of the short arm of chromosome 16. The interaction of ‚-thalassaemia with HbS results in a syndrome that most closely resembles the sickling disorders. the most common haemoglobin variant in the world. The overall result is the production of reduced amounts of the variant haemoglobin (HbE). ·-thalassaemia ·-thalassaemias are inherited disorders characterised by reduced or suppressed production of ·-globin chains.gov/health/prof/blood/ sickle/sick-mt. ·-thalassaemia is caused HbE/‚-thalassaemia constitutes the most common combination of ‚-thalassaemia with a structural variant. leading to an alternative splicing pathway. since patients with seemingly identical genotypes present with clinical manifestations very different in severity. Haemoglobin E disorder is the most common structural variant resembling thalassaemia desorders (see relevant Chapter 11: Thalassaemia Intermedia). with a carrier frequency of more than 50% in some regions. Guidelines for the management of sickle cell disorders have been formulated in recent years and a useful web-site for more information is: http://www. which typically do not require lifelong transfusions and are not consequently associated with iron overload. most prevalent in South East Asia. The related clinical manifestations 18 . results from a substitution of valine for glutamic acid at position 6 of the ‚-globin chain. HbE is the most common abnormal haemoglobin in South East Asia. Hb Lepore is another structural ‚ variant resulting from a fusion of the ‰ and ‚ globin genes. the peripheral blood smear demonstrates microcytosis with 20-80% of target red cells.htm. including Bangladesh. Homozygotes for HbE are clinically silent and may be only mildly anaemic.Beta structural haemoglobin variants relevant to thalassaemia management are variable in severity— ranging from those characterising thalassaemia intermedia to those described for severe transfusiondependent thalassaemia major. It is also prevalent in parts of the Indian subcontinent.nih. while Hb electrophoresis shows 85-95% of HbE and 5-10% of HbF.nhlbi. On microscopic examination. The homozygous state of Hb Lepore can result in moderate to severe transfusiondependent ‚-thalassaemia syndromes. Heterozygotes for HbE are clinically normal and manifest with 25-30% of HbE on electrophoresis and with only minimal changes in red blood cell indices. The reasons for this variability have only partially been defined. As for thalassaemia. Haemoglobin S disorders: HbS. HbE results from a mutation (G➔A) at codon 26 of the ‚-globin gene causing the substitution of lysine for glutamic acid – a mutation that results in a qualitative and quantitative ‚-globin gene defect since it is related to the activation of a cryptic splice site at codon 24-25.

is generally associated with the absence of all four ·-globin genes and death in utero. This mutation is found primarily in Asia and its co-inheritance with the deletion of two ·-genes results in a severe form of HbH disease. Absence of ·-globin genes in the “cis” position on the same chromosome (·Ôthalassaemia) is common in South East Asia. Silent carrier state: The presence of a single ·-globin gene deletion results in the silent carrier state occurring widely across the world. characterised by ineffective synthesis of a-globin chains. Deletions or abnormalities of three globin genes result in HbH disease. resulting from a defect on the relevant gene that causes their elongation. usually characterised by a moderate haemolytic anaemia. Mild anaemia and microcytosis. Other relevant structural variants include Hb Constant Spring. most commonly by deletions of large DNA fragments that involve one or both ·-globin genes. while it is rare in the Mediterranean area and even rarer in Africa. ·-thalassaemia trait is characterised by the presence of two residual functional agenes and is not related to any serious clinical or laboratory findings: Hb Bart’s hydrops fetalis. the most severe clinical manifestation of ·-thalassaemia.crisis. splenomegaly and acute haemolytic With permition from the Source: March of Dimes: Global Report 2006 19 . mainly in response to oxidant drugs and infections.

Blood Transfusion Therapy in
‚-Thalassaemia Major

relevant laws and taking into account
national needs, resources and prevalence of
infectious agents, should safeguard the
quality of blood transfusion services. Blood
donation practices, donor selection (e.g.,
through questionnaire) and product
screening constitute some of the most
important strategies that contribute to the
safety and adequacy of blood. For more
information on EU directives visit:
http://europa.eu.int and http://europa.eu.int
/consus/health/index_en.html.
On recommendations of the Council of
Europe visit http://www.coe.int, while on
WHO guidelines and American Standards visit
www.who.int/bloodsafety/gcbs/structure/en/
and http://www.aabb.org/content,
respectively. Other sites are also available
should the reader require to obtain more
information.

Goals of Blood
Transfusion Therapy
Appropriate goals of transfusion therapy and
optimal safety of transfused blood are the
key concepts in the protocol for routine
administration of red blood cells to patients
with thalassaemia. The major goals are:
ñ Maintenance of red cell viability and
function during storage, to ensure
sufficient transport of oxygen;
ñ Use of donor erythrocytes with a normal
recovery and half-life in the recipient;
ñ Achievement of appropriate haemoglobin
level, and;
ñ Avoidance of adverse reactions, including
transmission of infectious agents.

Quality and Adequacy
of Blood

Transfusion Therapy
in Thalassaemia

To safeguard the health of the
transfusion recipient, including
patients with thalassaemia,
blood should be obtained from
carefully selected regular
voluntary, non-remunerated
donors and should be collected,
processed, stored and
distributed, in the context of
dedicated, quality assured
national blood transfusion
centres.

This chapter will address five of the most
common questions related to the transfusion
therapy of patients with thalassaemia major:
(i)

When to initiate transfusion therapy and
whom to transfuse;
(ii) How blood is processed for effective
and safe transfusion therapy in
thalassaemia major;
(iii) Is there an optimal haemoglobin (Hb)
level for effective transfusion;
(iv) Do transfusion requirements affect the
success of iron chelation therapy;
(v) What are the most serious transfusion
related (TR) reactions (common and less
frequent);

Nationally developed legislation-based on EU,
Council of Europe, North American, World
Health Organisation (WHO) or other
international directives, recommendations or

20

For deciding whom to transfuse, the
following should be included in the
investigations:

Recommended blood
product

(i)

Patients with ‚-thalassaemia
major should receive
leucoreduced packed red blood
cells with a minimum
haemoglobin content of 40g.

Confirmed laboratory diagnosis of
thalassaemia major;
(ii) Laboratory criteria:
Hb < 7g/dl on 2 occasions, > 2 weeks
apart (excluding all other contributory
causes such as infections) or
(iii) Laboratory and clinical criteria,
including:
- Hb > 7g/dl with:
- Facial changes
- Poor growth
- Fractures, and
- Extramedullary haematopoiesis

Reduction to 1 X 106 or less leucocytes per
unit (mean counts as low as 0.05 x 106 are
achievable) (Council of Europe, RE 2006) is
considered the critical threshold for
eliminating adverse reactions attributed to
contaminating white cells (see Table 1,
below) and for preventing platelet
alloimmunisation.

REACTIONS

CAUSATIVE AGENTS

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.

21

Methods for leucoreduction include:

immunoglobulin A (IgA) deficiency, in which
the recipient’s preformed antibody to IgA
may result in an anaphylactic reaction.
Washing usually does not result in adequate
leucocyte reduction and should not be used
as a substitute for leucoreduction. Instead,
washing should be used in conjunction with
filtration. In addition, washing of red cell
units may remove some erythrocytes from
the transfusion product, and it is therefore
valuable to monitor post-transfusion
haemoglobin levels to ensure attainment of
the targeted Hb level.

ñ Pre-storage filtration of whole blood is
the preferred method for leucoreduction.
The delay in filtration (4-8 hours) may
allow some phagocytosis of bacteria (e.g.
Yersinia enterocolitica) (Buchholz, 1992).
This method of leucocyte removal offers
high efficiency filtration and provides
consistently low residual leucocytes in the
processed red cells and high red cell
recovery. Packed red cells are obtained
by centrifugation of the leucoreduced
whole blood.

Frozen (or cryopreserved) red cells is
the component derived from whole blood in
which red cells are frozen, preferably within 7
days of collection, using a cryopreservant
and stored at -60oC to -80oC or below, based
on the method used. These are used to
maintain a supply of rare donor units for
certain patients who have unusual red cell
antibodies or who are missing common red
cell antigens. The Council of Europe is
promoting an international network of rare
blood donor units and may be contacted as
follows:
Council of Europe – Point I
F67075 Strasbourg Cedex
France
Tel: +33 3 88 41 2000
Fax: +33 3 88 41 2781
Email: point_i@coe.fr
Internet: www.coe.fr/index.asp

ñ Pre-transfusion, laboratory filtration
refers to the filtration at the blood bank
laboratory of packed red cells, prepared
from donor whole blood.
ñ Bedside filtration refers to the packed red
cell unit which is filtered at the bedside,
at the time of transfusion. This method,
although equally sensitive to those above,
may not allow optimal quality control
because the techniques used for bedside
filtration may be highly variable.

Blood products for
special patient
populations

Red cells obtained by donor
apheresis: This method whereby two units

Washed red cells may be beneficial for
patients with thalassaemia who have
repeated severe allergic transfusion
reactions. Saline washing of the donor
product removes plasma proteins that
constitute the target of antibodies in the
recipient. Other clinical states that may
require washed red cell products include

of red cells are collected from the same
donor for transfusion of one patient is
associated with reduction of donor exposures
and consequently to a decreased risk (i) of
transmission of infections, and (ii) of
developing alloimmunisation and other
transfusion related complications.

22

the additive solution a suitable osmotic
strength. Thus the introduction of additives
such as AS-1, AS-3, AS-5 (see Table 2b) has
permitted considerably longer storage of red
cells for up to 42 days.

Neocyte or young red cell transfusion
may modestly reduce blood requirements
(Spanos, 1996). However, patients are
exposed to a higher number of donors, with
a consequent increase in cost, risk of
transmission of infections, and risk of
developing alloantibodies.

The maximum duration of
storage (expiry date) as noted
on each unit varies with the
type of preparation
(concentration of cells, formula
of anticoagulant, use of additive
suspension fluid, etc) and
should be determined for each
type on the basis of achieving a
mean 24 hours post-transfusion
survival of no less than 75% of
the transfused red cells.

Storage of donor red
cell units
The anticoagulant preservative solutions used
in blood collection (see Table 2a) have been
developed to prevent coagulation and to
permit storage of red cells for a certain
period of time. All of these solutions contain
sodium citrate, citric acid and glucose, some
of them may also contain adenine, guanosine
and phosphate (e.g., CPD-A).

The haemoglobin oxygen release function
(which is extremely important in thalassaemia
major) is impaired during storage due to
progressive loss of 2, 3-biphosphoglycerate
(2, 3-BPG, previously known as 2, 3diphosphoglycerate, DPG). Although, the
storage time of whole blood in CPDA-1 for
example is 35 days (CoE Re 2006), after 10
days of storage all 2, 3 – BPG is lost (CoE Re
2006). In the case of additives such as the
ones mentioned above (see Table 2b),
although storage times up to 42 days are
advocated and high levels of ATP are
maintained up to the 28th day of storage, 2,
3-BPG and P50 values may not be fully
maintained even for this length of time. In
addition, information about the red cell halflife in the recipient after prolonged storage
of donor blood is limited. Taking into
consideration all the above and in view of the
fact that in thalassaemia major, decreased
recovery and a shortened red cell half-life
may increase transfusion requirements and

When red cell concentrates are prepared, a
considerable part of the glucose and adenine
is removed with the plasma. If not
compensated for in other ways, sufficient
viability of the red cells can only be
maintained if the cells are not overconcentrated. Normal CPD-adenine red cell
concentrate should therefore not have a
haematocrit (Hct) above 0.70 on average
(CoE Re 2006). Newly developed additive
solutions, however, allow maintenance of red
cell viability even if more than 90% of the
plasma is removed, as they contain
considerably higher levels of the necessary
nutrients (see Table 2b). The use of glucose
and adenine is necessary for the
maintenance of red blood cell posttransfusion viability, phosphate may be used
to enhance glycolysis, and other substances
(e.g.; mannitol, citrate) may be used to
prevent in vitro haemolysis. Sodium chloride
or di-sodium phosphate may be used to give

23

30 Citric acid 8.100 900 Adenine 27 30 30 Monobasic sodium phosphate 0 276 0 Mannitol 750 0 525 Sodium Chloride 154. and in CPD-A for even less days – as fresh as possible.00 15. In general.30 26. In patients with cardiac disease and in small children. the current practice is to use red cells stored in additive solutions for less than two weeks. 2003: 162] Table 2a: Content of anticoagulant-preservative solutions (g/L) AS-1 (Adsol) AS-3 (Nutricell) AS-5 (Optisol) Dextrose 2.90 2. ed Technical Manul. for all patients.27 3.00 26.22 Monobasic sodium phosphate Adenine 0.00 70.10 31.30 26. particular attention should be paid to the increased volume resulting from additive solutions. ACD-A CPD CP2D CPDA-1 Trisodium citrate 22. the lower haematocrit of red cell units containing newer additive solutions should be taken into consideration when calculating the annual rate of transfusional iron loading (see Tables 2a & 2b). MD: American Association of Blood Banks.00 Sodium Citrate 0 588 0 Citric acid 0 42 0 [Source: Brecker M. ed Technical Manul.200 1.22 2. 2003: 183] Table 2b:Content of additive solutions (mg/100mL) 24 .27 Dextrose 24.50 51. 14TH ed Bethesda.0 3. 14TH ed Bethesda.22 2.27 3. MD: American Association of Blood Banks.275 [Source: Brecker M.50 25.as a consequence the rate of transfusional iron loading.

usually administered every two to five weeks. 25 . they must be identified so that in future blood lacking the corresponding antigen(s) can be used. the use of blood that is also matched for the C. 1990. Transfusion of blood from first-degree relatives should be avoided because of the risk of developing antibodies that might adversely affect the outcome of a later stem cell transplant. c. E and Kell antigens is highly recommended in order to avoid alloimmunisation against these antigens. Some centres use even more extended antigen matching. adequately suppresses bone marrow activity in most patients. It is recommended that: ñ ñ Before each transfusion it is necessary to perform a full crossmatch and screen for new antibodies. 5-10% of patients present with alloantibodies against rare erythrocyte antigens or with warm or cold antibodies of unidentified specificity. and minimises transfusional iron accumulation (Cazzola. Thus it is important to monitor patients carefully for the development of new antibodies and to eliminate donors with the corresponding antigens. e and Kell. to maintain the pretransfusion haemoglobin level above 9-10. patients should have extended red cell antigen typing that includes at least C. Transfusion programmes The recommended treatment for thalassaemia major involves lifelong regular blood transfusions. All patients with thalassaemia should be transfused with ABO and Rh(D) compatible blood. A complete and detailed record of antigen typing. allows normal physical activities. This transfusion regimen promotes normal growth. If new antibodies appear. and should be readily available when and if the patient is transfused at a different centre. 1995 and 1997). E. However.Compatibility testing ñ Development of one or more specific red cell antibodies (alloimmunisation) is a common complication of chronic transfusion therapy (Spanos. red cell antibodies and transfusion reactions should be maintained for each patient. A higher target pre-transfusion haemoglobin level of 11-12 g/dl may be appropriate for patients with heart disease or other medical In addition. in order to help identify and characterise antibodies in case of later immunisation.5 g/dl. Before embarking on transfusion therapy. Anti-E. Singer. anti-C and anti-Kell alloantibodies are the most common. 2000).

or overtransfusion. Some patients with milder forms of thalassaemia who only need sporadic transfusions in the first two decades of life may later need regular transfusions because of a falling haemoglobin level or the development of serious complications (see Chapter 11: Thalassaemia Intermedia and HbE). the level of ineffective erythropoiesis. and clinical criteria such as failure to thrive or bone changes. Younger children may require a fraction of a unit to avoid under. it is usually easier to avoid these differences in red cell concentration by ordering a certain number of units (e. for example. Spanos. 1990] .g. who receive their first transfusions in adolescence or later. (Michail-Merianou. The risk of alloimmunisation appears to be greater in patients who begin transfusion therapy after the first few years of life Age at First Transfusion Alloimmunisation Rate < 1 year old 7. Units with additive solutions may have lower haematocrits in the range of 60-70%. The decision to initiate lifelong transfusion therapy should be based on a definitive diagnosis of ‚-homozygous thalassaemia.7% > 1 year old 27.9% > 3 years old 47. For most patients. see Table 3). one or two) rather than a particular volume of blood. 1987.5% Table 3: Age and alloimmunisation in Thalassaemia 26 [Spanos et al.9% [Machail-Merianou et al. Recommendations regarding the volume of transfused red cells are complicated by the use of different anticoagulant-preservatives and additive solutions. and consequently larger volumes with a higher haematocrit level are needed to administer the same red cell mass (see Table 4). the choice of interval must take into account other factors such as the patient’s work/school schedule and other lifestyle issues. The initiation of regular transfusion therapy for severe thalassaemia usually occurs in the first two years of life.conditions and for those patients who do not achieve adequate suppression of bone marrow activity at the lower haemoglobin level. Presence of alloantibodies and autoantibodies (see below) may severely compromise transfusion therapy in patients with thalassaemia intermedia. 1990. This diagnosis should take into account the molecular defect. Although shorter intervals between transfusions may reduce overall blood requirements. For CPD-A units with a haematocrit of approximately 75%. the severity of anaemia on repeated measurements. Patients with cardiac failure or very low initial haemoglobin levels should receive smaller amounts of red cells at slower rates of infusion. 1987] Age at First Transfusion Alloimmunisation Rate < 3 years old 20. the volume per transfusion is usually 10-15 ml/kg. administered over 3-4 hours.

2 ml/kg 3. or automated red cell exchange. its use may be limited due to a two. With this information.4 ml/kg 7. the haematocrit of the units or the average haematocrit of units with similar anticoagulantpreservative solutions. 1986. or unexplained changes in response to transfusion.6 ml/kg 10.6 ml/kg 5. increased (i) costs. including the volume or weight of the administered units. 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. Table 4: Guidelines for choosing how much blood to transfuse The post-transfusion Hb should not be greater than 14-15g/dl and should be monitored occasionally to allow assessment of the rate of fall in the haemoglobin level between transfusions in evaluating the effects of changes in the transfusion regimen.5 ml/kg 8.08. the estimated amount of iron per ml of RBC (see Chapter 3: Iron Load and Iron Chelation) yields an approximate value for 27 . has been shown to reduce net blood requirements and thus the rate of transfusional iron loading (Berdoukas.2 ml/kg 3 g/dl 12.0 ml/kg 11.to three-fold increase in donor blood utilisation. (ii) risk of transmission of infections and (iii) development of alloimmunisation. Although erythrocytapheresis. The latter (RBC at 100% ht) when multiplied with 1. 2003]. the degree of hypersplenism. This calculation assumes a blood volume of 70ml/kg of body weight.8 ml/kg 14.8 ml/kg 2. and the patient’s weight.4 ml/kg 7. Friedman.4 ml/kg As an example. it is possible to calculate the annual blood requirements as volume of transfused blood and pure red cells (haematocrit 100%) per kg of body weight. A careful record of transfused blood should be maintained for each patient.8 ml/kg 4 g/dl 16.0 ml/kg 5.Haematocrit of Donor Red Cells Target Increase in Haemoglobin Level 50% 60% 75% 80% 1 g/dl 4.2 ml/kg 10.6 ml/kg 2 g/dl 8.5 ml/kg 2.

44 – 0.the amount of transfusional iron that the patient receives per kilogram of body weight in a year.44 mg/kg 250 – 300 ml/kg 200 – 240 ml/kg 150 – 180 ml/kg 0.27 mg/kg 120 – 160 ml/kg 90 – 120 ml/kg 0. 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 1.36 – 0. Patient weight: 40kg Transfusion amount and schedule: 600ml every 4 weeks. The rate of transfusional iron loading may be very important in choosing the appropriate dose of an iron chelator. Annual Blood Requirement (Haematocrit 60%) Annual Blood Requirement (Haematocrit 75%) 100 – 150 ml/kg 80 – 120 ml/kg 150 – 200 ml/kg Volume of Pure RBCs/kg (Haematocrit 100%) Daily Iron Loading 60 – 90 ml/kg 0. Figure 1 shows a detailed example of how the daily rate of iron loading (mg/kg/day) is calculated and Table 5 shows the relationship between the annual transfusion requirements and the daily rate of iron loading at two common haematocrits for donor blood.53 mg/kg Table 5: Relationship between annual blood requirements and rate of daily iron loading.18 – 0. 28 . the recommended dose of the chelator deferasirox is based in part on the daily or annual rate of transfusional iron loading.34mg/kg Figure 1: Calculation of annual blood requirements and transfusional iron loading. For example.27 – 0.36 mg/kg 200 – 250 ml/kg 160 – 200 ml/kg 120 – 150 ml/kg 0.08mg iron per ml pure red cells = 126mg iron Daily transfusional iron loading: 126mg iron/yr/365 days = 0.

which sharply reduces cytokine accumulation and leucocyte alloimmunisation. Adverse events (see Table 6) associated with transfusion include: ñ Nonhaemolytic febrile transfusion reactions: These were common in past decades. Specific guidelines for consideration of splenectomy in the presence of increasing transfusion requirements are difficult to establish because of a lack of information on the haematocrit levels of the transfused blood in earlier recommendations and uncertainty with regard to long-term consequences of splenectomy. Moreover. Thus. Adverse reactions Blood transfusion exposes the patient to a variety of risks. patients experiencing such reactions should be given antipyretics before their transfusions. it is vital to continue to improve blood safety and to find ways of reducing transfusion requirements and the number of donor exposures.000 Alloimmune 1/100 Anaphylactic 1/50. including sepsis and thrombosis. the decision to proceed to splenectomy must take into consideration the individual patient’s ability to control iron stores at a given level of transfusional iron loading. as the annual transfusion requirements rise above 200ml/kg/yr of pure red cells.000 Table 6: Broad categorisation of immune-mediated transfusion related (TR) reactions and reported frequencies 29 . but have been dramatically reduced by leucoreduction.500 Febrile non-haemolytic 1/100 Graft Vs Host Disease Rare Allergic (Urticarial) 1/100 TR Acute Lung Injury 1/10. Since fever may accompany a haemolytic transfusion reaction or the administration of a unit with bacterial ACUTE FREQUENCY DELAYED FREQUENCY Haemolytic (Intravascular) 1/25.Knowing the annual transfusion requirements is also valuable in identifying changes that may constitute important evidence of hypersplenism or accelerated destruction of donor red cells. In the absence of effective leucoreduction. especially pre-storage leucoreduction. splenectomy should be considered as a potential strategy to reduce the rate of iron loading.000 Haemolytic (Extravascular) 1/ 2. Nevertheless.

adherence to standard protocols for
screening for antibodies and carrying out
the necessary full crossmatching of donor
units and (4) use of multiple patient
identifiers before transfusing the blood.
In many transfusion units, two staff
members check the identification of the
unit and the recipient prior to beginning
the transfusion.

contamination, these causes should
always be considered in a patient who
develops fever during administration of
red cells.
ñ Allergic reactions are usually due to
plasma proteins and range from mild to
severe. Milder reactions include urticaria,
itching and flushing, and they are
generally mediated by IgE. More severe
reactions, such as stridor, bronchospasm,
hypotension or other symptoms of
anaphylaxis may occur, especially in
patients with IgA deficiency and anti-IgA
antibodies. Occasional mild allergic
reactions often can be prevented by the
use of antihistamines or corticosteroids
before transfusion. Recurrent allergic
reactions can be markedly reduced by
washing the red cells to remove the
plasma. Patients with IgA deficiency and
severe allergic reactions may require
blood from IgA -deficient donors.

If signs and symptoms suggest an acute
haemolytic reaction, the transfusion
should be stopped immediately and
intravenous fluids should be administered
to maintain intravascular volume.
Diuretics may help to preserve renal
function. Disseminated intravascular
coagulation (DIC) may require additional
measures such as heparin. The
identification of the patient and the
donor unit should be re-checked. The
blood bank should also be alerted to the
possibility of an undetected alloantibody.

ñ Acute haemolytic reactions begin within
minutes or sometimes hours of beginning
a transfusion and are characterised by the
abrupt onset of fever, chills, lower back
pain, dyspnea, hemoglobinuria and shock.
These unusual reactions most commonly
arise from errors in patient identification
or blood typing and compatibility testing.
The risk of receiving the wrong blood is
greater for a patient with thalassaemia
who travels to another centre or is
admitted to a hospital not familiar with
his/her case and medical history.
Haemolytic reactions in these patients
can still be avoided by (1) the use of
optimal methods for identifying the
patients and labelling of the sample when
blood is obtained for crossmatch, (2)
proper linkage of the sample to the
donor unit in the blood bank, (3)

ñ Delayed transfusion reactions usually
occur 5-14 days after transfusion and are
characterised by unexpected levels of
anaemia, as well as malaise and jaundice.
These reactions may be due to an
alloantibody that was not detectable at
the time of transfusion or to the
development of a new antibody. A
sample should be sent to the blood bank
to investigate the presence of a new
antibody and to repeat cross-matching of
the last administered unit(s).
ñ Autoimmune haemolytic anaemia is a very
serious complication of transfusion
therapy that usually but not always
occurs in patients with alloantibodies.
Even red cells from seemingly compatible
units (i.e., those units that do not contain
the antigen to which there is a known
alloantibody) may demonstrate markedly

30

complication of transfusion.
Immunosuppressed patients are at
particular risk, but TI-GVHD may also
occur in immunocompetent recipients of
red cells from a haploidentical donor such
as a family member. TI-GVHD usually
occurs within 1-4 weeks of transfusion
and is characterised by fever, rash, liver
dysfunction, diarrhoea and pancytopenia
due to bone marrow failure. To reduce
the risk of TI-GVHD, donated blood from a
family member should be avoided or if
used should always be irradiated before
transfusion. Leucodepletion alone is
inadequate for the prevention of this
complication.

shortened survival, and the haemoglobin
concentration may fall well below the
usual pre-transfusion level. Destruction
both of the donor’s and the recipient’s
red cells occurs. The serologic evaluation
by the blood bank usually shows an
antibody that reacts with a wide range of
test cells and fails to show specificity for
a particular antigen. Steroids,
immunosuppressive drugs and
intravenous immunoglobulin are used for
the clinical management of this situation,
although they may give little benefit.
Some patients have also been treated
with rituximab, but the effectiveness of
its use in this situation is presently not
well defined. Autoimmune haemolytic
anaemia occurs more frequently in
patients who begin transfusion therapy
later in life (Rebulla, 1991), and should be
carefully considered before instituting
transfusion therapy for teenagers and
adults with thalassaemia intermedia.

ñ Transfusion-associated circulatory
overload may occur in the presence of
recognised or unrecognised cardiac
dysfunction, or when the rate of
transfusion is inappropriately fast. Signs
and symptoms include dyspnoea and
tachycardia, and the chest radiograph
shows the classic findings of pulmonary
oedema. Treatment focuses on volume
reduction and cardiac support, as
required.

ñ Transfusion-related acute lung injury
(TRALI) is a potentially severe
complication that is usually caused by
specific anti-neutrophil or anti-HLA
antibodies (Swanson, 2006). This
complication is characterised by
dyspnoea, tachycardia, fever and
hypotension during or within six hours of
transfusion. Hypoxemia is present and the
chest radiograph shows bilateral infiltrates
typical of pulmonary oedema although
there is no reason to suspect volume
overload. Management includes oxygen,
administration of steroids and diuretics,
and, when needed, assisted ventilation.

ñ Transmission of infectious agents
including viruses, bacteria and parasites,
are a major risk in blood transfusion (see
Chapter 9: Infections in Thalassaemia
Major). Even in countries where residual
risk of transmission through blood of
clinically significant pathogens (HIV, HBV,
HCV and Syphilis) has been reduced to
minimal levels, problems continue to exist
or emerge because:
− A limited range of known pathogens
is targeted in mandatory donor
screening (excludes HPV B-19, HCMV,
EBV, HAV, Yersinia enterolitica,
parasites, e.g., malaria);

ñ Transfusion-induced graft versus host
disease (TI-GVHD) is caused by viable
lymphocytes in units of transfused red
cell. It is a rare but often fatal

31

− Transmission of viruses still occurs
(window period, sensitivity threshold
of tests);
− The clinical significance of newly
identified infectious agents (HGV,
GBV-C, TTV, SEN-V, HSV6,7,8) is not
yet completely clarified and donors
are not screened for these agents;
− Newly emerging infectious agents
(WNV, SARS, Avian Flu, prions),
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.

In many regions of the developing world,
where thalassaemia is most prevalent,
continued transmission of hepatitis B,
hepatitis C and HIV underscores the
importance of promoting the quality of
national blood transfusion services, including
voluntary blood donations, careful donor
selection and screening, and public health
services’ provision of necessary
immunisation.

Summary Recommendations:
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.

32

Iron Overload

Iron overload occurs when iron intake is
increased over a sustained period of time,
either as a result of red blood cell
transfusions or increased absorption of iron
through the gastrointestinal tract (GI). Both
of these occur in thalassaemia, with blood
transfusion therapy being the major cause of
iron overload in thalassaemia major and
increased GI iron absorption being more
important in thalassaemia intermedia.

based on the assumption that
200 mg of iron is contained in
each donor unit.
Thus, irrespective of whether the blood used
is packed, semi-packed or diluted in additive
solution, if the whole unit is given, this will
approximate to 200 mg of iron intake.
According to the recommended transfusion
scheme for thalassaemia major, the
equivalent of 100–200 ml of pure RBC per kg
per year are transfused (equivalent to 116232 mg of iron per kg body weight per year
or 0.32-0.64 mg/kg/day). Regular blood
transfusion therapy therefore increases iron
stores to many times the norm unless
chelation treatment is given.

In the absence of any
mechanism of the human body
to excrete excess iron, chelation
therapy is essential and
constitutes the second
important arm, besides
transfusion therapy, of the
clinical management of these
patients.

Increased gastro-intestinal absorption
of iron:
Normal intestinal iron absorption is about 1-2
mg/day. In patients with thalassaemia who
do not receive any transfusion, iron
absorption increases several-fold.

The Rate of Iron
Loading

It has been estimated that iron
absorption exceeds iron loss
when expansion of red cell
precursors in the bone marrow
exceeds five times that of
healthy individuals.

Blood transfusion:
Knowledge of the rate of iron loading from
transfusion to as high a level of accuracy as
possible will contribute significantly to the
formulation of chelation therapy appropriate
for each patient. Simple calculations, such as
those described in the Blood Transfusion
Chapter of this book, can provide the
treating physician with this information.

Transfusion regimens aimed at keeping the
pre-transfusion haemoglobin above 9 g/dl
have been shown to prevent such expansion
(Cazzola 1997). In individuals who are poorly
transfused, absorption rises to 3-5 mg/day or
more representing an additional loading of
1-2 grams of iron loading per year.

In case organisational or other
difficulties do not allow such
estimations, a rough
approximation can be made
33

000 6. Toxicity from Iron Overload Mechanism of iron toxicity Iron is highly reactive.5 -15. generating harmful free radicals 34 . organelles and DNA causing cell death and the generation of fibrosis.1-22.2 15.6 4. (Adapted from Porter JB.500-7. 2005. These can damage lipid membranes.1-8.1 Daily iron loading from transfusion (mg) 4. In health.2 5.19:1-6) (atoms or molecules with unpaired electrons).000-10.6 7. such as the heart and endocrine glands. easily alternating between two states – iron III and iron II – in a process which results in the gain and loss of electrons.8 -11. This in turn causes increased iron uptake by the liver and other parenchyma.9-31. saturation of transferrin and the appearance of Non-Transferrin-Bound Iron (NTBI) in blood.000 5.500-13. The resulting ‘free iron’ damages many tissues in the body and is fatal unless treated by iron chelation therapy.000-4.5 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.7 -9.000 Yearly iron loading from transfusion (g) 2.6-41.000 3.8 20. Hematol Oncol Clin North Am.3-4. but in iron overload their capacity to bind iron is exceeded both within cells and in the plasma compartment.5 11. with an increased daily delivery of haem iron to macrophages which leads to increased iron release rates from macrophages. iron is ‘kept safe’ by binding to molecules such as transferrin. The broken line indicates the effect of transfusion on iron turnover.Patient’s weight 20 kg 35 kg 50 kg 65 kg Pure red cell volume (ml) transfused yearly (if 100-200 ml/kg/yr) 2.

particularly if concomitant chronic hepatitis is present. however. 35 . such as those mentioned in this chapter. In thalassaemia intermedia. tailored to the individual patient’s specific needs. 1996.8 mg/g dry wt. is also a serious complication. Therefore although there is a broad correlation between serum ferritin level and liver iron. Up to a value of about 3.6 x the LIC (in mg/g dry wt) Normal LIC values are up to 1. Studies have identified a significantly lower risk of cardiac disease and death in at least two-thirds of cases where serum ferritin levels have been maintained below 2. et al 1994. while vitamin C deficiency may depress it. leading to hypogonadism and poor growth. generally correlating with body iron stores and prognostically relevant in thalassaemia major. Olivieri. 2004). hepatitis and/or liver damage may falsely Total body iron stores in mg/kg = 10. Davis. Liver disease with fibrosis and eventually cirrhosis. A sudden and unexpected rise in ferritin level should prompt a search for hepatitis. namely diabetes. with levels of up to 7 mg/g dry wt seen in some non-thalassaemic populations without apparent adverse effects.000 Ìg/L may be associated with additional advantages (Borgna-Pignatti. inflammation. using the formula: Serum ferritin This is a relatively easy test to perform. but above this value increasing proportions of ironladen ferritin ‘leaks’ from hepatocytes (Worwood. et al. other infections or inflammatory conditions. 2004) (see Table 2). Endocrine complications. hypothyroidism and hypoparathyroidism. Telfer PTl. 2000). Day-to-day variations are particularly marked: high degrees of iron loading. at least five studies have shown an association between the control of serum ferritin and prognosis (Gabutti V and Piga A.increase serum ferritin. are also seen.) Monitoring of Iron Overload Monitoring closely and assessing as accurately as possible iron overload is essential in establishing effective iron chelation regimes. 2000. However. Iron overload also causes pituitary damage. 2004). Borgna-Pignatti.500 Ìg/L (with desferrioxamine) over a period of a decade or more (Olivieri. Complications of iron overload Untreated transfusional iron overload in thalassaemia major is fatal in the second decade of life. (These complications are described in greater detail in the relevant chapters of this book. 2004.000 Ìg/L serum ferritin is secreted in an iron-free form from macrophages. Importantly. 1980. N. serum ferritin tends to underestimate the degree of iron overloading (Pootrakul 1981). some general principles of monitoring iron overload apply to all treatments: Liver iron concentration (LIC) Liver iron concentration is now regarded as the reference standard for estimating body iron loading and has been shown accurately to predict total body iron stores (Angelucci. Davis BA. Observations with larger patient numbers show that maintenance of an even lower serum ferritin of 1. well established. usually as a result of cardiac complications (Zurlo 1989). the prediction of iron loading from serum ferritin can be unreliable (Olivieri 1995). 1994).

Jensen. While the control of total body iron over a period of years is important to prognosis. 2000). liver iron concentrations are less important than cardiac iron in determining the immediate risk of heart failure. 36 . 2003). Thus. 1997) or liver function abnormalities (Jensen. 1993. Table 2: Measuring and interpreting serum ferritin Advantages Disadvantages ñ Easy to assess ñ ñ Inexpensive ñ ñ Repeat measures are useful for monitoring chelation therapy ñ Positive correlation with morbidity and ñ mortality In the absence of prior iron chelation therapy.Several studies link high Liver Iron Content (LIC) (above 15-20 mg/g dry wt) to worsening prognosis (Brittenham. the risk for specific organ damage to the liver or heart at any given time is best assessed by measuring the iron in the organ of interest. However. while patients with normal or near normal liver iron may have increased Indirect measurement of iron burden Fluctuates in response to inflammation. more recent studies have identified discordance between liver and cardiac iron loading in some patients receiving iron chelation: patients with increased liver iron may have normal cardiac iron stores. Telfer. abnormal liver function. liver fibrosis progression (Angelucci. while the long-term control of body iron is important to prognosis. the risk of myocardial iron loading increases with the number of blood units transfused (Buja and Roberts. 1971. metabolic deficiencies Serial measurement required cardiac iron. 2003).

Biopsy is an invasive procedure. or patients on chelation regimens with variable or uncertain responses). 2005). Inadequate sample size (<1 mg/g dry weight. and has been registered in the EU and US. One recently described approach.e. as this may reduce the risk of giving either inadequate or excessive doses of chelation therapy. LIC can also now be measured using MRI techniques. A particular advantage of this technique is that it can be applied with little training. only four such machines are currently available worldwide: they are expensive to purchase and maintain. However. For calibration. particularly in the presence of cirrhosis (Villeneuve 1996). and sensitive Allows for measurement of non-heme storage iron ñ Provides information on liver histology/pathology ñ Positive correlation with morbidity and mortality 37 . painful procedure associated with potentially serious complications ñ Risk of sampling error. Measurement of LIC can be done by chemical determination on a liver biopsy sample (fresh. may give misleading results. those with suspected co-existing hepatitis. et al. at any centre with a reasonably up-to-date MRI machine (see Table 4). Since the relationship of serum ferritin to iron overload and iron balance has not yet been established. The technique demonstrates an average sensitivity of >85% and specificity of >92% up to an LIC of 15 mg/g dry wt. assessment of LIC may be particularly useful when new chelating regimes are being used. 4 mg wet wt or about a 2. Liver iron measured by SQUID has the advantage of possessing a wide linear range but each SQUID machine has to be individually calibrated. the MRI machine must use a Phantom supplied by the company. 1993) or magnetic resonance imaging (MRI)(see Table 4). is the R2 or Ferriscan technique which appears to have acceptable linearity and reproducibility over the range of clinical interest (St Pierre TG. but in experienced hands has a low complication rate (Angelucci 1997).5 cm core length) or uneven distribution of iron. specific. especially in patients with cirrhosis ñ Requires skilled physicians and standardized laboratory techniques Direct measurement of LIC Validated reference standard Quantitative. fixed or from dewaxing of paraffinembedded material)(see Table3) or by noninvasive methods such as magnetic biosusceptometry (SQUID) (Brittenham. while the data acquired is sent via internet for analysis by dedicated Ferriscan software (payment per scan analysed). by the treating physicians for those patients whose serum ferritin levels deviate from expected trends (i. LIC determination should be considered. Table 3: Measuring LIC by liver biopsy Advantages Disadvantages ñ ñ ñ ñ ñ Invasive. and require dedicated trained staff.LIC can also be measured accurately using a method known as SQUID (supercoducting quantum interference device). previously limited to a relatively narrow linear range.

2001). which is a validated and standardised method for measuring LIC MRI=Magnetic Resonance Imaging 38 . 2007). 6 ms indicates a 38% chance. The T2* value in tissues shortens as the iron concentration increases. In centres where such methodology is available. 2004). while T2* measures storage iron – not in itself directly toxic to cells. factors affecting the risk of developing heart failure from myocardial iron overload are complex. patients with T2* values >20 ms have a very low chance of decreased LVEF. or lack of continuous exposure to intracellular chelation. T2* values of 10-20 ms indicate up to a 10% chance of decreased LVEF. MUGA or echocardiography. For example. the T2* value may identify patients at high risk of developing a fall in LVEF before it occurs permitting a more informed choice regarding patients whose chelation treatment should be intensified. and T2* values of just 4 ms indicate a 70% chance of decreased LVEF (Westwood. A shortening of Table 4: MRI assessment of LIC Advantages Disadvantages ñ Assesses iron content throughout the liver ñ Potentially widely available ñ Pathological status of liver and heart can be assessed in parallel ñ Indirect measurement of LIC ñ Requires MRI imager with dedicated imaging method Liver iron levels can be assessed using a technique known as R2 (spin echo) MRI. Factors that may increase the availability of labile intracellular iron to cause intracellular damage such as myocarditis. The ability to estimate heart iron offers an additional way to stratify risk. may influence the Myocardial iron estimation (T2* or other measures) Estimation of myocardial iron using MRI is becoming increasingly available but requires expertise in its use and standardisation.5 years allowing time for intensification of chelation treatment. However. Patients with a fall in ejection fraction below reference values for the method used have a 35-fold increased risk of cardiac failure and death. with a median interval to progression of 3. Heart function Regular monitoring of left ventricular ejection fraction (LVEF) has allowed identification of a group of patients with poor prognosis at high risk of subsequent heart failure and death who responded well to intensification of desferrioxamine (Davis et al.myocardial T2* to <20 ms (implying increased myocardial iron) is associated with an increased chance of decreased LV function (Anderson et al. opening up a new diagnostic window. The first two methods have advantages over echocardiography in that they are less operator-dependent and therefore more easily adapted to longitudinal monitoring. 8-10 ms indicates an 18% chance. Left ventricular function can be quantified using MRI.

Malondialdehyde (MDA) is increased in iron overload. Urinary iron estimation Measurement of the urinary iron excretion can assist in assessing the effect on iron excretion of desferrioxamine (about half of total iron excreted in urine) or deferiprone (over 80% of iron excreted in urine). transferrin. One way of measuring the NTBI fraction that is labile and can redox cycle is the labile plasma iron’ assay (LPI assay). its value as a guide to routine treatment or prognosis has yet to be demonstrated. NTBI is cleared by different cells than transferrin iron. although the measurement of NTBI (or LPI) has proved a useful tool for examining how chelators interact with plasma iron pools. and explain why only a proportion of people with short T2* values show abnormal heart function at any moment in time. depending on the level of iron stores. Plasma non-transferrin bound iron (NTBI) In iron overload. the inherent variability in daily iron excretion necessitates repeated determinations. However. iron overloaded patients should be monitored for evidence of hypoganadotrophic hypogonadism (growth and sexual development and biochemical NTBI consists of several chemical entities. These are discussed more fully in other chapters. Other markers of organ dysfunction.risk posed by excess heart iron. Because these forms of iron rapidly reappear once iron chelators are cleared from the blood. Non-Transferrin Bound Iron (or NTBI). Prospective data on the relationship between myocardial T2* and survival are still required. However. Other markers of oxidative damage A wide variety of markers for oxidative damage have been investigated. However. the dose of desferrioxamine and the level of haemoglobin (Pippard 1982). experts suggest that the optimal treatment is 24hour chelation (Porter. of which can redox cycle. There has been interest in the use of antioxidants or naturally occurring products that contain antioxidant properties. while a wide range of antioxidants are depleted. However. and is mainly responsible for the abnormal pattern of iron distribution in transfusional iron overload. such as Curcumin. However. until controlled data are available caution is advised in the use of these. the relationship between short T2* values (<10ms) and the risk of heart dysfunction is clear (see Table 5). as the effects of antioxidants in the presence of iron can be unpredictable due to redox cycling of iron between the iron (II) and iron (III) states. 1996). the normal carrier of iron in plasma becomes saturated leaving iron unbound i. only some of which are readily chelatable and only some 39 . but variable (30100%) to the amount of urinary iron excretion. Faecal iron excretion contributes an additional.e.

Table 5: MRI assessment of cardiac iron Advantages Disadvantages ñ Rapidly assesses iron content in the septum of heart ñ Iron levels can be quantified reproducibly ñ Functional parameters can be examined concurrently ñ Pathological status of liver and heart can be assessed in parallel ñ Indirect measurement of cardiac iron ñ Requires MRI imager with dedicated imaging method ñ Technically demanding ñ Methodology remains to be standardized and validated Cardiac iron levels can be rapidly and effectively assessed using a technique know as T2* (gradient echo) MRI. Iron is constantly being turned over. As mentioned above. while simultaneously making the iron as safe as possible by binding the toxic iron pools responsible for causing tissue damage. Thus. it may take months or years to reduce body storage iron to safe levels. removal of storage iron is slow and inefficient. which is becoming the new standard method MRI=Magnetic Resonance Imaging 40 . it is theoretically more appropriate to reduce the dose of chelator than to interrupt or decrease the frequency of chelation. either as a result of the breakdown of red cells in macrophages or the breakdown of ferritin within cells. when an iron chelator is given. Goals of iron chelation therapy The primary goal of chelation therapy is to maintain safe levels of body iron at all times. hypothyroidism and hypoparathyroidism. Once low levels of iron have been achieved. The twin goals of iron chelation in iron overloaded patients is therefore to decrease tissue iron to safe levels. Chelation must therefore begin soon after (2-3 years) the initiation of transfusion therapy. markers of HH). than others – for example.Iron appears to be removed more quickly from some tissues. in order to achieve the second goal of chelation – the minimisation of toxic (labile) iron pools – 24-hour chelation coverage is the ideal. before it is excreted or metabolised. once iron overload has accumulated. especially in heavily iron loaded patients. Once a patient is iron overloaded. the heart. such as the liver. by chelating the iron needed for normal tissue metabolism. because only a small proportion of body iron is available for chelation at any given time. the plasma component of this iron (NTBI) is mainly responsible for the iron loading of tissues. even with the most intensive treatment. Treatment of Iron Overload Increasing the dose of chelators given in an attempt to speed up iron removal runs the risk of increasing the toxicity of an iron chelator. Unfortunately. NTBI appears within minutes of a chelator being cleared from the body. Consequently. These same fractions are redoxactive and potentially harmful. diabetes mellitus (yearly GTT). only a small proportion of the drug binds iron.

The process of iron chelation ceases soon after an infusion of desferrioxamine is complete. Therefore. 1982). the results of a formal prospective study on the dose required to stabilise or decrease serum ferritin in large populations have only recently become available. Desferrioxamine has been in clinical use since the 1970s and widely used as subcutaneous infusions since about 1980. The study – a prospective evaluation of changes in ferritin levels and LIC as a function of dose in 290 thalassaemia major patients (Cappellini. with body iron stores and in vitamin C deficient patients with the addition of vitamin C. 2006). being eliminated rapidly in urine and bile. Borgna-Pignatti. Effects on serum ferritin Clinical experience over a period of three decades indicates that ferritin can be controlled with desferrioxamine monotherapy. the higher the proportion of iron excreted in the faeces rather than the urine. 1994). desferrioxamine is effective in controlling liver iron and hence total body iron stores (Brittenham. whereas faecal iron is derived from iron chelated within the liver (Hershko. 1993). The main disadvantages of the treatment are that it is costly and that it must be administered parenterally. desferrioxamine is poorly absorbed from the gut. whereas a mean daily dose of 51 mg/kg resulted in an average ferritin decrease of approximately 1. and that maintaining serum ferritin <2500 Ìg/L with this drug is closely linked to protection from heart disease and to improved survival (Olivieri. Desferrioxamine has a short plasma half-life (initial half-life 0. 2) administered regularly and 3) administered in adequate doses. Evidence for the effectiveness of desferrioxamine However. The higher the dose. Gabutti and Piga. The efficiency of desferrioxamine (measured in terms of percent of dose excreted in the iron bound form) administered at standard 812 hour intervals 5-7 days a week is Effects on liver iron Administered at least 5 times a week and in sufficient doses. Mechanism of action and pharmacology Due to its molecular size. Pippard. a mean daily dose of at least 50 mg/kg/day is recommended (except in children – see below).Desferrioxamine (Desferal® or deferoxamine) approximately 14%. Iron excretion with desferrioxamine increases with dose. 2006) – demonstrated that a mean daily dose of 42 mg/kg resulted in a small decrease in serum ferritin of 364 Ìg/L at one year. desferrioxamine has a wellestablished impact on survival and on cardiac and other complications of iron overload described above (Brittenham. 1979. 2004). 1996. Iron excreted in the urine is derived from the breakdown of red cells in macrophages.000 Ìg/L over one year. in a study 41 .500 Ìg/l. if the serum ferritin is >2. The relationship between dose and change in LIC was not examined systematically until recently (Cappellini. Provided that treatment is 1) begun within 2-3 years of beginning transfusion therapy.3h). 1993.

Cohen. including diabetes mellitus (Brittenham. Continuous intravenous doses of 5060 mg/kg/day typically normalised LVEF in a period of three months (Anderson LJ. subcutaneous treatment at relatively low doses of 35 mg/kg showed an average improvement in T2* of 1. However. It should be emphasised that these are average changes and that the dose required may increase or decrease depending on transfusion requirement (Cohen. intermittent doses.9 mg/kg dry wt. In patients with LIC values >14 mg/g dry wt. 1994. Olivieri. In patients with baseline T2* values of between 8-20 ms. a mean dose of 42 mg/kg resulted in a small decrease of 1. 1990). even in the most overloaded hearts. Tanner. Borga-Pignatti. sustained compliance is critical to outcome especially while increase myocardial iron remains (Davis. if advanced heart failure has developed before treatment is intensified. Improvement in cardiac T2*. significantly before liver or heart iron stores had been normalised. Early intervention therefore for decreased LV function is therefore recommended. 1993. Effects on morbidity Regular subcutaneous therapy started before the age of 10 years reduces the incidence of hypogonadism (Bronspiegel-Weintrob. 2005). as well as other endocrine disturbances. patients showed an improvement of 3 ms over one year (Porter et al. Effects on heart iron (T2*) Treatment with continuous intravenous desferrioxamine has been shown to improve myocardial iron. even at low. The same results can be obtained with excellent long-term prognosis with lower doses (50-60 mg/kg/day – see below) and consequently less drug toxicity using continuous dosing (Davis. 2005). a mean dose of 51 mg/kg resulted in LIC decreases of an average of 6. 1983. 1990). Symptomatic heart disease can be reversed by high dose intravenous treatment (Marcus. has been confirmed by two prospective randomised studies (Pennell. Wolfe. 1994.. 1985. 2004) 42 . 2004). The average rate of improvement at this level of iron loading of the heart is about 3 ms/year in severely overloaded hearts: if improvement is linear it would take several years to normalise the T2* to >20 ms (Porter 2002). the incidence of ironinduced heart disease has fallen progressively in cohorts of patients – with a key factor being the age of starting treatment (Brittenham.4 mg/g dry wt.8 ms over one year (Pennell 2006). Once heart function has been improved. 2006. 2000 and 2004).establishing that a mean dose of 37 mg/kg stabilised LIC for patients with baseline LIC values of between 3 and 7 mg/g dry wt. Effects on heart function Subcutaneous therapy has long been known to improve asymptomatic cardiac disease (Freeman. 2004) . with Thus a dose of 50 mg/kg at least 5 days a week is recommended if a significant decrease in LIC optimal levels (see above) is required. 2004). 2004). the chances of successful rescue are decreased. 2006). For patients with LIC values between 7 and 14 mg/g dry wt. five days a week. 1989). Aldouri et al. Borgna-Pignatti. 1984. Since the introduction of desferrioxamine. et al. average myocardial T2* values of <6 ms (Anderson. At a slightly higher dose of 40-50 mg/kg.

mainly as a result of decreased cardiac iron toxicity.5% 0. DFO introduced in 1975 † SC. 2004). 2004. Birth 1970–74* Birth 1980–84† Death at 20 years 5% 1% Hypogonadism 64.9% * IM. Effects on survival and complications of iron overload As mentioned previously.7% 4. 2004) Age (years) 43 . in patient cohorts born between 1960-64 and 1995-97 (Borgna-Pignatti.demonstrated by the improving survival in patients born between the 1960s and the present day (see Figure 3).5% 14.8% Hypothyroidism 17. DFO introduced in 1980 In 1995. desferrioxamine was first used to treat iron overload in thalassaemia in the 1970s but was only widely used by infusion after 1980. 121 patients switched to DFP (censored at the time) Survival probability Figure 3: Increasing probability of survival (% alive at ages shown) with desferrioxamine therapy for thalassaemia. Davis. and that age of starting treatment is a key factor in outcome (Borgna-Pignatti. 1993. Note that only patients born after 1980 will have started treatment at an early age. Brittenham.3% Diabetes 15. The benefits of its regular use are clearly Table 6: Decreasing complications in cohorts born after desferrioxamine was already available.

infections such as Klebsiella may also be exacerbated by continued treatment with desferrioxamine. Desferrioxamine can usually be reintroduced once symptoms have subsided and a full course of antibiotics completed. However. and should be treated as a medical emergency. Miller. Other Dose-related complications Administration of excessive dosage of desferrioxamine may cause the following complications in patients who are not heavily iron loaded: ñ 44 Hearing problems: High frequency sensory neural loss. 1986). an alternative chelator. Such an infection may be difficult to diagnose. Infection should be considered in any patient with a febrile illness. outweighing the risks of infection once antibiotics have been commenced. and when the therapeutic . The decision as to when to recommence treatment with desferrioxamine requires clinical judgement and a careful balancing of the potential risks and benefits. 1981). especially when associated with abdominal pain. Infection with Yersinia enterocolitica is an important risk associated with desferrioxamine treatment (described in detail in the Chapter 9: Infections in Thalassaemia Major). It is therefore recommended to cease administration of desferrioxamine in anyone with an unexplained fever. may be considered. Ulceration at the site of a recent infusion results from an intradermal infusion of desferrioxamine and should be addressed by deeper placement of the needle in subsequent infusions. until the cause has been identified and effective antibiotic treatment begun. carried out under close medical supervision (Bosquet. Unwanted effects of desferrioxamine Local skin reactions. with Yersinia enterolitica treatment with desferrioxamine should be temporarily discontinued. erythema. diarrhoea or joint pains. 1993) (see below). a patient with high cardiac iron or poor heart function may be at high risk if desferrioxamine is withheld during a septic episode. If unsuccessful. particularly to young children whose iron burden is low (Olivieri. where there is reasonable clinical suspicion of infection. Severe allergy to desferrioxamine is a rare event and can be treated by careful desensitisation. such as itching. Desensitisation is usually successful but may need to be repeated. such as Deferiprone or Deferasirox (see below). 1996). 1983. Fatal complications from iron overload are also decreased if body iron (as measured by liver iron) is kept below certain levels (Brittenham. induration and mild to moderate discomfort are common and may be due to inadequate dilution of desferrioxamine. For example. Desferrioxamine needs to be taken at least five times a week in order to optimise survival (Gabutti and Piga. tinnitus and deafness may occur when desferrioxamine is given in high doses.

particularly in the vertebrae. impaired visual fields and reduced visual acuity. 1986) but complications are also more likely in patients who have diabetes (Arden. In general. It is therefore advisable to monitor audiometry yearly. Recommended standard therapy Growth retardation: This may occur if desferrioxamine is administered at too high a dose. ñ Skeletal changes: These are more common in cases of excessive dosage of desferrioxamine where patients have a low level of iron loading (De Virgillis. In patients without iron overload. The main risk factor appears to be high dose (Olivieri. The standard dose is 20-40 mg/kg for children. Minor sensory neural deficit has been reversible in some cases. 1988. 1992. 1985). bearing in mind that audiometric changes due to excessive desferrioxamine are usually symmetrical. while it does not respond to hormonal treatment. average doses should not exceed 40 mg/kg until growth has ceased. Piga.essential in all children (see Chapter 4: Endocrine Complications). 1989). must be avoided. ñ ñ Effects on the eye: These were first noted when very high doses (>100 mg/kg/day) were given (Davies. but significant hearing loss is usually permanent. Olivieri. Treatment with desferrioxamine should be temporarily suspended in patients who develop complications. whereas milder cases are only demonstrable with electroretinography. impaired colour vision. Gabutti. 1996). 1983). Severe cases may show signs of retinitis pigmentosa on fundoscopy.025) (Porter. Rickets-like bony lesions and genu valgum may be seen in association with metaphyseal changes. to be reintroduced at lower doses once investigations indicate resolution of the problem. It is therefore recommended that doses do not exceed 40 mg/kg until growth has ceased. as they are irreversible. Another risk factor is a young age of starting treatment (<3yrs) (De Virgillis. Radiographic features include vertebral demineralisation and flatness of vertebral bodies. 1984) or those receiving concomitant phenothiazine treatment (Blake. ñ Rare complications: Renal impairment and interstitial pneumonitis have been reported at very high doses of 10 mg/kg/h or more. Symptoms may include night-blindness. Growth velocity resumes rapidly when the dose is reduced to <40 mg/kg day. index is exceeded (>0. 1988. Regular monitoring of growth is Standard dose and frequency The standard recommended method is slow subcutaneous infusion over 8-12 hours of a 10% desferrioxamine solution. 1985). as may occur during flushing of a line containing desferrioxamine. 1988). Patients should be regularly observed for such changes. Rapid intravenous injection. using an infusion pump. giving a disproportionately short trunk. asymmetry suggests other pathology. desferrioxamine has induced reversible coma when used with a phenothiazine derivative (Blake. 45 .

000Ìg/l. the dose of desferrioxamine may need to be reduced and desferrioxamine-related toxicities monitored particularly carefully. It is recommended not to give more than 2-3 mg/kg/day as supplements. If chelation therapy begins before 3 years of age. If an infusion pump is not available or if 10hour infusions are not tolerated. this should start as soon as transfusions have deposited enough iron to cause tissue damage. Figure 4: Therapeutic Index Therapeutic index = mean daily dose (mg/kg)* / ferritin (Ìg/l) The aim is to keep the index < 0. along with reduced desferrioxamine dosage. If possible. this index is not a substitute for careful clinical monitoring. SQUID or MRI) has recently been advocated as a more reliable alternative to serum ferritin (see below). This has not been formally determined. It is important that patients with high degrees of iron loading or at increased risk of cardiac complications receive adequate doses. When to start desferrioxamine therapy Use of desferrioxamine by subcutaneous bolus In thalassaemia major. In thalassaemia intermedia. Where a patient has just started on desferrioxamine and it has been decided to administer vitamin C. particularly careful monitoring of growth and bone development is advised. the rate of iron loading is highly variable and the relationship between serum ferritin and body iron can be different from that seen in thalassaemia major. 1989): Use of vitamin C: Vitamin C increases iron excretion by increasing the availability of chelatable iron. taken at the time of the desferrioxamine infusion so that liberated iron is rapidly chelated. alternating dose volumes between the higher and lower number of vials to achieve the desired mean daily dose. Dose adjustment At low ferritin levels. but current practice is to start after the first 10-20 transfusions or when the ferritin level rises above 1.Liver iron concentration (by biopsy. as an 812-hour subcutaneous infusion for a minimum of 6 nights a week. an estimation of liver iron is advisable before starting treatment to see whether iron has exceeded safe levels (see Figure 4). the vitamin supplement should not be given until after several weeks’ treatment. bolus subcutaneous treatment may be considered if the patient is not at high risk of heart disease. a dose of 50 mg/kg/day at least 5 days a week is required (Capellini. but if given in excessive doses may increase the toxicity of iron. the dose can be adjusted to the nearest whole vial (500 mg or 2 g). A randomised study has shown that serum ferritin and liver iron can be controlled equally effectively by giving an equivalent total dose (45 mg/kg x 5 per week) either as two subcutaneous ‘boluses’ or as a nightly 10-hour subcutaneous infusion (Yarali. To avoid wasting a costly drug such as desferrioxamine. Dose reductions can be made using the therapeutic index (see Figure 4) (Porter. 2005). To achieve negative iron balance in patients with average transfusion requirements.025 at all times *mean daily dose = (actual dose received on each infusion x doses per day/7) Although a valuable tool in protecting the patient from excess chelator. 46 . 2006). and up to 50-60 mg/kg for adults.

Figure 5: Rotation of infusion sites Figure 6: Insertion of needles for desferrioxamine infusion 47 . every effort should be made with each individual to help him or her to find the most convenient way to infuse the drug. giving a 10% solution. However because of local reactions such as erythema.Desferrioxamine use during pregnancy: This is discussed in detail in the Strength of infusion The manufacturers of desferrioxamine recommend that each 500 mg vial of the drug is dissolved in at least 5 ml of water. relevant Chapter 5: Management of Fertility and Pregnancy in ‚-thalassaemia). swelling and induration. it is often necessary to ‘rotate’ the sites used for injection (see Figure 5). but Desferrioxamine is not generally recommended unless the risk of cardiac disease in the mother without chelation treatment is high. nerves or organs. Some patients find that the skin over the deltoid or the lateral aspect of the thigh provides useful additional or alternative sites. Practical issues with subcutaneous infusion Because regular use of desferrioxamine is critical to a good outcome. Concentrations in excess of this may increase the risk of local reactions at the site of infusion. Site of infusion Care must be taken to avoid inserting needles near important vessels. The abdomen is generally the best place.

One successful approach may be to give patients a calendar. by adding 5-10 mg of hydrocortisone to the infusion mixture. and can be painful. The reasons for poor compliance are varied. pre-filled syringes or balloons may be useful. which returns to pre-treatment levels within minutes of stopping a continuous intravenous infusion (Porter. However. in severe cases. 1996). patient and parents. 24-hour intravenous administration of desferrioxamine via an implanted intravenous Supporting compliance It is clear that compliance with therapy determines prognosis. desferrioxamine treatment is troublesome and time-consuming. In others. Type of needle The best needle to use will depend on the individual. provided that as close to 24-hour exposure to chelation is achieved. continuous infusion of desferrioxamine is potentially more beneficial than periodic infusions because it reduces the exposure to toxic free iron (NTBI). Some pumps can log usage. Other patients prefer needles that are inserted vertically through the skin and are fixed with an adhesive tape attached to the needle (see Figure 6). are smaller. including balloon pumps. The route of administration is not critical. Patient preference is highly variable and clinicians should explore the best type of needle for each patient in order to maximise compliance. Helping a patient to take control or ‘self-manage’ is often a useful approach of long-term benefit (see TIF’s book on ‘Compliance to Iron Chelation Therapy with Desferrioxamine’). in which each infusion of desferrioxamine is noted down during the treatment.Compliance requires a sustained and secure relationship between doctor. Practical approaches to maximising compliance by decreasing local reactions and providing the most convenient pump system have been discussed above. mixing and drawing up desferrioxamine a problem. Sometimes a previously good complier may become less compliant when other life events or stresses become a burden (see Chapter 15: Psychosocial Support). Another approach has been to keep a record of empty vials returned to the provider of the desferrioxamine. Many patients are happy with butterfly needles of 25 gauge or smaller. parents cannot sanction the daily “ordeal” of chelation therapy for their child. is support from family and the health care team. however. compliance may only become a problem when a child reaches adolescence. Newer devices. and regular discussion and support are keys to maximising compliance. lighter. 48 . lowering the strength of infusion or. Rescue therapy with continuous infusions In high risk cases. Some pumps are designed to monitor compliance. and quieter than their predecessors. In some cases. Type of infuser There are many types of infusers now available. The needle tip should move freely when the needle is waggled. which are inserted at an angle of about 45 degrees to the skin surface. Especially important. For patients who find dissolving. Local reactions Persistent local reactions may be reduced by varying the injection sites. Monitoring compliance There is no perfect way to measure compliance. Intensification of treatment through continuous.

Consideration for intensive therapy Intensification should be considered in the following cases: ñ severe iron overload . Careful aseptic procedures must be followed in order to prevent possible infection by Staphylococcus epidermidis and aureus.liver iron > 15 mg/g dry weight * Management of in-dwelling intravenous lines Infection and thrombosis of the catheter may occur. it is advisable. The risk of thrombosis and infection is likely to be greater in centres that do not have regular experience in the use of long-term indwelling lines. to 5060 mg/kg) or the duration or the frequency of subcutaneous infusions. In non-high risk cases. As ferritin falls.g. options such as encouraging the patient to improve compliance or an increase in dose should be explored before moving to 24-hour treatment. Suggested dosing A dose of at least 50 mg/kg/day and not exceeding 60 mg/kg/day is recommended as a 24-hour infusion (Davis. provided treatment is maintained. in line with the therapeutic index (see above). 2000 and 2004). When cardiac disease is present. if possible to avoid placing the tip in the right atrium. reverse heart failure. 2004). Port-a-cath) (Davis. it would be usual to try to increase the dosing (for example. improve myocardial T2* (Anderson.significant cardiac dysrhythmias . Special attention must be given to avoiding 49 . 2000). As development of a thrombosis can occur at the tip of the catheter. Higher doses have been used by some clinicians however DFO is not licensed at these doses and the risk of retinopathy increases.delivery system (e. 24-hour intensive therapy(or combination therapy with desferrioxamine and deferiprone-see below) is necessary and simple increments in conventional 8-12-hour dosing are not recommended. which when established are difficult to eradicate and often removal of the infusion system becomes necessary. 1 g over 4 hours piggy-backed into the infusion line). ñ significant cardiac disease^: . the dose but preferably not the duration of treatment can be reduced. 2000) or subcutaneously (Davis.evidence of very severe heart iron loading (T2*<6 ms) ñ prior to pregnancy or bone marrow transplantation.g. when rapid reversal of iron loading may be desirable * If the only abnormalities are high ferritin or LIC.persistently very high ferritin values* . but its contribution to iron balance is very limited. Intravenous desferrioxamine with blood transfusion This has been used as a supplement to conventional therapy (e. 2002) and lead to long-term survival. Use of prophylactic anticoagulation is advised as line-thrombosis is relatively common in thalassaemia major (Davis.evidence of failing left ventricular function . Addition of vitamin C is recommended only when acute heart dysfunction has settled. which usually occurs by three months of continuous treatment (Anderson. 2004) has been shown to normalise heart function.

with no difference between the two drugs at 12 months (Maggio. Pennell. 1995) but not with values below 2. 2006). Effects on serum ferritin Four prospective randomised trials compare the effects of deferiprone on serum ferritin at baseline and at follow-up (Maggio.1995. 1998). 2000). The drug is rapidly metabolised and inactivated in the liver by glucuronidation of one of its iron binding sites (Kontoghiorghes.. and the efficiency of iron binding decreases with falling concentrations of iron or of chelator. Most of these have not been randomised controlled trials. 2006). 2005). Pennell. 2002). Agarwal. Kelfer®. Co-administration of desferrioxamine and blood can lead to errors in interpreting side effects such as acute fever. 1992. anaphylaxis and hypotension during blood transfusion. rashes. 2006. 2006). The effect on serum ferritin at this dose appears greater at higher baseline ferritin values.54 mg/g dry wt with desferrioxamine (n=30) (Pennell. 1992. Ha. It was first licensed for use in thalassaemia in India. Deferiprone (Ferriprox®. 50 . 2004. followed by the European Union and other countries outside the US and Canada. Ha.500 Ìg/L (Al-Refaie et al. Gomber. 2004. Pharmacology Effects on liver iron Three molecules of deferiprone are required to bind one iron atom. A second study showed an average decrease in LIC at 30 months with both deferiprone (n=21) and desferrioxamine (n=15) (Maggio.93 mg/g dry wt with deferiprone (n=27) and 1. Oliveiri. making comparison with desferrioxamine difficult. Unlike desferrioxamine.500 Ìg/L (Olivieri. Evidence of effectiveness of deferiprone There are considerable accumulated publications about the effects of deferiprone. A third study found decreases in LIC at one year of 0. L1) Deferiprone is an orally absorbed iron chelator that began clinical trials in the UK in the 1980. 2002.accidental boluses due to desferrioxamine collecting in the dead space of the infusion line. 1997). At currently used doses. 2002. Maggio. iron excretion is almost exclusively in the urine. There are numerous nonrandomised cohort studies demonstrating a lowering of serum ferritin at doses of 75 mg/kg/day administered in three doses. One study showed increases in LIC at 33 months of 5 mg/g dry wt with deferiprone (n=18) and 1 mg/g dry wt with desferrioxamine (n=18) (Olivieri. Four trials that measure change in liver iron concentration (LIC) from baseline after a period of treatment with deferiprone compared with desferrioxamine are available (Olivieri. 2006). 2006). In these studies significant decreases in serum ferritin are seen in patients with baseline values above 2. Hoffbrand. Desferrioxamine should never be added directly into the blood unit. Pennell. 2002. in the late 1990s.1998. Pooled analysis shows a statistically significant decrease in serum ferritin at six months in favour of desferrioxamine (Gomber. 2006. 1997a. Ha. Cohen. about 6% of the drug binds iron before it is excreted or metabolised (6% efficiency) (Aydinok.

no deaths were reported (n=157) in the Deferiprone arm in contrast to the desferrioxamine-treated patients (BorgnaPignatti. 2002). 1990). LIC increased from baseline by 28% at two years and by 68% at three years of treatment (Fischer.6 mg/g dry wt. 2006a). n= 7) (Ha. multiecho T2* demonstrated improved T2* values in the Deferiprone group compared to the Desferrioxamine group (Pepe. Effects on heart function One prospective one-year study found that in patients with normal left ventricular ejection fraction. Compliance with deferiprone One study comparing compliance with deferiprone and desferrioxamine found rates of 95% and 72% respectively (Olivieri. 2006). 51 .4 ms in the desferrioxamine group (Pennell. n=6) and desferrioxamine (2. but not in the Desferrioxamine arm was considered as due to cardiac complications (Ha. 2006).Another study reported decreases in LIC at six months with both deferiprone (6. 18% (Tondhury. In a retrospective cohort analysis of patients treated with deferiprone or desferrioxamine.5 ms in the deferiprone group. although some caution was expressed by the authors with regard to the interpretation of these results. using Deferiprone. deferiprone given at high doses (92 mg/kg) improved heart function (Pennell. no difference in LVEF or other measures of LV function was seen with either deferiprone at 75 mg/kg/day or desferrioxamine (Maggio. 2002). In another randomised study. no change in heart iron estimated by T2 Two important points to be taken into consideration are (i) compliance with any treatment tends to be higher in studies than in routine use. LIC has been found to be above 15 mg/g dry wt in variable proportions of patients: 11% (Del Vecchio. and (ii) although compliance with oral treatment is expected to be better. while another found 94% and 93% respectively (Pennell. 1998) and 58% (Hoffbrand et al. 2002). In a non-randomised prospective study. was reported for either drug (Maggio. as in the use of Desferrioxamine. mortality was not reported as an outcome measure while in a seventh. constant supervision and patient support. Patients with starting T2* values of between 8 and 20 ms showed an average increase from 13 ms to 16. it cannot be taken for granted requiring. 2006).3 to 14. A prospective study of the effects of deferiprone monotherapy on patients with abnormal LVEF or symptomatic heart disease has not been reported. of deferiprone and desferrioxamine administered at standard doses over one year. 2006). A recent study using a new technique multislice. In another randomised study over one year. Effects on heart iron The effect of deferiprone monotherapy on heart iron has been reported in two prospective studies. 2003). One study found significant improvement in T2* after one year at 92 mg/kg of deferiprone daily. 2006). In other studies where only single biopsies were performed after several years of Deferiprone treatment. 2006). one death reported in the Deferiprone arm. 1998). Effects on survival and complications of cardiac disease In six randomised prospective comparisons with desferrioxamine.9mg/g dry wt. In this analysis the author noted that there were no cardiac events in 750 patient years of exposure to Deferiprone in more than 150 patients. and 13.

2000 and 2003). Effects on liver Variable fluctuation in liver enzymes has been reported. 1998) has not been supported by other reports (Tondury. and as high as 33-40% in a study of patients in India (Agarwal et al. Choudhry et al. concomitant treatment that could affect the white cell count should be avoided. 2004). if severe neutropenia or agranulocytosis develop. but also isolated thrombocytopenia has occasionally been reported. safety alert. Wanless. <500/mm3). 46 cases of agranulocytosis. 2003) in a predominantly European patient group. Five of these cases were in patients who had been prescribed the drug for an unspecified ‘off label’ indication. Recently.reintroduced. In a prospective trial where weekly neutrophil counts were undertaken and where deferiprone was discontinued when the ANC was <1. and the use of GM CSF should be considered in the case of agranulocytosis. were reported. It is not yet clear whether these differences reflect environmental or genetic differences. Swedish Orphan has subsequently issued the following recommendations on the use of deferiprone: Nausea and change in appetite (loss or gain) occur in 3-24% of patients (Ceci 2002. from a few months to nine years. 2000). in Europe with nine related deaths (Swedish Orphan. 1992. over the same period and no difference in baseline and end-oftreatment liver function tests (Maggio. 1998. A relevant prospective randomised study investigating the progression to fibrosis. The condition may occur with thrombocytopenia. Unwanted effects with deferiprone Neutropenia.5% at one year (Cohen. 2002). showed no difference as compared with Desferrioxamine. agranulocytosis and thrombocytopenia Gastrointestinal symptoms The most serious and potentially fatal adverse effect of deferiprone is agranulocytosis (absolute neutrophil count. About a quarter of patients show ALT fluctuation of twice the normal upper limit (Cohen. * ANC: absolute neutrophil count 52 . Onset of agranulocytosis is variable. 2006). agranulocytosis developed in 0. using Deferiprone for one year. or ANC*. from as low as 4. Cohen et al.500/mm3.2/100 patient years and milder forms of neutropenia (ANC 500-1500/mm3) occurred in about 2. 2002). An observational report of fibrosis after treatment for three or more years (Olivieri. 2000) to 15% after four years (Cohen. and several were not receiving weekly blood count monitoring. One prospective randomised study showed no significant endof-study changes in liver enzymes with deferiprone or desferrioxamine (Pennell. 2000). 1998. the drug should be stopped and not The frequency of arthropathy varies greatly between studies.8/100 patient years (Cohen. 2006). Hoffbrand. offlabel use of the drug should be avoided. or differences in iron overload between populations at the start of treatment. Arthropathy ANC* should be monitored every week or more frequently if there are signs of infection.

Deferiprone could be used as a second line drug. establishing a statistically significant two-fold difference between deferiprone (34%) and desferrioxamine (15%). Effects on eye and ear There have been isolated reports of loss of vision (central scotoma). Pregnancy Deferiprone is teratogenic in animals and must never be given to patients attempting to conceive. As a result of the various unwanted effects. given in three doses. One study reported continued audiometric deterioration after switching from desferrioxamine to deferiprone (Chiodo. Treatment should be stopped where joint symptoms continue despite a reduction in deferiprone dose and are not controlled by non-steroidal antiinflammatory drugs. nystagmus. 2002). ataxia. have also been described. One trial has reported data that allows comparison of the probability of an adverse event with deferiprone and desferrioxamine (Maggio.Symptoms range from mild non-progressive arthropathy. Cases involving other joints. Until more is known. and avascular necrosis of the hips. such as wrists. but no difference between temporary or permanent treatment withdrawal. especially those with diabetes. ankles and elbows. 1998). Neurological effects Neurological complications are very rare and have been typically associated with unintentional overdosing. walking disorders. controllable with non-steroidal antiinflammatory drugs to (more rarely) severe erosive arthropathy that may progress even after treatment is stopped. potentially fertile sexually active women and men taking deferiprone must use contraception. 20-30% of patients are unable to sustain long-term treatment with deferiprone (Hoffbrand. It is therefore advisable to monitor for CNS. Other effects Zinc deficiency during deferiprone therapy has also been observed in some patients. Deferiprone should not be used in pregnant women. These effects appear to improve on cessation of treatment. for removing iron in patients who are unable to use Desferrioxamine or in whom DFO therapy has proven ineffective. dystonia and impaired psychomotor skills. Frequency of adverse events compared with desferrioxamine Adverse effects have been reported in four randomised studies comparing deferiprone with desferrioxamine. the drug is * EMEA: 53 European Agency for the Evaluation of Medicinal Products . Rare neurological effects have included cognitive effects. 1997). Recommended treatment regimens with deferiprone According to the official European licensing Agency (EMEA*). Standard dosing and frequency The daily dose of deferiprone that has been evaluated most thoroughly is 75 mg/kg/day. audiometric and visual function in patients on regimes containing deferiprone. typically in the knees. In the EU.

Age of commencement Although there have been some retrospective reports of its use in children. The standard dose of 75mg/kg/day administered in three separate doses is therefore recommended. Doses of 100mg/kg/day have been given in at least one prospective study (Pennell. such as when desferrioxamine is given three times a week (alternate nights) and deferiprone every day. only emphasise the importance of scrupulous The pharmacology of combinations of chelators may be fundamentally different depending on whether the drugs are present in cells or plasma at the same time. licensed for doses up to 100mg/kg/day but formal safety studies of this dose are limited. reserving the term ‘sequential therapy’ for when desferrioxamine is given at night and deferiprone during the day. either in the context of a formal trial or on an ad hoc basis. There is considerable variation in the way in which sequential treatment can and has been administered. and combination therapy with deferiprone and desferrioxamine (see below) or intensive therapy with desferrioxamine as a 24-hour infusion should be recommended for this group of patients. By giving desferrioxamine at night and deferiprone by 54 . A variety of regimens involving combinations of deferiprone and desferrioxamine have been used by clinicians. Recent reports of eight deaths from agranulocytosis in patients treated in Europe. at standard doses. combined with varying frequency and dosing of desferrioxamine. with no increase in side-effects reported. High dose monotherapy with deferiprone has not yet been prospectively evaluated for safety and effectiveness for patients with abnormal heart function. chelators can be given at the same time as each other (simultaneously) or following one another (sequentially). re-challenge is contra-indicated. Safety monitoring Weekly blood counts are necessary throughout treatment so that a falling white cell count can be detected early and treatment stopped before overwhelming sepsis develops. the safety and efficacy of this drug has not been formally evaluated in children under 10 years of age. Most regimes have tended to give deferiprone daily. In practice regimes may involve a component of ‘sequential’ and ‘alternating’ therapy. cited above.monitoring of the blood count throughout treatment. 2006). Pharmacology In principle. If severe neutropenia or agranulocytosis develops. usually when monotherapy with desferrioxamine or deferiprone has failed to control iron overload or its effects. Combined Desferrioxamine and Deferiprone Dose escalation with deferiprone. Use of vitamin C The effect of vitamin C on iron excretion with deferiprone is not clear and is thus not recommended. Some investigators have used the term ‘alternating therapy’ to describe the use of two drugs administered on alternate days.

see below). In short. 24-hour exposure to iron chelation can be achieved (similar to that achieved with 24-hour desferrioxamine infusion or once daily deferasirox. found no difference in the level of decrease in serum ferritin in patients randomised to combined treatment (two days desferrioxamine at 33 mg/kg + seven days deferiprone at 75 mg/kg) or to desferrioxamine five nights a week at 33 mg/kg. leading to increased drug-related toxicity.day (sequentially). However. Another prospective randomised study. comparing the effect of desferrioxamine monotherapy administered subcutaneously five times a week with that of deferiprone Effects of sequential use on serum ferritin Four randomised studies have compared levels of serum ferritin in patients using combined treatments with those under other treatment regimes. If the drugs are given at the same time (simultaneously). serum ferritin was decreased more by combined treatment (desferrioxamine five days a week plus deferiprone seven days a week) than with standard desferrioxamine monotherapy (40 mg/kg five times a week). in both arms of the study (Galanello. involving 30 patients and three different treatments (Gomber et al. Evidence of efficacy of combined treatments Effects of sequential use on liver iron One randomised study. achieved with two nights of desferrioxamine plus seven days of deferiprone at 75 mg/kg (n=14). there is also a possibility of chelation from metalloenzymes. 2005). these studies suggest that serum ferritin can be controlled with a relatively small dose of desferrioxamine given twice a week. the simultaneous use of these drugs has not been tested formally in large enough patient groups to allow firm. found that the decrease in serum ferritin was greatest with five nights of desferrioxamine. 2007). In a more recent randomised study of 65 patients (Tanner. However. they may interact in a process that involves the ‘shuttling’ of iron. albeit not significantly different from that achieved with a combined treatment of desferrioxamine two nights a week plus deferiprone seven days a week. data from several prospective studies indicate that sequential (or alternating) use of these chelators can be used to achieve control of iron overload and improvement in heart iron measurements. found LIC of <7 mg/g dry wt at baseline – a figure maintained. when combined with deferiprone at standard doses (75 mg/kg/day). 2004). Taken together. This has the theoretical advantage of 24-hour protection from labile (redox active) iron (Cabantchik. assessing the effects on liver iron of combined treatment compared to desferrioxamine monotherapy (n=60). 2006). involving 60 patients (Galanello. A third randomised study. on average. 2006). One study (Mourad et al. evidence-based recommendations about efficacy and safety. (For more on deferasirox (Exjade). which may lead to additional chelation of iron from cells or plasma and so improved iron removal. Another randomised study. 2003) found the decrease in serum ferritin achieved with five days of desferrioxamine monotherapy (n=11) to be similar to that 55 .

In an observational study. found that the decrease in liver iron was highest in the desferrioxamine monotherapy group and lowest in the deferiprone monotherapy group. one case of agranulocytosis and two of neutropenia were seen at one year in the combination arm. the T2 of the heart improved with combined therapy (Kattamis.5% in the combination arm and 0. Safety of combined treatment Formal safety data on combined treatment are limited. In an observational study of 42 patients with sequential use of treatment over three to four years (deferiprone 75 mg/kg/day plus desferrioxamine two to six days a week). In general. 2006).5% in the desferrioxamine monotherapy arm. 2007). 2005). Conclusions and possible treatment regimens The above-mentioned studies suggest that some combined regimens can control iron overload in the liver and heart where monotherapy is not having the desired effects. 2005). myocardial T2* changes with combined deferiprone 75 mg/kg seven days a week plus desferrioxamine five days a week were compared with patients on standard desferrioxamine five times a week (Tanner. including 32 patients (Tanner. although the number of patients that qualify for evaluation is small (Macklin. The increased incidence appeared to occur mostly in those regimes where the drugs were administered simultaneously. with sequential combination treatment showing an intermediate effect (Aydinok. found that an improvement in liver T2* (as a surrogate measure of LIC) was greater in the combination arm (Tanner. comparing deferiprone plus desferrioxamine five times a week with desferrioxamine monotherapy five times a week (n=65). there was an improvement in LVEF measured by echocardiography (Origa. Two observational studies have also reported changes in heart function under combined treatment. 2006). plus twiceweekly desferrioxamine. In 79 patients treated with a variable desferrioxamine regimen plus deferiprone at 75 mg/kg seven days a week for a variable time. A further randomised study. if a patient is not doing Effects of sequential use on cardiac iron In a randomised controlled study of 65 patients with moderate heart iron loading 56 . with baseline LVEF >56% changes in LVEF improved by approximately 2. 2007). 2007). IND submission to FDA. Effects of sequential use on heart function In the above-mentioned randomised controlled study of 65 patients (Tanner. the LV shortening fraction improved (Kattamis. 2007). In a recently reported prospective study.(T2* 8-20 ms). A meta-analysis of the incidence of agranulocytosis with combined regimes compared with deferiprone monotherapy suggests that the risk may be increased several-fold. 2004). while no increase in arthropathy was observed in the same group of patients. T2* improved in both groups but was significantly greater (6 ms) with combined treatment than with desferrioxamine monotherapy (3 ms). administered daily at 75 mg/kg daily or deferiprone at 75 mg/kg daily.

For patients with very high levels of heart iron or cardiac dysfunction. At this time. The tablet is dissolved in water (or apple juice) using a non-metallic stirrer. with two molecules binding each iron atom. Due to the long plasma half-life (nine to 11 hours). while mean LIC fell by 8. Negative iron balance was achieved at 30 mg/kg/day. Piga. The drug has been licensed as first-line monotherapy for thalassaemia major in over 70 countries worldwide. Metabolic iron balance studies show iron to be excreted almost entirely in the faeces. 2006). and consumed as a drink once daily. 2006). Dose effect on serum ferritin A dose-dependent effect on serum ferritin has been observed in several studies (Cappellini. The average follow up in large-scale prospective trials at the time of writing is three years. 2003).9 mg/g dry wt (equivalent to a decrease in body iron 57 . preferably before a meal. Longer-term analysis of ferritin trends shows that the proportion of patients with ferritin values <1. 2006). iron balance was achieved at 20 mg/kg/day. 2006). Evidence of effectiveness of deferasirox Deferasirox has undergone preclinical and clinical evaluation that has included largescale prospective randomised studies involving over 1. including the US (2005) and the EU (2006). oral monotherapy for the treatment of transfusional iron overload.000 patients. to assess safety. evidence of effectiveness is confined to serum ferritin and liver iron. Galanello. Deferasirox (Exjade) Deferasirox was developed by Novartis as a once-daily. Pharmacology This is an orally absorbed iron chelator.249 Ìg/L over one year (Cappellini. 2006.000 Ìg/L. once-daily administration Dose effect on liver iron and iron balance In the same prospective study. with an average fall of 1. The efficiency of chelation is 28%.000 Ìg/L and less than 2. 2003. combined treatment offers an additional approach (as does intensive therapy with at least 50 mg/kg/day of desferrioxamine for as many hours a day as is practicable-see above). over a wide range of doses and levels of iron loading. At 30 mg/kg. 2003). well with monotherapy. efficacy and the dose response effects of treatment.500Ìg/L is decreasing progressively with time (Porter. Metabolism occurs predominantly by glucuronidation in the liver. A prospective randomised study comparing the effects of deferasirox in 296 thalassaemia major patients with that of desferrioxamine in 290 patients found that 20 mg/kg daily of deferasirox stabilised serum ferritin close to 2. with mean LIC constant over one year (Cappellini. serum ferritin was reduced.provides 24-hour chelation from labile plasma iron (Nisbet-Brown.1% of the drug eliminated in urine (Nisbet-Brown. with less than 0. 24-hour treatment with desferrioxamine and daily therapy with deferiprone should be strongly considered.

2005). Gastrointestinal effects Gastrointestinal disturbances – typically mild and transient – occurred in 15% of patients and included abdominal pain. However. Unwanted effects with deferasirox A more moderate reduction in LIC occurred in children under six years old. diarrhoea and constipation.0 High (>0.of 94 mg/kg body weight) over one year. These are average trends and a closer analysis shows that the blood transfusion rate influences the response to treatment (Cohen. Retrospective analysis of effects on myocardial T2* after one year and two years of treatment suggests that this measure can be improved in a significant proportion of patients with pre-existing abnormal T2* values (Porter.9. lasting a median of less than eight days.8 -4.0 *in mg/g dry wt Table 7: Relation of transfusion rates with LIC.3-0. 2005).5 Intermediate (0.9 mg/kg in this subgroup. and estimated heart iron were not evaluated formally as part of the drug registration process.5 mg/kg/day) 59% -2 -9.5 mg/kg/day) 17% +1. 2005). and formal prospective studies on both heart function and heart iron are now in progress. 58 . Patients with normal LVEF showed no change in this measure over one year (Porter. and studies are currently underway to assess the effectiveness and safety of higher doses. These Effects on heart iron and heart function The effects of deferasirox on heart function Transfusion rate % of patients LIC change* LIC change* so transfused at 20mg/kg at 30mg/kg Low (<0. the average dose required to achieve iron balance is accordingly adjusted up or down from 20mg/kg/day (Cohen. nausea and vomiting. 2005). despite the administration of an average dose of 21. Thus for patients in the high or low transfusion category (see Table 7).3 mg/kg/day) 24% -4 -. Some patients will still fail to achieve negative iron balance at a daily dose of 30 mg/kg/day of deferasirox. these patients had the highest mean transfusional iron intake.

Further work on the mechanism of creatinine increases is being undertaken. neurosensory deafness or hypoacusis were reported as adverse events in eight patients on deferasirox and seven in desferrioxamine. Skin rashes These occurred in (11%) of patients and were typically pruritic.1 per patient for DFO and 8. 2005). Other effects No agranulocytosis. Comparing 296 patients who received deferasirox in a one-year prospective randomised study with 290 patients receiving desferrioxamine. dose reductions were instituted in only 13%. no evidence of progressive renal dysfunction has been reported where the above doses and modifications are used. In the randomised study. deafness. This compares with a dropout rate of 15% at one year with deferiprone (Cohen. 2006). Total withdrawals in deferasirox-treated patients were 6% at one year compared with 4% with desferrioxamine (Cappellini. A minority of patients required permanent discontinuation of therapy. Cataracts or lenticular opacities were reported as adverse events in two patients on deferasirox and five on desferrioxamine (Cappellini. 2005). maculopapular and generalised. In about 25% of those cases. the creatinine then returned to baseline. 2006). but occasionally confined to palms and soles of the feet.1 per patient for deferasirox. A rash typically developed within two weeks of starting treatment. Convenience and impact on quality of life Studies comparing satisfaction and convenience of DFS with DFO in thalassaemia major show a significant and sustained preference for DFS (Cappellini. which the investigator reported as related to the administration of the drug. most frequently at doses of 20 mg/kg and 30 mg/kg (Cappellini. Increase in serum creatinine An increase in serum creatinine ≥30% on at least two consecutive readings was observed in 38% of patients receiving deferasirox. published compliance data with DFO and the probability of complications from iron overload in relation to compliance with DFO. With follow up of a median of three years at the time of writing. while in the rest it remained stable or fluctuated between baseline and the maximum increase observed prior to dose reduction. arthropathy or growth failure was associated with deferasirox administration. 2000). never exceeding two times the upper limit of normal (ULN). These increases were sometimes transient and generally within the normal range. Based on thalassaemia patient reported preferences for DFS and DFO.symptoms rarely required dose adjustment or discontinuation. which paralleled improvements in LIC (Deugnier. and were more frequent in the population of patients having the most dramatic decrease in LIC and serum ferritin. Two patients out of 296 developed elevated ALT values greater than twice the ULN while receiving deferasirox for one year. * ALT: Alanine L-Aminotransferase 59 . and mild rashes often resolved without dose modification. 2006). Effects on the liver Overall a decrease in ALT* was seen. As the creatinine spontaneously normalised in a number of cases. a dose reduction of 33-50% was planned if at least two consecutive increases in serum creatinine were >33% above baseline. the cost effectiveness per qualityadjusted life year (QALY) gained is 4.

3-0. number of transfusions) do not differ from those of desferrioxamine. Galanello. A fall in LIC was seen across all age groups analysed. Deferasirox is contraindicated in patients with renal failure or significant renal dysfunction. For patients with evidence of significant heart dysfunction (e. once daily. For patients with a low rate of iron loading (<0. preferably before a meal. sexual development or bones were seen (Piga. Age of commencement Prospectively randomised studies of deferasirox in children as young as two years of age have been carried out (Cappellini. LVEF below reference range) there is very limited clinical experience and treatment cannot be recommended at this time for patients with heart failure or poor LV function. Experience of use in patients with pre-existing renal disease (baseline creatinine outside reference range) is insufficient at this time to recommend its use.5 mg/kg/day) or in patients with pre-existing high levels of iron loading. The drug should not be used in pregnant women.g.3 mg/kg/day). A starting dose of 20 mg/kg is recommended for thalassaemia major patients who have received 10-20 transfusion episodes and currently receive standard transfusion at rates of 0. 2006. 2006). with no age-related adverse effects: in particular. The combined use of deferasirox with other iron chelators has also not been formally assessed and therefore cannot be recommended at this time. On the basis of present knowledge. 2006). 30 mg/kg/day is recommended. the criteria for starting treatment (ferritin level.5 mg of iron/kg/day. Recommended dosing Other indications and contraindications The drug is taken orally as a suspension in water. a dose of 10-15 mg/kg may be sufficient to control iron loading.Recommended treatment regimens with deferasirox The drug also appears to be palatable to children at this young age. no adverse effects on growth. In those patients in whom there is a higher rate of iron intake from transfusion (>0. age. As the median follow up in large-scale studies is three years at this time. where a decrease in iron loading is clinically desirable. 60 . vigilance in monitoring for possible longterm effects is still advisable.

32-0.7 mg/g dry weight. Variability in daily excretion. Moderately high to high risk = 7 .000 mg/l.Summary of Iron Overload and its treatment: ñ 1.08 mg of iron in 1ml of pure red cells (HCT = 100%). Ferritin levels related to low risk are below 2. the following should be considered: (i) low body iron. ñ Urinary iron – used to monitor desferrioxamine or deferiprone dose effects.6 x LIC (mg/g dry weight). and ñ NTBI and LPI – not yet routinely used. (ii) vitamin C deficiency. 61 .15 mg/g dry weight.08 (annual transfusion requirements x donor Hct = volume of RBC).500 mg/l. When serum ferritin is low. Very high risk = > 15 mg/g dry weight. c) MRI – R2.8 .64 mg/kg/day. the following should be considered: (i) iron overload. Total body iron stores = 10. On average 200mg iron/donor unit. ñ Rate of iron loading: volume of RBC x 1.8 mg/g dry weight Low to moderate risk = 1. In thalassaemia intermedia. (ii) inflammation. LIC is measured by: a) Liver biopsy – indicated if ferritin levels deviate from expected trends. When high. b) SQUID – not universally available. ferritin underestimates the degree of iron overload. preferably below 1. ñ Cardiac iron reflected by heart function tests and measured by MRI T2*. if coexistent hepatitis and if uncertain response to chelation. and/or (iv) liver damage. (iii) hepatitis. ñ Serum ferritin broadly related to body iron. ñ Ranges of LIC reflecting levels of RISK:Very low risk = <1. ñ Recommended transfusion 100-200 ml/kg/year is equivalent to 116-232 mg iron/kg/year or 0.

Keep index < 0. ñ Standard treatment: a) Slow subcutaneous infusion over 8-12 hours. Indications: a) Persistently high serum ferritin.025 at all times. c) Significant heart disease. 62 . 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. b) LIC > 15 mg/g dry weight. b) 10% desferrioxamine solution (5 ml water for each 500 mg vial). ñ If before 3 years of age monitoring of growth and bone development is recommended.000 Ìg/l. Infuse 8-12 hours 6 nights minimum per week. and c) infusion pump (several types available). 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.Desferrioxamine: ñ Initiate treatment after first 10-20 transfusions or ferritin level above 1. ñ Intensive chelation with desferrioxamine – continuous 24-hourly infusions IV or SC. and b) adults 50-60 mg/kg.C. until growth has ceased). ñ Therapeutic index = mean daily dose (mg/kg) (Mean daily dose = actual dose of each infusion x doses/7 days) /ferritin (mg/l). and. ñ Alternative route: subcutaneous bolus – two S. in selected cases. boluses/day to a total daily dose of 45 mg/kg. It should be interrupted during the first trimester and can be used in the second and third trimesters. ñ Standard dose: a) children 20-40 mg/kg (not exceeding 40 mg/kg.

ñ Administration: Tablet dissolved in water (or apple juice). If pre-existing iron overload (or iron intake > 0. No recommendations as to which is the more effective combination can be made at present. the dose of 30 mg/kg/day is recommended. especially in simultaneous use. lower doses may be sufficient to control iron loading. Deferasirox: ñ Recommended dose: Starting dose 20 mg/kg/day. but as yet not enough information). ñ Vitamin C concomitant treatment not recommended.Deferiprone: ñ Standard dose: 75 mg/kg/day in 3 divided dose (up to 100 mg/kg/day.3 mg/kg/day). Taken once a day before a meal. CAUTION: agranulocytosis may be more frequent in combination therapy. It is recommended that sexually active patients should use contraception. and studies are currently underway to assess the effectiveness and safety of higher doses. ñ Children above 10 years of age. ñ Continuous Monitoring ñ Use in children > 2 (FDA) and >6 (EMEA) years of age ñ Contraindicated in renal failure or significant renal dysfunction. COMBINATION THERAPY. combined regimes offer an alternative that can reduce iron levels in both the liver and heart.5 mg/kg/day). In patients for whom monotherapy with desferrioxamine or deferiprone is not controlling body levels of iron or myocardial iron or in the presence of significant heart disease. For patients with low rate of iron loading (<0.3-0.5 mg/kg/day). using a non-metallic stirrer. some patients will still fail to achieve negative iron balance at a daily dose of 30mg/kg/day of deferasirox. After 10-20 transfusions (iron intake (0. ñ Weekly blood counts (more frequently if signs of infection). ñ Pregnancy – stop treatment. ñ Cannot be given during pregnancy 63 .

transfusional iron overload.7 5. growth hormone deficiency/insufficiency.5 2.5 7.8 3.1 8 6.8 . Growth Growth retardation is common in thalassaemia major.5 2.3 37. Determining the prevalence of endocrine complications is difficult because of differences in the age of first exposure to chelation therapy. Diagnosis and investigations Diagnosis requires careful clinical evaluation to establish: ñ slow growth rates: growth velocity expressed in cm/year.4 43. Key Short stature Primary hypothyroidism Insulin-dependent diabetes mellitus Impaired glucose tolerance Hypoparathyroidism Hypogonadism Growth hormone deficiency/insufficiency males females males females males females males females males females males females males females Based on a sample of 3. Patterns of growth are relatively normal until the age of 9-10 years when growth velocity begins to slow. 1991).8 3. and the continuing improvement in survival in well-chelated patients. zinc deficiency..1 30.817 thalassaemia patients in 29 countries Table 1: Growth and endocrine complications in thalassaemia 64 Number of patients 664 513 60 64 75 46 109 136 40 125 353 243 53 148 % 31. contributing factors to stunted growth in patients with thalassaemia may include chronic anaemia.7 7. The growth rates and endocrine complications of a sample of 3. undernutrition and psychosocial stress. Other contributing factors include hypothyroidism. hypersplenism and chelation toxicity (DeSanctis.1 8. below 1SD for age and sex (based on growth velocity charts) ñ short stature: height below the 3rd centile for sex and age (based on national growth charts) (see Appendix A) ñ signs of other pituitary hormone deficiencies (e. hypogonadism.g. gonadotrophins) ñ other possible causes of retarded growth. Despite early establishment of appropriate chelation therapy.Endocrine Complications In Thalassaemia Major Endocrine abnormalities are among the common complications of thalassaemia. problems such as delayed sexual maturation and impaired fertility may persist. chronic liver disease. 2004).817 thalassaemia patients in 29 countries are reported in Table 1 (De Sanctis.

and in girls as the absence of breast development by the age of 16 (de Sanctis. and investigation of glucose tolerance. and breast size at B3 (see Table 2). Arrested puberty is a relatively common complication in moderately or grossly iron overloaded patients with thalassaemia. pubertal staging (Tanner 1962) and bone age. Delayed puberty is defined as the complete lack of pubertal development in girls by the age of 13. urine analysis. and in boys by the age of 14. hypogonadism should be carefully investigated before starting growth hormone treatment which may result in decreased insulin sensitivity and abnormal glucose tolerance (de Sanctis. Delayed puberty and hypogonadism Delayed puberty and hypogonadism are the most obvious clinical consequences of iron overload. In such cases. growth hormone (GF) secretion. TSH). Possibly useful tests include: Insulin Growth Factor-I (IGF 1) and Insulin Growth Factor Binding Protein-3 (IGFBP-3). 1995). In such cases annual growth velocity is either markedly reduced or completely absent (de Sanctis. Evaluation of short stature/retarded growth.patients with thalassaemia receiving irregular transfusion. Hypogonadism is defined in boys as the absence of testicular enlargement (less than 4 ml). The secretion of GH is normal in the majority of patients with thalassaemia. alkaline phosphatase. an investigation of transglutaminase antibodies is also essential. It is important to bear in mind that desferrioxamine toxicity is an important cause of delayed growth (see Chapter on Iron load and Iron Chelation) Treatment Anaemia. assessment of levels of sex hormones. In peri-pubertal patients. 1999). Oral zinc sulphate supplementation should be given to patients with proven zinc deficiency. zinc. However. 1995). the testicular size remains 6-8 ml. to exclude celiac disease. folate deficiency and hypersplenism are traditional causes of poor growth in 65 . The first step in the investigation of short stature or retarded growth is the regular (six-monthly intervals) and accurate measurement of standing and sitting height. as well as in those regularly using desferrioxamine. and is characterised by a lack of pubertal progression over a year or more. Additional endocrine studies that may be helpful include thyroid function tests (FT4. Interpretation of absolute height must take into account the height of the parents. Investigation of a child with thalassaemia who has stunted growth is generally similar to that of a child without thalassaemia. calcium. including examination of metaphyses.

Insulin Growth Factor Binding Protein-3 (IGFBP-3). with secondary amenorrhoea developing over time. Increased pigmentation of scrotal skin and enlargement of testicles. serum 17-‚ Estradiol) Pelvic ultrasound to assess ovarian and uterine size Transglutaminase antibodies In selected cases. Insulin Growth Factor-I (IGF-I). 4-5 ml. Ovarian function in such cases is generally normal but gonadotrophin response to Gonadotrophin-Releasing-Hormone (Gn-RH) is low compared to patients with normal menstrual cycles. 15-25 ml) B4: Advanced puberty (areola and nipple project separately from the contour of the breast) PH4: Advanced puberty (hair corresponds to adult growth but less extensive) P5: Adult B5: Adult PH5: Adult (Fully developed breast. and scrotum) B3: Mid-puberty (breast and areolar enlargement) PH3: Mid-puberty (hair extends over the pubic junction) P4: Advanced puberty (enlargement of penis in length and breadth. particularly in poorly chelated patients. stimulation test for Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) Sex steroids (serum testosterone. little or no enlargement of penis) B2: Early puberty (breast bud stage) PH2: Early puberty (sparse growth) P3: Mid-puberty (enlargement of penis and further growth of testes. 8-12 ml. the areola no longer projects separately from the breast contour) Table 2: Pubertal assessment according to Tanner Most women with thalassaemia major present primary amenorrhoea. Growth Hormone (GH) stimulation test In selected cases. plasma zinc Treatment The treatment of delayed or arrested puberty and of 66 .Penile development P1: Prepubertal Breast development B1: Prepubertal Growth of pubic hair PH1: Prepubertal P2: Early puberty (enlargement of scrotum and testes. ñ ñ ñ ñ Investigations ñ ñ ñ ñ ñ Routine biochemical analysis Bone age (X-ray of wrist and hand) Thyroid function (TSH and FT4) Hypothalamic-pituitary-gonadal function: Gonadotrophin-Releasing-Hormone (Gn- RH).

Bone age may be helpful in evaluating hypothyroidism. administered intramuscularly. taking account of the complexity of the issues involved and the many associated complications. low oestrogen-progesterone hormone replacement is the recommended treatment. Collaboration between endocrinologists and other doctors is critical. Typically. hypogonadotrophic hypogonadism depends on factors such as age. the treatment consists of testosterone esters or topical testosterone gel. and the presence of psychological problems resulting from hypogonadism. constipation. along with TRH test and TSH response. In patients with hypogonadotrophic hypogonadism. decreased activity. The majority of patients have primary thyroid dysfunction. administered as for the treatment of delayed puberty and hypogonadotropic hypogonadism. beginning at the age of 12 years. low dosages of intramuscular depot-testosterone esters (25mg) are given monthly for six months. Signs and symptoms Pre-clinical hypothyroidism is asymptomatic.5-5 Ìg daily) for six months. chronic liver disease. The same effects can be achieved with topical testosterone gel. 1995. If breakthrough uterine bleeding does not occur. symptoms such as growth retardation. usually appearing in the second decade of life. the thyroid gland is not palpable. Sabato. 67 . For delayed puberty in males. oral oestrogen is re-introduced in gradually increasing dosages (ethinyl estradiol from 5-10 Ìg daily) for another 12 months. The fully virilising dose is 75-100 mg of depot-testosterone esters every 10 days. and their interpretation. If spontaneous puberty does not occur within six months after the end of treatment. In mild and overt hypothyroidism. above normal weight. treatment at a dose of 50 mg per month can be continued until growth rates wane. reduced school performance. Hypothyroidism This may occur in severely anaemic and/or iron overloaded patients. 1983). damage to the hypothalamo-pituitary-gonadal axis. Annual investigation of thyroid function is recommended. Secondary hypothyroidism caused by ironmediated damage of the pituitary gland occurs very rarely. thyroid antibodies are negative and thyroid ultrasonography shows an irregular echo pattern with thickening of the thyroid capsule. The incidence of hypothyroidism is slightly higher in females. For pubertal arrest. followed by hormonal reassessment. cardiac failure and pericardial effusion may be encountered. For girls. followed by hormonal re-assessment. are shown in Table 3. therapy may begin with the oral administration of ethinyl estradiol (2.It is important that the treatment of pubertal disorders is treated on a patient-by-patient basis. Free T4 and TSH are the key investigations. severity of iron overload. The condition is uncommon in optimally treated patients (de Sanctis.

A casual Plasma Glucose (PG) ≥11. Treatment ñ Diabetic type: Fasting Plasma Glucose (FPG) ≥7. 68 . 1973) Table 3: Hypothyroidism and its treatment Abnormal thyroid function may be reversible at an early stage through intensive chelation.1mmol/l (200 mg/dl). L-thyroxine is given. TSH-thyroid stimulating hormone. The persistence of “diabetic type” indicates that a subject has diabetes. viral infection and/or genetic factors.1 mmol/l (110 mg/dl) and 2hPG <7. The type of glycaemia may be classified as diabetic. with differences in the age of onset (it may start early in the second decade of life) and slow progression of disturbances in glucose metabolism and insulin secretion. TRH-thyrotrophin-releasing hormone (adapted from Evered. borderline or normal.Hypo-thyroidism Serum FT 4 Serum TSH TSH Response to TRH Increased Subclinical Normal Mild Overt Marginally low Low Marginally increased (TSH: 4.5-8mIU/l) Elevated Exaggerated Elevated Exaggerated Treatment Observation L-thyroxin L-thyroxin KEY: FT4-free thyroxine. Diabetes in thalassaemia is rarely complicated by ketoacidosis.1 mmol/l (200 mg/dl) also indicates diabetic type. ñ Normal type: FPG <6. Sub-clinical hypothyroidism requires regular medical follow-up and intensive iron chelation therapy. according to cut-off values for venous PG measurements. In patients with mild or overt hypothyroidism. The pathogenesis resembles type-2 diabetes. ñ Borderline type: includes those who are neither diabetic nor normal types. chronic liver disease. Impaired carbohydrate metabolism Impaired glucose tolerance and diabetes mellitus may be the consequence of ‚-cell destruction secondary to iron overload. and good compliance.8 mmol/l (140 mg/dl). Treatment depends upon the severity of organ failure.0 mmol/l (126 mg/dl) and/or plasma glucose 2 hours after 75 g glucose load (2hPG) is ≥11.

is a recognised late complication of iron overload and/or anaemia and usually begins 69 . weight reduction. as hypercalcaemia is a common complication of this treatment. under careful cardiac monitoring. triglycerides) ñ Urinary protein ñ Evaluation of retinopathy Hypoparathyroidism Hypocalcaemia. 0. 1995). Parathormone may be normal or low. Treatment ñ Impaired glucose tolerance may be improved by a strict diabetic diet. ñ In patients with persistently high serum phosphate levels. In cases with low serum calcium and high phosphate levels. Weekly blood tests are required at the start of treatment. This should be carefully monitored. where applicable. with low readings for 1.25-1. The majority of patients show a mild form of the disease accompanied by paraesthesia. and possibly intensive iron chelation therapy ñ In symptomatic patients. For children.after the age of 16 (de Sanctis. is usually sufficient to normalise plasma calcium and phosphate levels. parathyroid hormone should also be evaluated. followed by quarterly plasma and daily urinary calcium and phosphate measurements. Monitoring diabetes and its complications ñ Blood glucose (daily or on alternate days) ñ Ketones – check if blood sugar is above 250 mg/dl ñ Fructosamine estimation is more helpful than glycosylated haemoglobin levels ñ Urinary glucose is influenced by increased renal glucose threshold ñ Renal function (serum creatinine) ñ Serum lipids (cholesterol: HDL. ñ Calcitriol. a phosphate binder (other than aluminium) may be considered. Investigations Oral Glucose Tolerance Test (OGTT) should be performed annually from the age of puberty. due to hypoparathyroidism. Treatment ñ Oral administration of vitamin D or one of its analogues. serum phosphate and phosphate balance. seizures or cardiac failure.75 g/kg (to a maximum of 75 g) is used for OGTT. More severe cases may demonstrate tetany. Investigations should begin from the age of 16 and should include serum calcium. followed by oral vitamin D. Some patients require high doses of vitamin D to normalise their serum calcium levels. insulin treatment is normally required but metabolic control may be difficult to achieve ñ Where hyperinsulinism is insufficiently managed by diet alone.0 Ìg. a dose of 1. twice daily.25 dihydroxycholecalciferol (vitamin D). LDL. acarbose may be a useful first-line therapy for glycaemic control ñ The role of oral hypoglycaemic agents remains to be fully determined Bone radiology shows osteoporosis and malformations. ñ Tetany and cardiac failure due to severe hypocalcaemia require intravenous administration of calcium.

Skordis. indicating that fertility is usually salvageable. may also influence the outcome of fertility treatment and need to be corrected by standard care. 1998). However. and the expectation of having a family—an important dimension of quality of life—is consequently an important aspiration for many. particularly those with splenectomy and autoimmune antibodies. with minor modifications. However. the reproductive medicine specialist. patients’ quality of life has also increased significantly. the cardiologist and the obstetrician. Planned pregnancy is essential both in spontaneous and ART conceptions. these risks can be minimised through pre-pregnancy counselling with the haematologist. whereas TM’s. Although spontaneous fertility can occur in well-chelated and -transfused patients with spontaneous puberty. as HbTh pregnancies are high risk for the mother and the baby. Management of fertility Although 80-90% of patients have HH. other endocrine disorders. Successful spontaneous pregnancies. in conjunction with the specialist nurse. in addition to complications specific to iron overload. The fertility options are dependent on two factors (a) partners’ carrier status and (b) site of damage to the H-P-G axis.Management of Fertility and Pregnancy in ß-thalassemia gonadal axis (Chatterjee and Katz.rcog. Fertility assessment of patients with thalassaemia should also include evaluation of the partner according to standard criteria (see http://www. Older patients with thalassaemia major usually have hypogonadotrophic hypogonadism and are unlikely to conceive spontaneously. The management of patients of thalassaemia intermedia (TI) is similar to that of thalassaemia major (TM). namely diabetes and hypothyroidism. also face the risk of thromboembolism. Management of infertility requires a thorough work-up. the majority are infertile due to hypogonadotrophic hypogonadism (HH) consequent to transfusional haemosiderosis (Chatterjee and Katz. Christou et al. ovulation in females and spermatogenesis in males can be induced by exogenous gonadotrophin therapy.e. gonadal function is usually intact in the majority of patients. Advances in the primary care of ‚thalassaemia major (HbTh) by optimal blood transfusion and chelation therapy have improved patient survival into adulthood.uk). ‘bypassing’ the H-P axis. Also. 2000. At the same time. 1999). whereas patients with thalassaemia intermedia are potentially fertile with intact pituitary- 70 . including pre-pregnancy counselling of the couple (see below). have been documented in HbTh females and males (Aessopos et al. i.org. 2006). 2000) and need Assisted Reproductive Techniques (ART). the management during pregnancy are different in that TI patients have an increased thrombotic risk and need transfusion during pregnancy (Nassar. as well those resulting from the induction of gametogenesis.

1998 review). another option may be adoption. If both partners are homozygous for ‚thalassaemia. when gonadotrophins are pulsatile. This method may be more acceptable to certain communities with religious beliefs against termination of affected pregnancy. as sperm can be more easily available from sperm banks.H-P damage. followed up through. Methods for induction of ovulation Induction of ovulation with pulsatile GnRH infusion is only possible at the early stage of FIGURE1 71 . For such procedures. whereas the use of donor eggs is technically more complicated with an unpredictable success rate (Deech. according to Human Fertilisation and Embryology Authority (HFEA) guidelines (Deech. where there is good family support. But majority of patients with HH are apulsatile with functional gonads. it is important to obtain the consent both and imperative of the patients and involved clinicians and carefully documented notes should be kept throughout. preferably donor sperm is the ideal option. Lastly. multiple pregnancy. Induction of ovulation should only be undertaken by a specialist reproductive team. in patients with severe organ damage or where both partners have HbTh. use of donor gametes. 1998 review). and are therefore likely to benefit from HMG/HCG therapy with 80% success rate. Patients with endometrial damage respond better to IVF programmes. then Pre-implantation Genetic Diagnosis (PGD) is another option. vaginal ultrasound scans. ectopic pregnancy and miscarriage. If the partner is heterozygous. The regime to be followed will be dependent on the team’s local protocol (See Figure 1 for an established protocol). where diagnosis can be made prior to conception. Patients should be counselled regarding risk of hyperstimulation syndrome. The risk of hyper-stimulation and multiple births can be minimised by vigilant monitoring of the induced cycle.

patients. The induction process must be
undertaken according to HFEA guidelines,
with an emphasis on consent and counselling
(Deech, 1998 review) (See Figure 2 for an
established protocol).

Key points in induction of ovulation:
ñ Careful monitoring of the cycle by serial
vaginal ultrasound scans
ñ DFO should be continued until HCG is
injected/biochemical pregnancy is
confirmed
ñ Luteal support with progesterone may be
required
ñ After a maximum of six cycles, reassess
and refer for IVF

However, the recent advent of
micromanipulation techniques such as intracytoplasmic sperm injection (ICSI) has
improved conception rates, even in oligoasthenospermic patients. Therefore, sperm
should be cryopreserved in all subjects unless
azoospermic, to better preserved fertility and
so the chance of conception. However, our
recent literature on sperm DNA damage in
HbTH (Perera, Pizzey et al, 2002) males raises
anxiety about mutagenic risks in these
individuals, especially after ICSI, where natural
protective barrier against gamete selection
during fertilisation is lost.

Induction of
spermatogenesis
The induction of spermatogenesis in male
patients with thalassaemia is more difficult
that the induction of ovulation in their
female counterparts, with a success rate of
10-15% in moderate to severely iron loaded

FIGURE 2

INDUCTION OF SPERMATOGENESIS
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

SAVE

ñ If azoospermia persists, stop treatment

72

Pre-pregnancy
counselling

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

Before embarking on fertility treatment, it is
important that patients and their partners
attend pre-pregnancy counselling, which has
a three-fold purpose (a) evaluation of
eligibility, (b) physicians to review
medications involved and (c) physician/s,
patient and partner to discuss the risks
associated with induced fertility and
pregnancy.

1. The most important is cardiac function
because cardiac complications remain the
leading cause of death in both transfused
and untransfused patients. The cardiac
load is increased during pregnancy by at
least 25-30% due to increased heart rate
and stroke volume. This, along with iron
load, has a real potential for premature
death from cardiac failure. Therefore it is
prudent that all patients with TM should
have cardiac assessment by ECHO (Left
ventricular ejection fraction >65%;
fractional shortening >30%), by ECG, both
at rest and with exercise, and by 24 hr
tapes to check for rhythm disorders. If LV
dysfunction can be demonstrated in
patients under stressful conditions or if
significant arrhythmias have occurred,
then women should be strongly advised
against planning pregnancies (Hui et al,

Evaluation of
eligibility (Figure 3)
Each patient should be assessed regarding
suitability to embark on pregnancy with
optimum outcome both for the mother and
the fetus. There are at least 3 important
factors that must be seriously considered

Figure 3

EVALUATION OF ELIGIBILITY FOR PREGNANCY
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

Diagnosis and Management of
Osteoporosis in ‚-thalassaemia). Patients
should also be screened for diabetes,
thyroid function, and acquired red cell
antibody. Both partners should be
screened for haemoglobinopathy.

2002). Most of the non-invasive cardiac
investigations are relatively insensitive for
detecting early cardiac loading. Modified
MRI has recently been developed using
gradient T2* measurements to quantify
iron levels, and can accurately relate
these to LV dimensions assessed using
the same technique (Anderson et al,
2001). If the facility exists, cardiac MRI
should be performed and the aim should
be to have T2* closer to 20 ms.

Review of
medications

2. Liver function should be evaluated by
biochemical test while iron overload
status by liver biopsy and MRI. Liver
biopsy can also provide information on
fibrosis and cirrhosis.

(Figure 4)

This is a good opportunity to review
medications and to give advice to patients
regarding diet, smoking and alcohol, and to
commence supplements of folic acid, calcium
and vitamin D. Patients on oral chelators
(deferasirox or deferiprone) are
recommended to switch to desferrioxamine
prior to induction of
ovulation/spermatogenesis (Singer and
Vichinsky, 1999). Hormone replacement
therapy should also be stopped at least 4-6
weeks prior to induction of gametogenesis.
Bisphosphonate is contraindicated during
pregnancy and breast-feeding, as both are
states of considerable negative calcium
balance. It is therefore prudent to ensure
adequate calcium and vitamin D intake
before and throughout pregnancy. Other
medications that should be discontinued at
least six months prior to fertility treatment
include interferon, ribovarin and hydroxy
urea. Hypothyroid patients receiving thyroid
replacement therapy should receive
increased doses, to ensure they are
euthyroid. Hyperthyroidism is rare in patients
with thalassaemia. However, if a patient is
receiving an anti-thyroid drug such as
carbimazole, this should be replaced by
propyl thiouracil.

3. All patients should be screen for HIV,
Hepatitis B, Hepatitis C and rubella. The
opportunity should not be missed to
ensure rubella immunity prior to
pregnancy. If the patient is HIV positive
and wishes to have a family, she should
be advised of the usual recommendations
for care which include appropriate
antiviral agents, delivery by CS and the
avoidance of breast feeding to reduce
the risk of vertical transmission to <5%
(RCOG clinical Green Top Guidelines,
2004). As regards Hepatitis C-positive
cases, these women should be given a
course of antiviral agents to attain
Hepatitis C RNA negative status.
4. Before embarking on pregnancy, it is also
important to establish bone heath by Xray of spine and DEXA scan of hip and
spines (BMD score) and correction of
osteoporosis/osteopenia by institution of
appropriate therapy (see Chapter 6:

74

Figure 4

REVIEW OF MEDICATIONS PRIOR TO PREGNANCY
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

pregnancy. Serum ferritin is likely to alter by
10%, despite increase in frequency of blood
transfusion (Aessopos, 1999; Tuck, 1998;
Daskalakis, 1998; Butwick, 2005). The aim
during pregnancy is to maintain pretransfusion haemoglobin concentration
above 10g/dL (Aessopos, 1999).

Risks associated with
pregnancy (Figure 5)
All patients should be made aware that
pregnancy per se does not alter the natural
history of thalassaemia. If pregnancy is
managed in a multidisciplinary setting, the
foetal outcome is usually favourable with a
slight increase in incidence of growth
restriction (Aessopos, 1999; Ansari, 2006;
Tuck, 1998). It has been shown that the risks
of pregnancy-specific complications such as
ante-partum haemorrhage and pre-eclampsia
in thalassaemia are similar to the background
population. It has also been shown that DFO
is not required during pregnancy in patients
that are not iron overloaded and that have
adequate cardiac function prior to

Management of
pregnancy (Figure 6)
Once pregnancy is confirmed, the patient
should be managed in a multidisciplinary
team consisting of obstetrician, midwife,
physician, haematologist and anaesthetist.
The patient should be made aware that
although pregnancy is high risk, the outcome
is usually favourable (Aessopos, 1999).

75

thromboprophylaxis by low molecular weight heparin is required 76 . Although there is a predisposition to venous thrombosis in postsplenectomy patients. particularly those with thalassaemia intermedia. 1998). 1989). this should be repeated again at 28 weeks. Daskalakis. in each trimester. no reports of thrombotic episodes have been reported in the literature (Tuck. Eldor and Rachmilewitz. Serial ultrasound scans from 24-26 weeks onwards must be undertaken to monitor foetal growth. HIV ñ Risk of iso-immunisation ñ Risk of pre-maturity and growth restriction is increased in multiple births from mid-trimester (Nassar. with caution. Folate demand in pregnancy is normally increased and this may be relevant in patients with thalassaemia due to bone overactivity. which can be minimised by ensuring optimal cardiac function before embarking on pregnancy. Regular folic acid supplementation is recommended in mothers with thalassaemia major to prevent superimposed megaloblastic anaemia. DFO may be used. 1998. The key points include evaluation of cardiac function by ECHO. In selected cases. although this has only been demonstrated individuals with ß-thalassaemia minor (carriers) (Leung. if normal. 2006. and of liver and thyroid functions. If cardiac function deteriorates during pregnancy. as evidence regarding The main risk to the mother is cardiac complications.Figure 5 Risks associated with pregnancy 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. 2002). All patients should be screened for gestational diabetes at 16 weeks and.

DFO can be recommenced but not oral chelating agents. Although most skeletal deformities are largely prevented by regular transfusion. Patients with osteoporosis usually have vertebral bodies with reduced height and the segmental position of the conus may be lower than predicted (Borgna-Pignatti. one could await the spontaneous onset of labour. 1967). progesterone-only pill or barrier methods are usually appropriate. Intrauterine devices should be avoided because of risk of infection. to avoid the risk of difficult intubation associated with general anaesthesias due to severe maxillo-facial deformity in TM patients (Orr. Although there are currently no reports regarding human foetal anomaly from DFO. however bisphosphonate therapy for osteoporosis should only be resumed after cessation of breastfeeding. All patients should be counselled regarding contraception. It is therefore important to correct osteoporosis prenatally by hormone replacement (and premidronate therapy). largely due to short stature and skeletal deformity in this cohort. similar to reported data. it is the authors’ experience that 80% of women with thalassaemia will require caesarean section (CS) because of higher frequency of cephalopelvic disproportion. As regards the newer oral chelating agents. if pregnancy is non-complicated. Breastfeeding should be encouraged in all cases except in those who are HIV and/or hepatitis C RNApositive and/or HBsAg positive because of the risk of transmission via breast milk. It is desirable to use epidural anaesthesia for CS wherever feasible. 1999). 1967). despite transfusion therapy (Borgna-Pignatti. the manufacturer’s product information for DFO includes risk of skeletal anomalies in animal pregnancies. teratogenicity of DFO is equivocal (Singer and Vichinsky. Osteoporosis and scoliosis are common in TM. But. patients should be informed about this prior to its use during pregnancy. 2006b). As regards the management of labour. to increase bone density so that spinal anaesthesia at CS becomes feasible. 2006b). spinal abnormalities associated with TM are relevant to regional blockade. combined with normal foetal growth. data on fetotoxicity are lacking. In most cases.After delivery. However. Taking oestrogen-containing birth control pill is also not advisable because of the risk of thrombo-embolism (Orr. Male patients with hypogonadotrophic hypogonadism are not fertile spontaneously and therefore contraception is not required. 77 . Calcium and vitamin D supplements should be continued during breast-feeding. where required.

barrier method ñ Avoid intrauterine device and oestrogen-containing preparations ñ Resume bisphosphonate after breastfeeding has ceased 78 .Figure 6 Key points for pregnancy care 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.

polymorphism of the VDR gene and COL 1 gene seem to play an important role in the development of low bone mass (BorgnaPignatti. which can affect the structural and material properties of bone which are complicated and difficult to assess in routine clinical practice (Sambrook. Voskaridou. Genetic factors. 2002). 2004) is accompanied by a comparable or even greater increase in osteoclast activity through RANK/RANKL/osteoprotegerin pathway as the final. for instance. osteopeniaosteoporosis syndrome (OOS) is a major cause of bone pain of hip and spine and fragility fractures especially of the lumbar spine which may be found in 70-80% adult patients with ‚-thalassaemia world-wide. Chan. as well as the degree of mineralisation. The causes of OOS in thalassaemia syndromes are multifactorial (Chatterjee. 2003). Diagnosis and investigations (Figure 1 and Figure 2) Aetiology and pathogenesis The commonest presentation is bone pain and backache with or without past history of fractures. Lasco. and include marrow expansion secondary to ineffective erythropoiesis (Borgna-Pignatti. low vitamin D levels due to aberrant vitamin D-PTH axis (BorgnaPignatti. 2003) but the underlying pathogenesis is still speculative. matrix and mineral composition. many other skeletal characteristics also contribute to bone strength (Mahachoklertwattana 2003). 2000). 2004. 2006). These include bone macro architecture (shape and geometry). 2004. 2006). low IGF1 (Lasco. accounting for significant bone morbidity (Chatterjee. 2000. 79 . 2006). Patients may also be asymptomatic in 20% cases. bone micro architecture (both trabecular and cortical). 2000). and the rate of bone turnover. use of deferioxamine (Voskaridou. 2003. 2006.Diagnosis and Management of Osteoporosis in ‚-thalasaemia Osteoporosis is a skeletal disease characterised by low bone mass and micro architectural deterioration with a resulting increase in bone fragility and hence susceptibility to fracture (Sambrook. Voskaridou. multiple endocrinopathies such as hypogonadothrophic hypogonadism or primary hypogonadism (Chatterjee. Morabito. transfusional haemosiderosis (Borgna-Pignatti 2006) . anaemia . The diminished osteoblast function with reduced osteocalcin (Morabito. 2001). (A) DEXA Scan The diagnosis is best confirmed by bone mineral density (DEXA) according to WHO criteria (Figure 1). dominant mediator (Voskaridou. 2003) or oral chelation agents for iron overload (Chan. Several studies have shown reduced bone mass in osteoporotic patients with thalassaemia (Chatterjee. 2002. Although bone mineral density remains the best available noninvasive assessment of bone strength in routine clinical practice. 2001). 2002). 2000). delayed puberty (Chatterjee. micro damage accumulation. With increased life expectancy. 2006). Morabito. BorgnaPignatti 2006b.

TFT ñ Liver function test ñ Spinal X-ray ñ DEXA-Spine-hip. bilirubin. testosterone and oestradiol assays (Chatterjee. phosphate. LH. specially in TI patients and also to check for degenerative changes. 2000). PTH. 25(0H) vitamin D. LH. Chatterjee. PTH 24h urinary calcium. if available. (alkaline phosphate. MRI of spine. 2001.5 SD below the young normal mean (T score) Figure 2 List of investigations ñ Bone profile-serum Ca. skeletal dysplasia and disc prolapse. Overload). 80 . ñ Endocrine profile FSH. (C) Radiology (E) Assessment of iron load and chelation therapy (see Chapter 3: Iron AP and lateral X-ray of the spine is important to rule out fractures even in asymptomatic patients who may have micro fractures. PO4. E2/T. must be undertaken to determine extramedullary haematopoiesis. ulna-annually ñ Markers of iron overload (B) Biochemical (D)MRI All patients must have endocrine and bone profile including 25 (OH) vitamin D3. ALT. radius. albumin) FSH. liver function tests. calcium.5-2.5 SD below the young normal mean (T score) or Standard deviations in relation to patient’s age (Z score) Osteopenia BMD >1.Figure1 World Health Organisation (WHO) criteria for diagnosis of OOS Osteoporosis BMD > 2.

2000.5 and one or more prevalent spine fractures (Borgna-Pignatti 2006b). Route of administration and dose: They can be given as pamidronate 1-2 mg/kg body weight once a month as IV infusion for 3-5 years (Chatterjee. (1) Sex steroid replacement therapy In symptomatic or asymptomatic TM patients with proven OOS (DEXA scan) and hypogonadism. orally as alendronate 70 mg orally per week (Borgna-Pignatti. Chatterjee. Carmina. 2001. previous therapy. 2006). 2001. 2006b) or zolandronic acid two–three times per year (Mahachoklertwattana 2006). strengthen the bone and offer symptomatic relief. An ideal therapy should be safe and effective. 2001). the potent inhibitors of osteoclast function. asymptomatic (morphometric) and symptomatic spine fractures in women with bone mineral density T scores of less than -2. the past history of type and number of fractures. symptoms and severity of clinical presentation. several issues are now arising with respect to bisphosphonates including the risk of jaw osteosclerosis in long-term users (BorgnaPignatti 2006b). with results of clinical trials showing reductions in the risk of vertebral fractures (40–50%) and non-vertebral fractures (20–40%). Bisphosphonates. able to correct the specific defect of bone remodelling unit. Lasco. while overlapped with those of thalassaemia major (TM) have a different emphasis with intramedullary expansion being more important and hypogonadism less important than in TM. associated hypogonadism. 81 . 2006).(2) Calcimimetics Vitamin D deficiency must be corrected (oral dose of 1000-1500 IU/day) and calcium supplementation (500 mg-1G orally/day) (Sambrook. Daily alendronate and risedronate have reduced the risk of single and multiple spine fractures. including hip fractures. hyperparathyroidism. lifestyle issues. (3) Anti-resorption agents Bisphosphonates represent the biggest advance in the treatment of osteoporosis in the past decade in non-thalassaemic patients (Sambrook. General guidelines include assessment of other drugs. The aim is to improve BMD score and prevent/reduce future risk or fracture with/without offering pain relief in thalassaemia patients. (A) Therapeutic Options (Figure 3) Controversy exists regarding the best therapeutic option for osteopeniaosteoporosis. 2004). exercise and diet. Despite their impressive anti-fracture efficacy. it is logical to correct hypogonadism first by sex hormone replacement therapy for at least two years (Chatterjee. The choice of therapy depends on the age of the patient. It is likely that the factors contributing to OOS in thalassemia intermedia (TI). can be used as second line therapy in TM patients (non-responders or poor responders) and those without hypogonadism (TI) with encouraging results. presence of risk factors of nephrocalcinosis. MANAGEMENT Principles of management of OOS are the same as other patients with osteoporosis due to other conditions (Sambrook et al. 2006). the type of thalassaemia including transfusion dependence.

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

Signs and symptoms of right heart failure may predominate. importantly. In more advanced stages of heart failure. Subtle early signs may be confused with the effects of the underlying condition.The Management of Cardiac Complications in Thalassaemia Major The quality and duration of life of transfusion-dependent patients with thalassaemia has been transformed over the last few years. The development of the signs of classical heart failure implies advanced disease with a poor prognosis. but bi-ventricular involvement is the norm. In the absence of effective iron chelation therapy. Clinical manifestations Patients with considerable iron overload of the heart may remain free of symptoms. prompt intervention. The regular assessment of cardiac status helps physicians to recognise the early stages of heart disease and allows for 83 . Establishing the best treatment protocols requires co-operation between the treating physician and cardiologists experienced in dealing with cardiomyopathies. Even after significant effects on heart muscle. including symptoms of heart failure.1994). Once myocardial dysfunction develops. peripheral oedema. cardiac symptoms and premature death from cardiac causes are still major problems. cardiac arrhythmia. those where the risk may be minimal. breathlessness during exercise may be attributed to anaemia. with their life expectancy increasing well into the third decade and beyond. For example. As mentioned above. many patients sustain iron-induced myocardial damage resulting in cardiac failure. Iron related heart complications are the leading cause of death and one of the main causes of morbidity. ideally. Nevertheless. Ideally. a quantitative assessment of the degree of myocardial iron overload is required in order to identify those patients at risk of developing heart complications as well as. an important The unique capacity of the heart to recover from the effects of iron overload only emphasises the importance of early detection and. discernible symptoms are related to the degree of ventricular impairment. acute survival may be as low as 50%. hepatic congestion and severe exercise limitation. until the acute situation is resolved. Zurlo 1989). progressive congestive cardiac failure or sudden death (Brittenham. however. clinical presentations are equivalent to those seen with any severe heart muscle disease and may include dyspnoea. aggressive iron chelation can restore myocardial function to normality. prevention. once overt heart failure is manifest. with a good quality of life (Olivieri 1995.

and sometimes a preponderance of right ventricular voltages. the prognostic implications of arrhythmia are related to the degree of myocardial iron-overload and any associated myocardial dysfunction. can produce symptoms requiring prophylactic drug treatment (often with beta-blockers). with a secondary strategy of symptomatic treatment of the documented arrhythmia. Thus in the case of a non-iron overloaded patient. Chest pain is uncommon in thalassaemia. usually supraventricular but occasionally ventricular. The frequency of these complications appears to differ between countries. Where available. In brief. undertaken according to published guidelines.distinguishing feature of heart failure due to iron overload is the capacity of heart function to make a complete recovery with appropriate chelation therapy—a fact that may not be widely appreciated by physicians and cardiologists unaccustomed to dealing with patients with thalassaemia. especially as these transient events can trigger more sustained arrhythmias. such as the investigation of cardiac arrhythmia (Holter or 24-hour ECG) or functional assessment by exercise tests. and are a frequent cause for anxiety—both for patients and their physicians. Electrocardiogram The electrocardiogram is frequently abnormal. Occasionally P-waves are 84 . but does not necessarily imply an adverse outcome. but changes are typically nonspecific. Patients frequently present with epigastric pain due to liver congestion. but may accompany intercurrent illnesses including pericarditis or myocarditis. being rare in the UK but more prevalent elsewhere. Additional tests may also be valuable for the detailed assessment of individual clinical problems. the development of an arrhythmia such as atrial fibrillation (AF) deserves simple investigation and possible pharmacological treatment. cardiac magnetic resonance imaging (CMR). Ectopic activity. which should also include: 12-lead electrocardiogram and a detailed echocardiogram. Clinical examination A thorough medical history and physical examination are required for a basic cardiological assessment. These changes commonly include depolarisation changes in the T-waves and ST segments of the anterior chest leads. It must be emphasised that the patient may require support of failing circulation for a period of several weeks in order to achieve a full recovery. used to quantitatively estimate cardiac iron overload. particularly if cardiac dysfunction is present. Arrhythmias that produce symptoms of haemodynamic compromise (dizziness. may be the harbinger of severe decompensation and requires immediate response and probable hospitalisation. Palpitations must therefore be investigated and treated in the context of the patient as a whole. Symptoms of palpitations are common in patients with thalassaemia. Treatment is directed towards the relief of iron overload. diminution in exercise capacity and also dyspnoea and cough. has become an invaluable tool in the estimation of clinical risk for the development of heart complications in thalassaemia. particularly AF. syncope or pre-syncope) pose a significant clinical risk and are associated with significant myocardial iron-overload. The same arrhythmia in a heavily iron overloaded heart.

relatively inexpensive and easy to perform. also affected. CMR is rapidly becoming the tool of choice in the clinical assessment of patients with thalassaemia and is hampered only by the limitation in access to appropriate scanners in some parts of the 85 . When new ECG abnormalities appear during follow-up. by treadmill or cycle ergometer. may be of value in identifying patients at risk for cardiac arrhythmias or for assessing functional capacity. in response to exertion or simulated exercise using i. which are parameters closely related to the functional status and prognosis of patients with left-ventricular dysfunction.right and left heart dimensions. A minimum data set should include: As a result. to minimise variability of clinical parameters. Cardiac Magnetic Resonance Imaging (CMR) The CMR scan provides a combination of morphological. in order to establish whether the ejection fraction can rise from its basal level.v. Examination by echocardiography of the ventricular response to exercise may also be useful. Adequacy of treatment of cardiac disease can also be gauged by exercise test performance. Greater accuracy can be achieved by monitoring resting ejection fraction and the response to a reproducible stress. Echocardiography Echocardiography is widely available. Radioisotope studies: The use of MUGA (Multiple Uptake Gated Acquisition) to determine the overall left-ventricular ejection fraction is an outmoded technique (both in requiring the use of radioactive isotopes and its high cost). Ambulatory monitoring of ECG The standard method for detecting and investigating cardiac arrhythmia is via Holter ECG recording for 24 or more hours. Exercise ECG Exercise testing. Longitudinal follow-up assessments should be carried out at approximately the same time in the patient’s transfusion cycle. further investigation is required in order to detect the cause. Conduction disturbance in the forms of bundle branch block may be seen but higher degrees of conduction disturbance are rare. biventricular function (left ventricular fractional shortening and ejection fraction). There are now many types of recorders suited to the detection of intermittent cardiac arrhythmia. estimated intracardiac pressures (pulmonary artery pressure. or even falls. A large number of parameters can be obtained from the cardiac ultrasound investigation but even the simplest measurements of chamber size can provide immediate and valuable data on cardiac status and clinical progress. highlighting individuals with subclinical disease in whom the ejection fraction fails to rise. dobutamine. suggesting bi-atrial enlargement. systolic and mean) and Doppler analysis of intra-cardiac flows. functional information on the heart as well as—uniquely— quantitative estimates of tissue iron overload. An exercise test with gas-exchange evaluation allows verification of: VO2 peak (maximal O2 utilisation at the peak of the stress) and VO2 AT (anaerobic threshold). as long as they are obtained by a skilled practitioner following a standardised protocol.

consideration of combined chelation regimes using parenteral and oral chelators simultaneously. An immediate CMR will help guide management while subsequent scans provide an indication of response to treatment. Impaired myocardial function may require specific cardiac treatment. ñ Surveillance and adequate management of other causes of heart failure such as hypothyroidism. late teens to early 20s. ñ Regular iron-chelation therapy and.c. The timing of a first CMR is not determined but should probably wait until the time of greatest actuarial risk.measures. and 1011 g/dl in patients with heart disease. Overall Management Strategy The therapeutic strategy to diminish the risk of heart complications in patients with thalassaemia involves a number of general (see Chapter 3: Iron Overload for details on 86 . for patients with high iron loads or cardiac disease. Such measures might include: world. ñ Patients with symptoms of cardiac impairment: weekly to every one to four months. Scan times have been progressively reduced with modern protocols and very few patients are unable to tolerate the procedure due to claustrophobia. or i. Monitoring cardiac function can be a useful guide to a patient’s overall prospects. lack of physical exercise and excess alcohol consumption.5 g/dl in patients without heart disease. or awareness of high total body iron burden. ñ Maintenance of pre-transfusional haemoglobin level close to 9-10. Avoidance of unhealthy life styles. renal dysfunction. with repeat examinations yearly. Specific Cardiological Care The essence of treatment of cardiac disease should be aggressive chelation therapy to rapidly counteract iron toxicity and progressively remove excessive iron deposits (Davis and Porter 2000).v. ñ Well-chelated patients: first assessment at puberty.). depending on clinical condition. but it also calls attention to the immediate need for much stricter adherence to chelation protocol or the initiation of a more intensive chelation programme. hypoparathyroidism. including smoking. Cardiological management protocols The frequency of cardiological assessments described above depends on the age of the patient and a clinical assessment of the likely risk of significant myocardial iron overload.e. along with particular cardiological interventions. constant infusion regimens (s. which may then be followed by repeat examinations at six to 12 months to ensure treatment strategies are associated with a fall in heart iron content (rise in CMR T2* parameter towards 20 msec). An initial CMR will give evidence of specific myocardial iron burden. vitamin C deficiency. in order to prevent an inexorable progression to severe cardiac failure. ñ Asymptomatic patients with any evidence of cardiac impairment: every three to six months. i. coincidental valve or structural heart disease.

but require careful monitoring of electrolytes. these agents have been shown to reduce mortality in patients without thalassaemia established cardiomyopathy and to reduce the rate of appearance of heart failure in those with asymptomatic left-ventricular dysfunction. This aids careful titration of the doses of diuretic on an hour-to-hour basis.fibrillation. according to urine output. Inotropic support may be indicated in severe cases. designing an appropriate chelation programme under these conditions).v. These results are very promising. In controlled trials. such as losartan. The dose should be increased to the maximum tolerated. The tendency for patients with thalassaemia to have restrictive physiology. Recent evidence supports the use of spironolactone as adjunctive treatment in non-thalassaemic patients with cardiac failure. When dealing with severe congestive cardiac failure in hospital. Potassium sparing agents can be used with ACE inhibitors. it is advantageous to use constant intravenous infusions of loop diuretics. means that the reduction in pre-load due to a loop diuretic can produce a sudden fall in cardiac output. and while their extension to heart failure in thalassaemia remains conjectural. Diuretics are the mainstay in producing symptomatic improvement in those individuals who develop pulmonary congestion or signs of right-sided heart failure. These individuals should be treated with angiotensin II receptor antagonists. volume depletion. Even though support for this drug in cardiac failure is not strong at present. These diuretics should therefore be used with caution in patients with thalassaemia. fall in cardiac output and worsening of renal function that can follow large i. bolus doses of loop diuretics. Loop diuretics such as Frusemide and Bumetanide will produce a reduction in circulating volume. Certain patients are unable to tolerate ACE inhibitors due to the development of chronic cough. This and related agents reduce potassium depletion induced by loop diuretics and counteract hyperaldosteronism. with diastolic heart failure. the haemodynamic profile approximates that of ACE inhibitors. it is widely applied in clinical practice. which may considerably decrease pre-load. limited by hypotension in patients with thalassaemia. Digoxin has a very specific role in the maintenance of reasonable ventricular rates in patients with established atrial 87 . To restate. These effects may precipitate prerenal failure. Over recent years there has been a trend towards treating patients with thalassaemia exhibiting mild ventricular dysfunction with agents known to improve myocardial function in other forms of cardiomyopathy. The usual precautions for initiating treatment in patients who are well hydrated and starting at low doses are recommended. loop diuretics should be used cautiously and mainly in the late stages of disease. Managing such patients can be aided by Digoxin should not be used in the early stages of cardiomyopathy but may have a role as an inotropic agent in patients with cardiac dilatation accompanied by low blood pressure. Treatment of myocardial dysfunction is best undertaken using angiotensin converting enzyme inhibitors (ACE inhibitors). thus avoiding the dangerous situation of massive diuresis.

as reestablishing synchronised cardiac conduction improves cardiac failure. cardioversion from AF to normal rhythm should be considered early on. The decision to treat arrhythmias in patients with thalassaemia must therefore be carefully considered. the arrhythmias are supraventricular. reassurance of the patient is generally appropriate. The role of other drugs. Anti-arrhythmic agents: In many instances. In heart failure. In the majority of instances. Amiodarone does have an enormous potential for side effects. Dosages should be low at first with careful slow upward titration over days and weeks. Intensive chelation treatment has been demonstrated to reduce arrhythmias. Overall. to prevent the potentially life-threatening complication of intra-atrial thrombus formation with embolisation and the development of pulmonary hypertension. utilising biochemical markers of heart failure (BNP or pro-N-terminal BNP). bearing in mind that iron toxicity is the primary cause of this complication. the use of drugs to treat relatively benign but symptomatic arrhythmias may produce greater morbidity and mortality than in untreated individuals. these agents should be avoided. Carvidelol and Bisoprolol have a special role. Without more formal study. Amiodarone has a very wide spectrum of effectiveness against supraventricular and ventricular arrhythmias and produces a survival benefit in non-thalassaemic individuals with life-threatening ventricular dysrhythmias. although ventricular tachycardia may occur in seriously ill individuals. arrhythmias require very careful assessment. Anti-coagulation: All patients with in dwelling central venous lines require formal anti-coagulation with warfarin or other suitable Coumadin derivatives. via intensified chelation. whereas patients with ventricular arrhythmias require urgent attention to address associated high myocardial iron load. the use of such drugs cannot yet be recommended for the treatment of patients with thalassaemia. such as calciumantagonists and class I antiarrhythmic agents. one of which—disturbances of thyroid function—is of particular relevance in patients with thalassaemia. since they all have a tendency to produce negative inotropic effect. Generally. The development of arrhythmia may be associated with a deteriorating ventricular function. Data support delaying hospital discharge in decompensated heart failure until BNP levels have reverted to normal. since arrhythmias tend to be associated with more severe levels of myocardial impairment.to long-term prognosis. and are indicated in patients with stabilised heart failure as they improve the medium. Their use has not been widespread. For most supraventricular arrhythmias.treatment of AF. while Sotalol may have advantages for the prophylactic 88 . However. if only as a temporary measure prior to Beta-blocking agents can also be used to control many arrhythmias. In the situation of acute heart failure. Values are high in decompensated heart failure and fall in response to treatment. and can be improved by addressing the latter problem. Cardioversion should be considered in patients who fail to respond to iron chelation therapy and pharmacological intervention. Patients in AF also should be considered for anti-coagulation. has yet to be established.

spironolactone should be introduced if possible ñ digitalis.v. Warfarin: if central line in situ. if in atrial fibrillation. The outcome of transplant in patients with thalassaemia needs to be carefully studied to determine the effectiveness of this approach. 1994).with or without symptoms: ñ intensification of iron chelation: i. B) For patients with increased cardiac iron content (measured by CMR) but normal cardiac function (or. in forms that encourage patients to comply with treatment—treatment that must be allied to more precise definition of tissue-specific iron loads. bisoprolol or carvidelol remain first choice ñ diuretics. those with iron related complications and/or a poor chelation history): ñ intensification of iron chelation: s. desferrioxamine (24 hours x 7 days/week). consider combination treatment with oral deferiprone and s/c desferrioxamine ñ slow blood transfusion with diuretics ñ specific cardiac medications: ñ ACE inhibitors. intensive chelation therapy is still required to remove iron from other organs and to prevent iron accumulation in the transplanted heart. or if in AF cardioversion.v. 89 . irreversible cardiac damage. or i. and this procedure has also been combined with liver transplant (Olivieri. or ARII blockers where ACE not tolerated ñ beta-blockers: carefully introduce once acute heart failure stabilised. so that patient and physician alike have a better idea of individualised risk. If surgery is successful. Summary A) For asymptomatic patients with a normal heart and no myocardial iron content by CMR (or. The presence of iron-induced damage to other organs may adversely affect the outcome of heart transplant. At the same time. effective iron chelation. individualised regimes of management. use sparingly whilst monitoring renal function. Close co-operation between the medical disciplines is called for. where no CMR is available. where no CMR is available. patients with proven good chelation records and an absence of iron-related complications): ñ encourage continuation of current. consider combination treatment with oral deferiprone and s/c desferrioxamine ñ as for group A C) For patients with cardiac impairment. Heart transplant: A few patients have undergone heart transplant for severe. the fundamental treatment aim remains to provide regular. for the symptomatic relief of fluid overload.c. effective chelation ñ encourage maintenance of a healthy lifestyle Conclusion The prospects for patients with thalassaemia have improved with a greater understanding of the disease and with better. desferrioxamine (24 hours x 7 days/week).

According to this study. In a subsequent study (Aessopos. while individual mechanisms involved include the prolonged anemic state. should be applied in every patient with thalassaemia. 2005). A close collaboration between attending physicians. chest X-ray and echocardiography. a recent study (Aessopos. A follow-up strategy with clinical examination of the cardiovascular system. It has been shown that a peak systolic tricuspid pressure gradient in the presence of tricuspid regurgitation higher than 30 mmHg is indicative of the presence of pulmonary hypertension. age-related PHT was found in nearly 60% of cases followed by right heart failure in 5% of patients. Although both forms of the disease share a common molecular background. In this context. it seems that PHT in ‚-thalassemia results from a rather complex combination of mechanisms. It should be noted that all those patients had preserved left ventricular systolic function and normal pulmonary capillary wedge pressure. electrocardiography. 2001) of a large 110-patient series. and the coexistent endothelial dysfunction (Aessopos. was present only in TM cases with a prevalence of 8%. 2000). both treated uniformly in the currently accepted manner. pathophysiology. Heart failure was observed in 3% of TI patients and 4% of TM ones. the diverse severity of the genetic defect and of the In what concerns the development of PHT in TM. in contrast. Chronic tissue hypoxia and chronic hemolysis are believed to hold the central pathogenetic role. pulmonary hypertension (PHT) is part of the cardiopulmonary complications of the disease (Aessopos. Cardiac involvement represents the primary cause of mortality in both thalassemia major (TM) and thalassemia intermedia (TI). hematologists and cardiologists is required in this context. which lead to the increase of both cardiac output and pulmonary vascular resistance. diagnosis and management of pulmonary hypertension in ‚-thalassemia In terms of pathophysiology. moderate to severe PHT was observed only in TI patients with a prevalence of 23%. the thalassemiarelated elastic tissue defects. 1995). Pulmonary hypertension was initially documented in a small group of 7 TI patients with right heart failure (Aessopos. The prevalence. or in shorter intervals if clinically indicated. the hepatic abnormalities. performed on an annual basis. following those observations PHT is currently considered to be the primary cause of heart failure in TI patients. 2007). The diagnosis of PHT in patients with thalassaemia may be performed simply and non invasively using transthoracic Doppler echocardiography (Aessopos. 2007) compared cardiac disease between two large aged-matched groups of TM (n=131) and TI (n=74) patients. Systolic left ventricular dysfunction. the presence of a hypercoagulabilable state.in TI. namely regular transfusion and chelation therapy in TM and absence of any particular treatment 90 . the increased percentage of hemoglobin F. Thus.

should be considered for regular transfusion and chelation therapy (Aessopos. if not the majority of them. The applied treatment. The currently applied regular lifelong therapy in TM patients eliminates chronic hypoxia and thus prevents the development of PHT. should definetely aim at prevention and not palliation of anaemia-induced complications. 2007).resulting clinical phenotype impose a different therapeutic approach. The accumulated experience indicates that a large number of TI patients. 91 . once started. Until research data becomes available. Two crucial points that remain to be clarified are the patient selection criteria and the timing of treatment onset. the judgement should be based on individual clinical and laboratory assessment of patients. 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. On the other hand.

the remaining 1. and alterations in microsomal enzymes.The Liver in Thalassaemia overload (HIC in mg/g dry weight x 10. having previously been termed non-A non-B hepatitis. An increase in hepatic iron is associated with an increased risk of impaired glucose tolerance. about one-third of storage iron (ferritin and haemosiderin) in the body is found in the liver. 2002). with the risk of late development of fibrosis and cirrhosis. the threshold hepatic iron concentration for the development of fibrosis is about 16 mg/g dry weight liver (Angelucci. bile ductular cells and fibroblasts. The majority of HCV isolates studied so far can be divided into six major groups. In patients with ‚-thalassaemia. This excess iron is initially confined to the Kupffer cells but when transfusion requirements produce massive iron overload. in absence of co-factors. The liver plays a central role in iron homeostasis. and haemosiderin. Under normal circumstances. which make up 80% of total liver mass. 1996) Hepatic iron concentration (HIC) is the gold standard for the measurement of body iron 92 . Clinical studies suggest a relationship between hepatic iron concentration and the development of ironinduced hepatotoxicity. with subdivisions in each (subtype a. ferritin.). Iron also has a direct effect on collagen synthesis and/or degradation. Progressive accumulation of storage iron is associated with cellular toxicity. In addition to iron released from transfused red cells. although the specific pathophysiologic mechanisms for hepatocytes injury and liver fibrosis are not entirely understood. Hepatitis C Virus (HCV) This RNA virus was first characterised in 1989. diabetes mellitus. cardiac disease and death. c. Iron that enters the cell in excess of that required accumulates in the major storage forms of iron. Approximately 98% of hepatic iron is found in hepatocytes. etc. Hepatic iron stores are closely correlated with cumulative transfusional iron load and have been used as a marker for the effectiveness of chelation therapy and prognosis. spillover to hepatic parenchyma cells quickly occurs. 2000).5-2% of total liver iron is found in reticuloendothelial cells. biomagnetic liver susceptometry (SQUID) and magnetic resonance imaging (MRI). designated genotypes 1-6. Non-invasive techniques used to assess hepatic iron include computed tomography.6 = whole body iron store in mg/kg) (Angelucci. Active infection is diagnosed by the presence of circulating HCV RNA in blood (Sharara. increased lysosomal fragility and decreased mitochondrial oxidative metabolism. relaxation rates R2 (1/T2) and R2* (1/T2*) measured by MRI appear to be the most promising and accurate (Wood. Of these. Antibodies that develop after infection are not protective but rather are indicative of current or past infection. an enhanced rate of gastrointestinal iron absorption has been suggested. b. endothelial cells. These include lipid peroxidation of organelle membranes. 2005).

with a 79% rate of 10-year survival. Score 5-6 (Score A) is characterised by: No ascites. 1996). Bilirubin < 2mg/dl. increasing by 1-4% each year thereafter (Colombo.g. autoimmune thyroidits and vasculitis (Sharara. 2002). * Liver cirrhosis is divided to 3 stages following the Child-Pugh score. Extra-hepatic manifestations of HCV infection include porphyria cutanea tarda. Prevention and early detection of HCC are more effective than attempted cure. Preventative measures to minimise the risk of posttransfusional hepatitis C include careful selection of voluntary donors and appropriate blood donor screening. Cirrhosis usually takes as long as two to three decades to develop from the time of acquisition. as well as hostspecific (e. Fiveyear survival in patients with compensated cirrhosis is 91%. Natural history and complications of infection Acute infection: generally benign. Anicteric Fulminant Hepatitis is very rare. Child-Pugh stage A can be defined as “well compensated disease”. 5-year survival falls to just 50%. Recurrent hepatitis C infection occurs in > 90% of cases after transplant but is usually mild. ranging from < 5% in young. healthy people. INR <1.Reversibility: The reversibility of advanced fibrosis and even early cirrhosis (Child A – compensated or well-compensated*) has been documented in thalassaemia once causes of liver injury (iron overload and HCV infection are removed) (Muretto. Therefore.g. averaging 65% after 5 years (Gane. 93 . immunity) and virus-specific (e. to approximately 25-35% of cases of patients with relevant comorbidities. with >80% asymptomatic. Long-term survival after liver transplantation for hepatitis C is similar to that for other diagnoses. for the early detection of hepatocellular carcinoma. essential mixed cryoglobulinemia. for reasons that are not completely understood. Cirrhosis: develops in a variable percentage of HCV-infected patients. Hepatocellular carcinoma (HCC): Chronic infection: develops in 70-80% of develops in 1-5% of infected individuals after 20 years. Cirrhosis patients should undergo a regular six-monthly screening programme. including liver ultrasound examination and alpha-fetoprotein check. Albumin>3. the clinical outcome is highly variable. 1991). cases. Hepatitis C is currently the commonest reason for liver transplantation worldwide. glomerulonephritis. particularly after the development of cirrhosis. Age and co-morbidities appear to be the most important factors affecting the risk of developing cirrhosis. leading to chronic liver disease. When cirrhosis is decompensated however. End-stage liver disease: should lead to consideration of liver transplantation. 1996). co-morbidities. no encephalopathy. Determinants of disease severity or chronicity as well as response to therapy include age at acquisition.7. most important. However.5g/dl. genotype) factors and.

2006). treatment of HCV in patients with thalassaemia is aimed at eradication of the virus. the current standard for the confirmation of viremia. Diagnosis and monitoring Initiation of treatment in chronic hepatitis C has traditionally been based on one or more of the following: ñ confirmed presence of HCV-RNA ñ moderate to high serum ALT levels ñ abnormal liver histology Antibody testing This is most valuable for screening blood and blood products and as initial testing in patients with chronic unexplained elevation in serum transaminases or those suspected of having chronic liver disease. Special features of hepatitis C in thalassaemia major Treatment This is a rapidly changing field and the treatment of hepatitis in patients with thalassaemia should therefore be undertaken in close collaboration with a specialist in liver disease. face an increased risk of developing cirrhosis. with a reciprocal multiplicative effect (Angelucci. The severity of chronic hepatitis C in patients with thalassaemia may be greater because of concomitant iron overload. where the patient has no other contraindications to treatment or other significant co-morbidities. HIV) and possible infection with mixed hepatitis C genotypes. other concurrent viral infections (HBV. means that the presence of serum HCV-RNA alone is sufficient to consider treatment in patients with thalassaemia. 1995). 94 . particularly those with poor control of iron overload. Selection of patients for therapy Patients diagnosed with acute HCV infection and persistently positive serum HCV RNA after 12 weeks of exposure or diagnosis should receive treatment (Sharara.to guide decisions on therapy and anticipate complications (Angelucci. reduction of the risk of liver cirrhosis and hepatocellular carcinoma. 2002). Encouraging results for the treatment of HCV in thalassaemia. improvement in liver histology. Confirmatory testing is done using HCV RNA detection by polymerase chain reaction (PCR). Ascertaining the genotype and quantity of HCV RNA in serum is useful only in determining the type and duration of treatment (see below). It appears therefore that patients with thalassaemia. Similar to non-thalassaemia patients. Liver biopsy in thalassaemia major Liver biopsy prior to treatment is helpful in determining the extent of liver damage and Response to treatment Depending on HCV genotype and viral load. combined with the abovementioned risks of greater severity of chronic hepatitis C in such patients. It has been demonstrated that iron and HCV infection are independent but mutually reinforcing risk factors for the development of liver fibrosis and cirrhosis.

Because of the possible role of iron overload in reducing the likelihood of successful treatment of hepatitis C and for general. concomitant infections). Type of interferon: Pegylated interferon ·-2a or ·-2‚ given subcutaneously once weekly Duration: 24 to 48 weeks. depending on genotype Side effects: Typical side effects in most patients include flu-like symptoms. HIV) 40-80% of patients with chronic hepatitis C will respond to the current standard treatment of pegylated interferon and ribavirin. insomnia. well-known clinical reasons. effective chelation therapy should be strongly considered before initiation of antiviral therapy in patients with bad control of transfusional iron. Controversial in this specific setting is the role of iron overload. and cognitive and mood changes. Treatment regimens The gold standard is combination therapy with pegylated interferon and ribavirin. the current recommendation is to measure the biochemical (serum ALT) and virological (HCVRNA) response after 4 to 12 weeks of therapy. carried out 24 weeks after completion of therapy. monitoring response is based on viral HCV RNA. Monitoring response Depending on HCV viral genotype. Because serum ALT may be raised for other reasons in patients with thalassaemia (iron overload. An example of an algorithm used for Hepatitis C managament is presented in Figure 1. and to continue therapy for an additional 12 to 24 weeks in patients with undetectable HCV-RNA.ñ High baseline HCV-RNA level and the absence of its early decay (4-12 weeks) upon initiation of treatment ñ HCV genotypes 1 or 4 ñ Presence of bridging fibrosis or cirrhosis ñ Co-existence of other viruses (HBV. Response is defined on the basis of a negative highly sensitive qualitative HCV RNA PCR assay. withholding therapy on the basis of factors suggesting a poor response is unwarranted. This is in practice equivalent to viral eradication of HCV ñ Non-responders: lack of significant decline (defined as > 2-log reduction from baseline) in HCV RNA after 12 weeks of therapy ñ Relapsers: re-emergence of HCV-RNA after a satisfactory end of treatment response Since no baseline factor is specifically predictive of treatment success or failure. Patient responses are classified as follows: ñ Early viral response (EVR): defined as an undetectable HCV RNA or a > 2-log reduction in viral load after 12 weeks of treatment ñ Response at end of treatment (ETR): defined as absence of HCV-RNA at the end of treatment ñ Sustained viral response (SVR): absence of HCV-RNA > 6 months after concluding treatment. especially in the first two weeks after starting interferon. Dose-dependent neutropenia and thrombocytopenia commonly occur during Prediction of poor response Negative predictors in all patients with hepatitis C are: 95 .

Figure 1 96 .

Heart failure has been seen in a few patients with thalassaemia receiving interferon. approaching 80%. An expedited second treatment option may need to be considered in patients with advanced fibrosis on liver biopsy. it has limited antiviral activity in hepatitis C but in combination therapy with interferon has been shown to significantly increase sustained response rates compared to interferon alone. Monitoring for side effects: Close monitoring for hypothyroidism is mandatory in patients receiving interferon. 2005). This approach has been validated in patients with thalassaemia where an SVR of 64% is seen in patients infected with genotype 1 and 4 and who have exhibited an undetectable HCV RNA at 12 weeks of treatment (Inati. Ribavirin is a nucleoside (guanosine) analogue. 2005).000. Regular monitoring of blood counts is also necessary. to identify neutropenia or thrombocytopenia. Particular attention should be paid to this complication in patients with thalassaemia and hypersplenism. interferon therapy. In the absence of EVR. Alone. Since both deferiprone and interferon may cause neutropenia. For genotypes 1 or 4. and testing for thyroid function and the presence of anti-thyroid antibodies should precede initiation of therapy. Treatment options for nonresponders These have not been firmly established and are currently considered experimental. well absorbed orally. and this combination should be initiated with caution and under careful monitoring. Some patients have experienced exacerbation of local reactions at the site of desferrioxamine infusion during interferon treatment. Given the high rate of SVR for genotypes 2 and 3. Side effects: Haemolysis occurs in most patients without thalassaemia.In thalassaemia major this may be associated with a more marked haemolysis and a 30% increase in transfusion requirement. Inati. Treatment duration and viral load monitoring: Depends primarily on the HCV genotype. Cessation of therapy should be considered if the absolute neutrophil count falls below 1. which requires careful adjustment of the transfusion interval and intensification of iron chelation therapy (Li. Hypothyroidism is an important complication of interferon treatment. It is important to note that dose-reduction of ribavirin is associated with an inferior sustained viral response and it is hence recommended that transfusion-chelation requirements be adjusted to compensate for ribavirin-associated haemolysis rather than altering the recommended ribavirin dose (Inati. a 12-week determination of viral load is not usually necessary. treatment is administered for 48 weeks provided there is a positive early viral response (EVR) at 12 weeks. with a decrease in haemoglobin of 10-20% from baseline levels. and special care should be given if prescribing interferon for patients with pre-existing heart disease. 2005). For genotypes 2 or 3. 97 . 2002. there are theoretical risks associated with their combined use. treatment is usually discontinued and further treatment options considered. treatment is limited to 24 weeks. and typically given in doses of 800-1200mg/d.

Sexual transmission risk is generally low. Clinical significance of HBV markers Despite the availability of good screening tests for hepatitis B. Consultation with a physician experienced in the management of liver disease is especially important in the clinical management of the following patient populations: ñ Children ñ Patients with cirrhosis ñ Immunosuppressed patients ñ Pregnant patients ñ Patients with acute hepatitis C Prevention There is currently no vaccine or immunoglobulin to prevent hepatitis C. The following recommendations are made to reduce the risk of non-parenteral transmission: Current HBsAg positivity in thalassaemia major ranges from <1% to >20% and Hepatitis B infection remains a significant cause of chronic liver disease and hepatocellular carcinoma in patients with thalassaemia in many regions of the developing world. and special measures such as to segregate towels and eating utensils are probably unnecessary. HBsAg is a reliable marker (can be present for 4-5 months).Management of special patient populations HBsAg. and other public health measures. to avoid transmission to family members. as well as other parts of the world. HBeAg is also transiently present (1-3 months). ñ Chronic infection (overt carrier) is marked by the presence of HBsAg and anti-HBc in the blood (usually accompanied by HBeAg or anti-HBe). General measures. Anti-HBc IgM is the most reliable test for the diagnosis of acute HBV infection. the risk of transmission is low. However. mainly in developing countries. are advised. the interpretation of results may be difficult or misleading. have led to a significant reduction in hepatitis B infections in most countries of Europe and North America. Hepatitis B nevertheless remains a formidable medical problem. and that safe sexual practices should be encouraged. insufficient data exist to recommend changes in current recommendations: that patients encourage their sexual partners to be tested for hepatitis C. such as avoiding sharing toothbrushes. overt carriers can be classified as: Hepatitis B Virus (HBV) ñ active carriers. ñ Acute infection. identified by the presence of HBeAg or anti-HBe antibodies and a viral load ≥5 log10 copies/ml (although others cite a figure Incidence Vaccination strategies. razors. In accordance with international definitions. etc. screening of blood donors for 98 . However.

co-infection with hepatitis C may increase the severity and rate of progression of liver disease. For patients with chronic hepatitis B infection. as may concomitant HCV infection. when available. with IgM anti-HBc <0. the possibility of HBV reactivation after a previous infection has been demonstrated. Severity is variable. ñ ñ Progression to chronic hepatitis B occurs in 5-10% of otherwise healthy adults and in 90% of neonates. hemopoietic stem cell transplantation). Patients with thalassaemia should be screened for all serological markers of hepatitis B and classified according to Table 1. Progression to fulminant hepatic failure is rare (≤1%). Natural history Acute hepatitis: This is the most common presentation. the histological finding. previous infection: the presence of anti-Hbc antibodies ± anti-Hbs indicates previous infection. In the majority of such subjects. such as deep immunosuppression (i. Cirrhosis occurs at a rate of 1-2. Iron loading in thalassaemia may increase the risk. probably occurring in less than 2% of cases. Acute hepatitis B is usually managed by supportive measures alone. according to most recent standardisations. characterised by the persistent normality of transaminase in an anti-HBe-positive subject. ñ inactive carriers. This category of patients can therefore also be defined as potential occult carriers (Marzano. eventually. with an incubation period of 420 weeks. which provides a list of possible 99 . Hepatocellular carcinoma is a wellrecognised complication of chronic hepatitis B infection.e. The great majority of active carrier cases are associated with the presence of hepatic disease.2% per year. does not reveal significant liver disease (necroinflammatory activity <4 HAI). In particular circumstances. corresponding to about 17. with an icteric period often preceded by a prodromal illness with arthralgia and urticaria.2 IMx Index.interpretations of screening results. In acute icteric hepatitis B in adults.200 IU/ml. associated with levels of viremia below the threshold (<5 Log10) and. 2007). while in a small minority of cases it is possible to observe effects of a chronic (sometimes even cirrhotic) disease which have became silent spontaneously or thanks to the effect of the antiviral treatment. of ≥4 log10 copies/ml). vaccination: the presence of HBsAg antibodies (if anti-HBc is not present) indicates vaccination. transition to chronicity appears to be rare.

4. Table 1: Possible interpretations of Hepatitis B screening results 100 . Recovering from acute HBV infection. HBsAg anti-HBc anti-HBs HBeAg + + + Carrier with chronic infection (if HBsAg+ 6 months or more) Highly infectious Further evaluation.potential occult carrier.Test Results HBsAg anti-HBc anti-HBs - HBsAg anti-HBc + + or - Interpretation Recommendation Susceptible to infection/never exposed to virus Consider vaccination Acute or chronic infection Further evaluation HBsAg anti-HBc anti-HBs anti-HBeAg +/+ - Resolution of previous infection HBsAg anti-HBc anti-HBs anti-HBeAg +/- Past infection*. Chronic HBV infection with undetectable serum levels of HBsAg. 3. False positive anti-HBc. with susceptibility to HBV infection. with loss of HBsAg but anti-HBs has yet to appear (“window period”). Immune to HBV but anti-HBs never appeared or has fallen below the level of detection. * Interpretations 2 and 4 are the most common explanations of this serologic pattern. 2. including HBV-DNA levels HBsAg anti-HBc anti-HBs HbeAg Anti-HBe + - Carrier with chronic infection (if HBsAg+ 6 months or more) Further evaluation. including HBV-DNA levels HBsAg anti-HBc anti-HBs HBeAg Anti-HBeAg + - Immunisation without infection * Other interpretations include: 1.

liver failure and hepatocellular carcinoma.Prevention: HBV 2007 Treatment Overview (Hepatitis Annual Update 2007 Vaccination: All newly diagnosed patients with ‚thalassaemia should be vaccinated against hepatitis B. normalisation of ALT levels. website:http://clinicaloptions. * AASL: American Association for the study of Liver Disease ** EASL: European Association for the study of Liver Disease *** APASL: Asian Pacific Association for the study of Liver Disease 101 . Prevention of vertical transmission: Transmission of hepatitis B from mother to infant occurs during the perinatal period.com/Hepatitis/AnnualUpdates) The primary goal of therapy for Chronic Hepatitis B (CHB) is long-term suppression of serum HBV-DNA which in turn will likely reduce progression to cirrhosis. which has almost completely replaced standard interferon alfa-2b. In individuals acutely exposed to known contaminated blood. Unlike hepatitis C. hepatitis B is highly infectious through the sexual route and close personal contact. HBeAg seroconversion in HBeAg-positive patients. Mothers with acute hepatitis B during pregnancy transmit the virus in up to 70% of pregnancies if infection occurs in the third trimester. The risk of infection is 26-40% if the mother is HBeAg positive. Lamivudine and Telbivudine are not preferred first-line drugs in most populations. AASLD*. because of high resistance rates. Entecavir and Pegylated Interferon. This results in >90% reduction of the risk of transmission. Recent trends include treatment of patients with any elevation of HBV-DNA with compensated or decompensated cirrhosis. EASL**. and the relatively rare event of HBsAg seroconversion. the currently preferred first-line monotherapy treatment options include the use of Adefovir. hyperimmune globulin can limit the risk of acute infection. and APASL*** Guidelines. The information provided below is derived from US treatment algorithms. Three injections (at 0. Combination therapy with nucleos(t)ide analogues is also now widely used in cirrhotic patients as well as in patients with HBV and HIV co-infection or in patients who have undergone BMT after HBV infection. histologic improvements. Measures to prevent vertical transmission include administration of hepatitis B vaccine and hepatitis B immuno-globulin (HBIG) to neonates within 12 hours of delivery by a carrier. 1 and 6 months) are required to produce an antibody response in 95% of normal individuals. and up to 90% if it occurs within 8 days of delivery. according to which. Detailed advice and immunisation need to be given to the patient’s immediate family and sexual partner(s). The key endpoints in determining the efficacy of therapy include suppression of serum HBV DNA to low and preferably undetectable levels. The vaccine is ineffective in those already exposed to hepatitis B.

particularly tenofovir that is in late-stage studies and shows promise of high potency and low rates of resistance. and therapy should probably used be long-term.000 IU/mL and ALT levels are elevated ñ Genotype testing should be used more broadly. Knowledge of genotype may be useful in predicting natural history. Oral drugs with a high genetic barrier to resistance and/or high potency are generally preferred to reduce the likelihood of resistance.000 IU/mL should be treated. particularly if ALT levels are elevated. For patients considering pegylated interferon therapy.6% in HBeAg-negative patients at year 2). genotype is useful in predicting response to therapy: HBV genotype A responds much better than genotype D (common genotypes in whites). it may be appropriate to treat all patients with cirrhosis and viraemia regardless of HBV DNA levels.6% in HBe-Agpositive and 8. For example. primarily to reduce the rate of resistance with long-term therapy ñ All patients with chronic hepatitis B and cirrhosis with HBV DNA levels ≥ 2. intermediate with adefovir (30% at 5 years of therapy in HBe-Ag-negative patients). but higher in lamivudineresistant patients (~42% at year 4). Interferon and peginterferon therapy have not been associated with the development of resistance Summary: Implications for Clinical Practice The key recommendations based on updated treatment guidelines for treatment of chronic Hepatitis B are as follows: ñ Patients with HBeAg-positive chronic Hepatitis B should receive treatment when serum HBV DNA levels are ≥ 20. In addition. and low with entecavir in nucleoside-naïve patients (<1% at year 4).000 IU/mL and ALT levels are elevated. particularly 2-fold ñ Patients with HBeAg-negative chronic Hepatitis B should receive treatment when serum HBV DNA levels are ≥2. and genotype B responds somewhat better than genotype C (common genotypes in Asia) ñ Potential future therapies for chronic Hepatitis B include pegylated interferon and other nucleos(t)ide analogues. Preliminary evidence also supports the use of combination nucleos(t)ide agents in these patients. somewhat less with telbivudine (21. even after HBeAg seroconversion in HBeAg-positive patients 102 . genotype C HBV is associated with more advanced disease and a higher rate of HCC than genotype B in Asians.ñ The rates of genotypic resistance with long-term therapy are high with lamivudine (70% at 4-5 years). The role of combination therapy is evolving.

Treat.com/Hepatitis/AnnualUpdates 2007 AASLD Guidelines on Management of Chronic Hepatitis B Patients with Compensated Cirrhosis ñ Who to treat .com/Hepatitis/AnnualUpdates 103 .Patients who are HBeAg positive or negative .May choose to treat or observe .Adefovir or entecavir preferred Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions. telbivudine or entecavir) ñ HBV DNA < 200 IU/mL or ≥ 200 IU/mL and decompensated cirrhosis .Examples of treatment algorithms for specific groups with HBV infection include: US Treatment Algorithm Recommendations for Treatment of HBeAg-Positive or HBeAg-Negative Cirrhotic Patients ñ HBV DNA < 2.Long-term treatment required.Wait-list for liver transplantation Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions. telbivudine or entecavir) .Combination therapy preferred (adefovir or tenofovir plus lamivudine.000 IU/mL and compensated cirrhosis .Consider treating if ALT elevated for patients with HBV DNA < 2.000 IU/mL and compensated cirrhosis .Patients with HBV DNA > 2.000 IU/mL.Adefovir or entecavir preferred.Long-term treatment required . pegylated interferon alfa-2a may be option in early well-compensated cirrhosis ñ HBV DNA ≥ 2.000 IU/mL . adefovir or entecavir are first-line options . no ALT specified . and combination therapy may be preferred (adefovir or tenofovir plus lamividine.Observe for patients who are HBV DNA negative ñ Drugs of Choice .

com/Hepatitis/AnnualUpdates Potential Management of Hepatitis B Antiviral Drug Resistance Resistance Type Strategy 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.Refer for transpalntation Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.Combination of lamivudine or telbivudine plus adefovir or entecavir monotherapy is preferred (interferons contraindicated) ñ Duration of therapy .HBeAg positive or negative at any HBV DNA level ñ Drugs of choice .2007 AASLD Guidelines on Management of Chronic Hepatitis B Patients with Decompensated Cirrhosis ñ Who to treat .com/Hepatitis/AnnualUpdates 104 .Long-term ñ Other recommendations .

14% at Yr 2. However. The authors of this book have made an effort to provide readers with essential information on CHC and CHB treatment. 3% at Yr 2. 33% at Yr 3. and 30% at Yr 5 of therapy in HBeAgnegative patients) Entecavir ñ Oral administration ñ Excellent tolerance ñ High potency in lowering HBV DNA levels ñ Use in adefovir failures ñ Drug resistance: rare in nucleosidenaïve parents (estimated at < 1% at Yr 4). should be decided in consultation with and monitored by a specialist hepatologist.com/Hepatitis/AnnualUpdates treatment of CHC/B.0% at Yr 1. and 21. website:http://clinicaloptions.6% at Yr 2 in HBeAg-positive patients.Advantages and Disadvantages of Current Therapies for Chronic Hepatitis B Agent Advantages Disadvantages Interferon alfa-2b ñ HBsAg loss rates ñ Short treatment duration ñ No drug resistance ñ Parenteral administration ñ Frequent adverse effects Lamivudine ñ ñ ñ ñ ñDrug resistance common (~20%/yr and up to 70% with 4-5 yrs of therapy) Adefovir ñ Oral administration ñ Excellent tolerance ñ Use in ESLD* ñ Use in lamivudine failures ñ 24-to 48-week HBV response less potent than entecavir and telbivudine ñ Drug resistance delayed and less common than with lamivudine. Keeffe. 11% at Yr 3.6% at Yr 2 in HBeAg-negative patients) Oral administration Excellent tolerance Use in ESLD* Use in adefovir failures * ESLD. 105 . but more common than with entecavir with extended therapy (0% at Yr 1. and 8. end-stage liver disease Reference: Hepatitis Annual Update 2007-Emmet B. but common in patients with lamivudine resistance (estimated at 6% at Yr 1. and 42% at Yr 4) Pegylated Interferon ñ HBsAg loss ñ Fixed duration of treatment ñ No drug resistance ñ Parenteral administration ñ Frequent adverse effects but less than recombinat standard interferon Telbivudine ñ Oral administration ñ Excellent tolerance ñ High potency in lowering HBV DNA levels ñ Drug resistance: intermediate rates of drug resistance in treatment-naïve patients (5. 19% at Yr 4.

However. Clinicians involved in the care of thalassaemia will be fully aware of this risk and the importance of any intervention that may limit it (Rahav.Infections in Thalassaemia Major briefest interaction with patients with thalassaemia. 106 . 2006). Volach et al. Infections are the second commonest cause of death in thalassaemia major. should have the same awareness. all medical and nursing staff. as should patients themselves. including those with the Blood borne transmission Relevance for severity Anaemia Splenectomy Parvovirus B19 HIV Orientation for practical management Iron Iron overload chelation Vaccine Sensitive to broad Suspend available spectrum chelation antibiotics if suspected ++ +++ - - - No - No +++ +- +? + - No - No Note Pregnancy HBV +++ - - +? - Yes - No HCV +++ - - ++ - No - No CMV ++ + - ? - No - No - +? +++ - - Yes Yes Yes Meningococcus - - +++ - - Yes Yes Yes Hemophilus - - +++ - - Yes Yes Yes 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 - - - ++ ++ No No Yes Deferrioxamine- Stem cell transplant Streptococcus pneumoniae Influenzae enterocolitica Mucor species Immunosuppression Pythium - ++ +++ ++ - Yes No Yes? Farming insidiosum Table 1: A summary of the effects of infection in thalassaemia and their practical implications. A basic outline of the effects of infection in thalassaemia and their practical implications are provided in Table 1 (see also Table 2 for more blood-borne infections).

Protozoan infections due to Babesia have been implicated in a fulminant haemolytic febrile state in splenectomised patients. particularly if the disease is well compensated by treatment. and. pneumoniae) and Pseudomonas aeroginosa. ñ Haemophilus influenzae. and Malaria is repeatedly reported as more severe in asplenic people with an increased risk of death (Boone and Watters. rod-shaped bacteria. On the other hand. occurrence of macrophages. Klebsiella species (e. The best-described association between bacterial infection. ñ Neisseria meningitides. Infections with gram-negative. occur with increased frequency in asplenic patients and are often associated with high mortality. iron and iron chelators involves Yersinia enterocolitica (see below). it is recognised by treating physicians through clinical observations and practice that several factors linked to the disease. 1995) (for blood-borne infections see Table 2). ñ Iron overload and ñ Iron chelation.. that a variety of microorganisms are more pathogenic in the presence of iron overload. including reduction in neutrophil numbers. ñ Transmission of pathogens by blood transfusion.g. however. It is clear.The pathogens most commonly associated with post-splenectomy sepsis are encapsulated organisms. Other gram-negative organisms have also been implicated in postsplenectomy sepsis. 1973). Modern preventative measures (see below) have reduced this risk but the overall impact of these measures is unclear. the risk of postsplenectomy sepsis in thalassaemia major is increased more than 30-fold in comparison with the normal population (Singer. its complications and treatment may facilitate or aggravate the severity of infections. the main causes to be considered include: ñ Splenectomy. changes in number and function of natural killer cells. Splenectomy The major long-term risk after splenectomy is overwhelming sepsis. ñ Streptococcus pneumoniae (accounting for more than 75% of documented bacterial infections in asplenic patients). 107 . many alterations to the body’s immune system have been described in thalassaemia. chemotaxis and phagocytosis and interferon gamma production. In older studies. notably Escherichia coli. increase in number and function of CD8 suppress cells. Even in the absence of any evidence-based data on a direct relationship between these alterations and the development of severe infections in thalassaemia. Iron overload The role of iron load in susceptibility to infection has not yet been fully established in clinical trials. Where infection is suspected. particularly: A patient with thalassaemia major must not be considered as immuno-compromised per se.

On the other hand. as in deferoxamine. HIV-infected) and fail to mount an effective antibody response to the virus. B-19 infection may cause an acute. the infection may be persistent and may mimic or trigger autoimmune inflammatory disorders. patients are typically immune to further infections by the agent. The cessation of erythropoiesis lasts for 5-7 days and haematologically complicates chronic haemolytic anaemia. Following recovery from an acute B-19 infection. transplanted. and so become more virulent. is estimated at 1% of blood donors. mild to severe aplastic crises and myocarditis. Similar observations have been reported for Rhizopus infections. Streptococcus pneumonia. This has been demonstrated in vitro and in vivo for Yersinia enterocolitica.g. The incidence of B-19-infected individuals with persistently detectable levels of B-19 DNA. Pseudomonas aeroginosa. is impaired in patients with thalassaemia with iron overload compared with individuals without thalassaemia. Escherichia coli. Specific infections B-19 may be transmitted via the respiratory system or blood derivates. Legionella pneumophila and Listeria monocytogenes. as in thalassaemia. In patients with an already shortened red cell lifespan (15-20 days) combined with anaemia due to haematological disorders such as spherocytosis. The condition is characterised by: Several observations in vivo indicate that infections are more frequent or severe in patients with iron overload either related to genetic haemochromatosis or to transfusions. Iron chelators A potential risk of natural siderophores. life-threatening red cell aplasia. Many other organisms. Where patients are immunosuppressed (e. ñ A virtual absence of red blood cell precursors in the bone marrow at the beginning of the crisis and ñ B-19 DNA viraemia. ñ A variable fall in haemoglobin. such as Klebsiella species. have been shown to have increased virulence in the presence of excess iron. which has a receptor on the outer membrane that efficiently binds ferrioxamine. During pregnancy severe foetal anaemia and myocarditis may lead to lethal non-immune hydrops fetalis. is that they may be used by micro-organisms as a source of iron. sickle-cell anaemia.2%). autoimmune haemolytic anaemia and thalassaemia. The resulting risk of Viral Infections Human Parvovirus B-19 (HPV B19) Parvovirus B-19 is a common pathogen that may cause a wide range of clinical 108 . commonly referred to as “transient aplastic crisis”. despite the presence of specific IgG.manifestations: erythema infectiosum or fifth disease in children. A clear relationship between Mucormycosis and desferrioxamine has been reported in dialysis patients but only sporadically in thalassaemia. tested in vitro. phagocytic efficiency. The role of iron overload in aggrevating Mucormycosis in bone marrow transplanted patients has been demonstrated. ñ Disappearance of reticulocytes from peripheral blood (< 0.

policies addressing the problem, as well as on
the local prevalence of blood transmissible
pathogens.

infection is estimated at between 1/625 and
1/50,000, depending on a number of factors
(including detection methods, seasonal
outbreaks, B-19 DNA load of the donor and
co-presence of B-19 IgG antibodies) (Lefrere,
Maniez-Montreuil et al, 2006). There is
currently no general rule on action to be
taken to prevent blood-borne transmission of
B-19 in high-risk populations, including
thalassaemia major patients.

With the use of standard
procedures for prevention, it is
possible to keep the risk of HIV
transmission very low; with the
use of the most sensitive
screening measures, it is
possible to lower this risk still
further.

Management of acute B-19 crises includes
close monitoring and adequate blood
transfusion adjustment. Immunoglobulin
administration may be beneficial in chronic
illness.

Natural history
In the absence of treatment, the median
time from HIV seroconversion to the onset of
AIDS in transfused patients is about 7-11
years. Factors affecting progression are
symptomatic primary infection, age at
infection and viral load (HIV1-RNA
concentration in plasma).

Human
Immunodeficiency
Virus (HIV)

Management of HIV in thalassaemia
A detailed account of the treatment and
monitoring of HIV patients is beyond the
scope of this book. Patients with
thalassaemia identified with HIV infection
should be managed in collaboration with an
infectious diseases’ unit with expertise in HIV.
Advances in drug treatment have
revolutionised the care of patients from
strategies aimed at preparing patients to die
to treatments that may fully control the
disease. However, accessing the best—and
most expensive—treatment will depend on
local conditions.

Risk of transfusion-associated
infection
Although sensitive and specific laboratory
serologic tests became available soon after
the discovery and description of HIV, a
number of patients with thalassaemia who
received transfusions previous to HIV
screening have been infected. Many more
are still being infected in countries where
effective protective measures for blood
safety, including blood donor selection and
testing, have yet to be applied.

The prevalence of HIV infection
in thalassaemia varies greatly
worldwide, from <1% to >20%. In Italy,

Special considerations in thalassaemia
Although antiretroviral therapy should be
administered to patients with thalassaemia
major based on the same general guidelines
used for other infected non-thalassaemic
individuals, side effects such as endocrine
dysfunction and diabetes could be more
significant.

for example, the prevalence is currently 1.7%
while in Cyprus it is 0.17%. The rate of HIV
infection as with other infections among
transfused patients depends on the timing of
introduction and quality of public health

109

Viruses
enveloped

non-enveloped

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

Bacteria
Gram-positive

Gram-negative

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

Protozoa
Plasmodium
Plasmodium
Plasmodium
Plasmodium

vivax
falciparum
malarias
ovale

Trypanosoma cruci
Babesia microti
Toxoplasma gondii
Leishmania donovani

Others
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

organ transplant recipients, CMV infection
constitutes a major, if not one of the most
important causes of morbidity and mortality.

There is general agreement that a patient’s
iron status influences the outcome of HIV-1
infection. In HIV-infected patients with
thalassaemia major, the rate of progression
of HIV was significantly faster in patients with
low level of chelation with deferoxamine and
higher serum ferritin concentrations. Further
to the capacity to remove iron, iron
chelators, mainly deferiprone, show
interesting antiviral properties in vitro, but
there is so far no evidence of a direct
antiviral effect. Optimal control of iron
overload with iron chelation is therefore
recommended in HIV-positive patients with
thalassaemia and the choice of chelator
should take into consideration the above
data as well as the individual’s needs.
Because of an increased risk of neutropenia,
deferiprone should be used with caution in
such cases.

Unlike the case with other infectious agents,
the presence of serum CMV IgG antibodies
does not preclude infectiousness. It is
estimated that approximately 2-12% of antiCMV positive healthy donors are infectious,
i.e. can transmit the virus.
The increasing use of bone marrow
transplantation as a treatment for
thalassaemia demands special attention to
the serological status of CMV. Prevention of
transmission through blood products is
effectively achieved by the use of anti-CMV
negative donation, but this policy may be
applied only in special conditions, such as
stem cell transplantation, because exclusion
of CMV positive donors (50-75% of the adult
population are anti-HCMV positive) will affect
significantly the national pool of blood
supply. As CMV is WBC-associated virus, the
widespread use of leucocyte filtration, in
recent years recommended for all patients
with thalassaemia, no matter what their
condition, constitutes an effective
preventative measure.

While there is no direct evidence that
splenectomy facilitates the progression of
HIV infection, a decision to perform
splenectomy in an HIV-positive patient with
thalassaemia should be made with extreme
caution. Of particular concern is the removal
of an important fraction of T cells and the
potential for overwhelming infection in
immuno-compromised patients.

Bacterial infections

Human
Cytomegalovirus
(HCMV)

Yersinia enterocolitica
Mechanisms of infection
The Yersinia organism is most commonly
transmitted by the ingestion of
contaminated food, meat, milk or water,
although it is commensal in healthy
individuals. On rare occasions it becomes
virulent, crossing the intestinal membrane
and provoking life-threatening infections. The
best known factor predisposing the organism

Transfusion-associated CMV has a wide
clinical spectrum. In the immuno-competent
patient-host, it is usually sub-clinical or may
appear as an infectious mononucleosis-like
syndrome. In the immuno-compromised
host, however, such as bone marrow or

111

Post-infection sequelae include erythema
nodosum and reactive arthritis, mostly in
adults.

to virulence is the availability of a large
amount of iron, as is the case in severe iron
overloaded patients or in those undergoing
iron chelation with desferrioxamine (Vento,
Cainelli and Cesario, 2006), as described
above.

Laboratory diagnosis
Specific culture conditions (at 22oC for 48
hours) are necessary to identify Yersinia
species and in this context, the treating
physician should inform the laboratory of
his/her suspicions in order to enable it to
proceed to the correct culture conditions for
blood and stool samples.

Transfusion-associated transmission of
Yersinia enterocolitica may occur from
apparently healthy donors, albeit rarely, as
the organism can survive and multiply under
normal storage conditions (4oC). The
mortality rate among recipients of
contaminated blood is >50%.

Serologic tests for Yersinia are problematic
because of the likelihood of cross-reactivity.
However, a four-fold rise in IgG titres in serial
samples obtained 15 days apart may be
suggestive of recent infection. Overall, the
pickup rate for stool, blood culture and
seroconversion is low. In some cases
diagnosis may only be made after obtaining
samples of affected tissue (e.g. gut, lymph
node).

Clinical manifestations
The clinical manifestations of Yersinia
infection depend on the age and health of
the host. While variable, these manifestations
are severe in over 80% of cases involving
patients with thalassaemia. Fever is the most
common presenting feature, often
associated with abdominal pain and diarrhoea
or vomiting. Extra gastrointestinal
manifestations, such as acute respiratory
distress syndrome, arthralgia and skin rashes,
are also sometimes seen.

Treatment
The basic but most important point is that
anyone involved in the care of a patient with
thalassaemia with the above-described
symptoms must be aware of the risk of
Yersinia infection and its management.
Simple information leaflets issued by the
treating centre and carried by the patient or
parents of children may be of help, especially
when travelling.

The most typical clinical picture is an ‘acute
abdomen’ that mimics and may even be
indistinguishable from acute
appendicitis/peritonitis, caused by
mesenteric lymphadenitis. It is important to
have this critical point in mind, as the two
conditions require a very different
antimicrobial approach.

In the absence of a quick reliable laboratory
diagnosis, treatment must begin on the basis
of clinical suspicion. In such cases, the
following measures should be taken:

The most dangerous condition is septicaemia,
which, in the absence of specific antibiotics,
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

Escherichia coli. Splenectomy seems to be the main predisposing factor. Predisposing factors seemed to be iron overload and liver function derangement (Chung et al. Vibrio vulnificus. the prevalence was reported to be 7. Salmonella species and Mucor species. Recent papers also report Vibrio vulnificus is sporadically reported as the cause of severe infections. and permanent neurological sequelae 25%. Mortality rate was 16%. 113 . Iron overload is likely to be the most important predisposing factor. there is no in vivo evidence that the prevalence and severity of related infections in thalassaemia is higher than in the nonthalassaemic population. Pseudomonas aeruginosa in thalassaemia constitutes the most common pathogen-related infection to the central venous catheter. trimethoprimsulfomethoxazole or cephalosporins may be added or used as an alternative. Klebsiella species Klebsiella infections in thalassaemia major and even more in HbE/b-thal are associated with high mortality and morbidity rates are occasionally reported in the literature. In a large retrospective study including 160 patients. intracranial infection. 2003). Some patients relapse after restarting desferrioxamine. wound infections and meningitis in patients with thalassaemia in South-East Asia.infection by Campylobacter and Chryseobacterium meningosepticum. Pseudomonas species. ñ Stop iron chelation therapy immediately ñ Obtain suitable laboratory samples ñ Commence antibiotic treatment immediately Yersinia species are typically intracellular and therefore antibiotics with good intracellular penetration are recommended. including septicaemia. with a clinical spectrum including sinusitis. Lin et al. Iron chelation should not be restarted until the patient has been asymptomatic for over a week.v. septicaemia and pyogenic abscesses of the liver. meningitis. immediate parenteral therapy is mandatory with the same drug. In severely unwell patients. In mild suspected cases. It is generally advisable to continue antibiotics for at least two weeks after proven infection. It may cause severe infections such as meningitis (Wang. deferiprone and deferasirox do not seem to trigger Yersinia enterocolitica virulence. I.5%. Despite the in vitro data for micro-organisms such as Listeria monocytogenes and Salmonella. Whenever possible. the synthetic chelators. lung and kidney. oral ciprofloxacin is the recommended first line treatment. Other bacterial infections Melioidosis of the musculoskeletal system caused by Pseudomonas pseudomallei has been sporadically reported in thalassaemia. 2003). In contrast to deferoxamine. an alternative chelator should be prescribed. Other micro-organisms that may cause severe infections and should be seriously considered in the management of unwell patients with thalassaemia include Klebsiella species.

have been observed in patients with thalassaemia (Krajaejun et al. Escherichia coli is not reported as a significant pathogen in thalassaemia major. as for Klebsiella. severe infections have been observed only in immunocompromised subjects after stem cell transplantation. The disease has high rates of morbidity and mortality and early diagnosis and prompt initiation of effective treatment are extremely important. Helicobacter pylori In thalassaemia. being clinically significant in patients with HbE/‚-thalassaemia. Human pythiosis has been reported in Thailand among farmers and their relatives although zoonosis is prevalent in many other parts of the world. 2006) Salmonella species Many in vitro data suggest that patients with thalassaemia. A vaccine has been recently developed which has demonstrated at this preliminary stage effectiveness in patients with thalassaemia. in vivo the prevalence of Salmonella infections does not seem higher than in normal subjects. pylori infection was not statistically different from matched nonthalassaemic healthy subjects. Common infections not related to thalassaemia Haemophilus influenzae Thalassaemics appear to have a lower natural immunity to this microorganism. Overall. (Krajaejun et al. however vaccine-induced immunity seems to be effective. dengue was reported to be frequent and more severe than expected in patients with thalassaemia. vascular and disseminated pythiosis) 114 . underscoring the need for providing special awareness of proper diagnosis and management. Dengue Haemorragic fever due to dengue viral infection is endemic in Southeast Asian countries where thalassaemias are also common. have a decreased opsonic activity and phagocytic efficiency against Salmonella species. Pythiosum insidiosum Pythiosis is caused by the oomycete Pythium insidiosum. 2006). The most severe forms (cutaneous. The organism does not respond to antifungal agents. particularly in these regions of the world. In an uncontrolled study from Thailand. In one study of patients with thalassaemia with recurrent abdominal pain. however. Fungi Mucor species Mucormycosis or Zygomycoses are opportunistic fungal infections caused by ubiquitous organisms of the Zygomycetes class. particularly those that are splenectomised. the prevalence of H. The relationship with conditions of iron overload and deferoxamine use is well known.

and in this context. being a healthy carrier of a haemoglobinopathy provides protection against the clinical severity of malaria. 115 . However. Plasmodium species and Trypanosoma cruzii may remain viable for at least two weeks in refrigerated blood components as well as in frozen plasma. Patients must therefore be provided with specific advice for the prevention of malaria before and during periods of travel in endemic areas. ‚- thalassaemia major or intermedia are not protected from severe malaria and may indeed be more prone to severe forms of the disease.Malaria and thalassaemia ∆ransfusion-related Malaria and Chaga’s disease There is evidence that in most cases. Council of Europe. and national standards including donor selection have been drawn up based on WHO. Patients with Post-transfusion malaria and Chaga’s disease have been known for more than 50 years. EU and North American Authorities’ recommendations. in order to prevent or minimise the transmission of these diseases. there are great concerns that increased tourism to and from endemic countries might increase the frequency of transfusion-transmission of these pathogens. Both infections remain an important topic for blood transfusion services. splenomegaly. depending on their clinical condition (anaemia. iron overload and other complications). the same is not true for the homozygous state.

1977. optimal clinical management from the time of diagnosis may delay or even prevent hypersplenism. Splenectomy should be considered when: ñ Annual blood requirements exceed 1. but the recovery period is shorter and there is virtually no surgical scar. by ultrasonography. However. and changes in the haematocrit of the transfused units. Throughout the care of the patient with thalassaemia. the size of the spleen should be carefully monitored on physical examination and.5 times those of splenectomised patients. The rate of iron overload should also be taken into consideration. The laparoscopic approach requires a longer operative time and may not be practical for patients with very large spleens.g. splenectomy may be unnecessary. Surgery The two surgical techniques most commonly employed for total splenectomy are the open and laparoscopic approaches. 1990). It is generally advisable to delay splenectomy until patients are at least five years old because of the increased risk of overwhelming sepsis below this age (see below). ñ Leucopenia or thrombocytopenia due to hypersplenism causes clinical problems (e. For patients who maintain effective chelation therapy despite increased blood requirements. reduction in the rate of transfusional iron loading by splenectomy may be an important component of the overall management of iron overload. as needed.Splenectomy in ‚-thalassaemia splenomegaly causes concern about possible splenic rupture. this increase in transfusion requirements represents consumption of more than 200-220 ml of red cells (assuming haematocrit of transfused cells is 75%)/kg/year (Modell. the ñ Splenic enlargement is accompanied by symptoms such as left upper quadrant pain or early satiety. Before considering splenectomy in this situation. For patients with increasing iron stores despite good chelation therapy. partial splenectomy is used to preserve some of the immune function of the spleen while reducing the degree of hypersplenism (De Montalembert. Splenomegaly due to periods of undertransfusion with blood of inappropriately low haemoglobin may be reversible. Cohen. Many surgeons now have extensive experience with this approach. Massive 116 . In some centres. In particular. provided that they are on the same transfusion scheme and have no other reasons for increased consumption. Such reasons include new alloantibodies. thereby increasing the efficiency of transfusion therapy and reducing the need for splenectomy. The long-term success of this approach is still undergoing evaluation. recurrent bacterial infection or bleeding). Many patients with thalassaemia major require splenectomy. the patient should be placed on an adequate transfusion programme for several months and then re-evaluated. infection. For patients maintaining a pre-transfusion Hb level of about 10 g/dl. 1980).

positive findings will lead to cholecystectomy at the same time as splenectomy. However. with platelet counts often reaching 1. 1983). Modern preventative measures (see below) have reduced this risk but the overall impact of these measures is unclear. special consideration should be given to the use of low-dose aspirin (80 mg/kg/d) for patients with high platelet counts. Reduction of splenic tissue by embolisation is a less invasive approach to hypersplenism than complete or partial surgical splenectomy (Pringle. Complications of splenectomy Peri-operative complications include bleeding. occur with increased frequency in asplenic patients and are often associated with high mortality. this approach has not gained wide acceptance and may be complicated by fever. atalectasis and subphrenic abscess. vomiting and headache. thrombotic tendency. Because patients with thalassaemia may have an increased Characteristics of overwhelming postsplenectomy sepsis include the sudden onset of fever and chills. The pathogens most commonly associated with postsplenectomy sepsis are encapsulated organisms (Pedersen. 1982). In some cases. Klebsiella and Pseudomonas aeroginosa. significant pain and the possible need for a subsequent total splenectomy. 117 . Splenectomy also provides a good opportunity for a liver biopsy to assess the liver histology and iron concentration. Removal of the appendix at the time of splenectomy may prevent later problems in distinguishing infection with Yersinia enterocolitica from appendicitis.likelihood of splenic re-growth and the volume of splenic tissue required to preserve immune function are two questions outstanding. Protozoan infections due to Babesia have been implicated in a fulminant haemolytic febrile state in splenectomised patients. Postoperative thrombocytosis is common. Appropriate immunisations should be administered at least 2 weeks before splenectomy (see below). or the use of anticoagulation for patients with a history of previous thrombosis or other risk factors. Malaria is reportedly more severe in asplenic people (Boone.000/mm3. In older studies.000. Embolisation does not permit a search for accessory spleens. 1995) and carries an increased risk of death. 1973). especially if the patient has experienced symptoms suggestive of biliary tract disease. notably Escherichia coli. The major long-term risk after splenectomy is overwhelming sepsis. particularly: An evaluation for gallstones should be performed prior to surgery. Other gram-negative organisms have also been implicated in postsplenectomy sepsis. the risk of postsplenectomy sepsis in thalassaemia major is increased more than 30-fold in comparison with the normal population (Singer. Any surgery on the spleen should include a careful search for accessory spleens.000.000-2. ñ Streptococcus pneumoniae (accounting for more than 75% of documented bacterial infections in asplenic patients) ñ Haemophilus influenzae ñ Neisseria meningitidis Infections with gram negative. rod-shaped bacteria.

The mortality rate for such infections is approximately 50%. 2006). previously splenectomised patients. 2004). The protection rate with the 23-valent vaccine is 70-85%. Meningococcal polysaccharide vaccine should also be administered to patients who are undergoing splenectomy and to nonimmunised. even in the absence of many of the above findings. Chemoprophylaxis 3. and is commonly accompanied by disseminated intravascular coagulation. fulminant bacteraemia has been reported in adults as much as 25-40 years after splenectomy. Pneumococcal vaccine should be given at least 2 weeks in advance of a splenectomy and then in 3-5 years. Patients who underwent splenectomy without being given pneumococcal vaccine may still benefit from vaccination postsplenectony. Immunoprophylaxis 2. early intervention on the basis of clinical suspicion. 1. However.(Landgren. ñ Time since splenectomy—the greatest risk appears to be in the period 1-4 years after surgery ñ Immune status of patient If not administered as part of routine childhood immunisations. A conjugate vaccine will be available shortly. The immune response to this polysaccharide vaccine is poor in children less than two years of age. The illness rapidly progresses to hypotensive shock. The risk of overwhelming postsplenectomy infection varies with: ñ Age—risk is very high in children <2 years of age. is critical. Tsoumas et al. Bjorkholm et al. Preventative measures The three types of protective measures a physician can utilise to prevent postsplenectomy sepsis include: These vaccines can be given at the same time in different syringes at different sites. Yearly administration of influenza virus vaccine is recommended to prevent this febrile illness that might otherwise require intensive evaluation and management of a febrile episode in the splenectomised host with thalassaemia (see below). despite intensive supportive measures. The currently available pneumococcal vaccine is a 23-valent polysaccharide vaccine that can be given subcutaneously or intramuscularly. Patient education Immunoprophylaxis Vaccination against Streptococcus pneumoniae is a critical step in preventing overwhelming infection after splenectomy 118 . Postsplenectomy sepsis has many of the features of adrenal haemorrhage (Waterhouse-Friederichsen syndrome). Therefore. Children vaccinated under the age of two should be re-vaccinated at age two. Haemophilus influenzae vaccine should be given to patients before they undergo splenectomy and should also be given to splenectomised patients (Spoulou.

febrile illnesses and seeking immediate medical attention. If bacteraemia is suspected. the physician should strongly consider: Chemoprophylaxis Chemoprophylaxis with oral penicillin. for children two years and over is recommended to reduce the risk of postsplenectomy sepsis. and 250 mg b. Patients also need to be made aware of the potential for travel-related infections such as babesiosis and malaria. trimethoprim-sulfomethoxazole and erythromycin. Other complications which have been recognized in splenectomised patients include: ñ Thrombophilia ñ Pulmonary hypertension Education Thrombophilia. an appropriate antibiotic should be made available for the patient to carry with him/her. including a complete physical examination Obtaining blood and other cultures as indicated. The value of chemoprophylaxis after this age is unproven. For all febrile episodes. Patients and parents should recognise that chemoprophylaxis does not prevent all cases of post-splenectomy sepsis: the risk of death from febrile illnesses remains. while others treat patients whose spleens are removed after the age of five years only for the first two years after splenectomy. Beginning treatment with an antimicrobial regimen effective against Streptococcus pneumoniae and Neisseria meningitidis. The use of prophylactic antibiotics will need to be regularly re-evaluated as improved vaccines become available and as new data regarding antibiotic-resistant bacteria are developed. In the latter case. as well as the risk inherent in travel to an area where medical care is not readily accessible.d. 125 mg b. The phenomenon of increased coagulability is related to the fact that damaged red cells Patient and parent education can be highly effective in preventing overwhelming postsplenectomy infection.d. However. The importance of compliance with prophylactic antibiotics should be stressed repeatedly to patients and parents. Physicians should emphasise to the patient and parents the importance of recognising and reporting 119 .i. Patients should be reminded always to alert consulting physicians about their splenectomised status. but a higher risk is seen in splenectomised patients. Evaluating the patient. irrespective of age. Some clinicians continuously treat all splenectomised patients with prophylactic antibiotics.this is a complication which occurs more frequently in thalassaemia intermedia (see relevant chapter). the patient should be treated with parenteral antibiotics and observed in a medical facility until the cultures are evaluated. Alternative antibiotics for patients unable to take penicillin include amoxicillin. All splenectomised children under five years of age should be treated with prophylactic antibiotics. and rapid evaluation of febrile episode is essential (see below). for children under two years.i. the limitations of antibiotic prophylaxis must also be emphasised.

prothrombin fragments (F1. 120 . especially in splenectomised patients. Pulmonary hypertension – this complication is more frequent in thalassaemia intermedia. but it is also increasingly identified in thalassaemia major. persist in the circulation and trigger mechanisms of Thrombin generation (see Figure 2 Chapter 11: Thalassaemia Intermedia and HbE).2) fibrinopeptide A (FPA) and D-dimer should be assessed annually.normally removed by the spleen. In postsplenectomy patients markers of thrombin generation such as thrombin AT III (TAT) complexes. and anticoagulant prophylaxis prescribed where indicated.

Camaschella and Cappellini. associated with increased HbF. Ismaeel and Cappellini. iron and bilirubin metabolism that can affect clinical expression. meaning that both ‚-globin loci are affected. due to the interaction of genetic and environmental factors. if any. ñ inheritance of a mild ‚+ mutation. but too mild to be called major’. Thalassaemia intermedia encompasses a wide clinical spectrum. Relevant environmental factors include social conditions.Thalassaemia Intermedia and HbE compound heterozygotes for ‚-thalassaemia. The mild clinical characteristics of TI compared with thalassaemia major are primarily the result of the following three mechanisms: Definition The clinical phenotypes of thalassaemia intermedia (TI) lie between those of thalassaemia minor (heterozygous state) and major (homozygous state). Analysis of the genotypes of patients with thalassaemia intermedia is important for an early diagnosis of the milder disease. Patients with more severe thalassaemia intermedia generally present between the ages of 2 and 6 years. although there is substantial clinical overlap between the three conditions. and although they are able to survive without regular transfusion therapy. 2006. and ñ co-inheritance of ·-thalassaemia on the ‚-globin locus. TI was first described in 1955 by Rietti-Greppi-Micheli. The clinical spectrum of thalassaemia intermedia indicates the need for an individualised treatment approach. experiencing only mild anaemia and maintaining haemoglobin levels between 710g/dL. thus avoiding unnecessary blood transfusions. occurring either by the triplication of · genotype associated with ‚-heterozygosity.or Á-chain genes). who referred to patients as being ‘too haematologically severe to be called minor. 2006).and ‰‚thalassaemia (Taher.promoter region. 2006). which can cause either complete or marked reduction in ‚chain synthesis. The phenotype of TI may also result from the increased production of ·-globin chains. the imbalance is greater than that seen in ‚-thalassaemia trait and less than that of ‚-thalassaemia major. Primary genetic modifiers are the numerous genetic alleles at the ‚-chain locus. nutrition and the availability of medical care (Taher. Predicting phenotype from genotype in TI is still difficult. growth and development can be retarded. 1995). Mechanism of TI The pathophysiology of thalassaemias is based on an imbalance of globin-chain synthesis. Mildly affected patients are completely asymptomatic until adult life. or by the interaction of ‚. Secondary genetic modifiers are those that have a direct effect on modifying the amount of excess ·-chains (inheritance of abnormal ·. ñ presence of a polymorphism for the enzyme Xmn-I in the GÁ. Despite the availability of a number of treatment options. Most TI patients are homozygotes or 121 . In the case of ‚-thalassaemia intermedia. These patients require only occasional blood transfusions. the lack of clear guidelines can present a significant clinical challenge (Taher. Tertiary modifiers are polymorphisms occurring at loci involved in bone.

Weatherall. 2001). haematological. Unfortunately. Wainscoat. Differential diagnosis Differentiation at presentation between thalassaemia major and thalassaemia intermedia is essential for designing appropriate treatment for an individual patient. Nevertheless.Borderline HbA2 Severe No Mild/silent Yes No Yes No No Yes Yes Genetic Parents Molecular Type of mutation Coinheritance of ·-thalassaemia.High HbF ‚-thalassaemia . 1987. 2006.accurate identification of these two phenotypes at the onset is remarkably difficult. while the timely diagnosis of thalassaemia major will allow an early start to a transfusion programme. the Helpful clues in differentiating between thalassaemia major and thalassaemia intermedia Thalassaemia major more likely Thalassaemia intermedia more likely Clinical Presentation (years) Hb levels (g/dl) Liver/ spleen enlargement <2 6-7 Severe >2 8-10 Moderate to severe Haematological HbF (%) HbA2(%) >50 <4 10-50 (may be up to 100%) >4 Both carriers of high HbA2 ‚-thalassaemia One or both atypical carriers: . The accurate prediction of a mild phenotype may avoid needless transfusions and their complications. Hereditary persistence of fetal haemoglobin ‰‚ thalassaemia GÁ XMN1 Polymorphism Table 1 122 . thus preventing or delaying hypersplenism and reducing the risk of red cell antigen sensitisation. (see Table 1 for an outline of the major differences between thalassaemia intermedia and major). genetic and molecular data may allow a reasonable conclusion for treatment (Taher. a careful analysis of clinical. however.

degree of ineffective erythropoiesis is the primary determinant of the development of anaemia. The Complications and management of TI In addition to the defining symptoms of thalassaemia intermedia. ineffective erythropoiesis). a-chains are highly unstable and precipitate into erythroid precursors in the bone marrow.e. Cappellini. Figure 1: Pathophysiological sequelae of untreated thalassaemia and corresponding clinical manifestations 123 . Figure 1 highlights the multitude of complications in untreated thalassaemia (Taher. chronic anaemia and iron overload. patients with thalassaemia intermedia experience a number of specific complications that are rare in thalassaemia major. while peripheral haemolysis of mature red blood cells and an overall reduction in haemoglobin synthesis are secondary determinants. causing membrane damage and cell death (i. 2006. Hypertrophy of erythroid marrow in medullary and extramedullary sites. The severity of clinical sequelae depends primarily on the underlying molecular defects. which are seen to a lesser or greater extent in other forms of thalassaemia. Cerino et al. results in characteristic deformities of the skull and face and may also cause cortical thinning and pathological fractures of long bones. Ismaeel and Cappellini. Pathophysiology of Thalassaemia Intermedia (TI) Three main factors are responsible for the clinical sequelae of thalassaemia intermedia: ineffective erythropoiesis. a consequence of severe ineffective erythropoiesis. 2001).

Borgna-Pignatti. Olivieri. Castelli. 2006). Saxon. 2003. Merlo et al. lymph nodes. chest and spine. 2001. Cappellini. Aoun. Karimi and Cappellini. liver. MRI is the radiological method of choice for diagnosing extramedullary haematopoietic masses and for delineating the extent of spinal cord involvement. 2006. In case of spinal cord compression. 2003. 2006. 1998).Splenomegaly and Splenectomy Extramedullary haematopoiesis Splenectomy is now uncommon and is mainly performed late in life. which can lead to hydronephrosis and kidney failure. the laparoscopic approach is safe and feasible and preferred over open surgery. as a minimally invasive alternative that may become the treatment of choice in ‚-thalassaemia patients who require concurrent operations. Kidney stones As a result of ineffective erythropoiesis and peripheral haemolysis TI patients are susceptible to kidney stones. targeting at higher Hb levels. Ismaeel and Cappellini. Galanello. The main indications for splenectomy in thalassaemia intermedia are a significant enlargement of the spleen and a decrease in mean haemoglobin levels in the absence of other transient factors such as infection (Taher. involving many blood transfusions over a period of weeks to compensate for the demands of erythropoiesis. and intra-thoracic masses. As for the type of surgery. Management includes transfusion therapy. 2001). These masses can be detected by magnetic resonance imaging (MRI). Koussa et al. 2003. The 124 . Merlo et al. 2001. Leandros et al. During splenectomy. 2004. Rigon. Chehal. BorgnaPignatti. 2001. Gall stones and cholecystectomy Gallstones are much more common in thalassaemia intermedia than in thalassaemia major as a result of ineffective erythropoiesis and peripheral haemolysis. laparoscopic cholecystectomy has more favourable and feasible outcome than open cholecystectomy (Taher. They may cause neurological problems such as spinal cord compression and paraplegia. Similar to laparoscopic splenectomy. Piras. as well as radiotherapy and hydroxyurea (Taher. Cappellini. 2006. Galanello. leading to the formation of erythropoietic tissue masses that primarily affect the spleen. Rigon. Barella et al. surgeons should assess the gallbladder for any stones and perform cholecystectomy whenever gallstones are found (Leandros et al. clinical awareness is crucial for early diagnosis and prevention of irreversible neurological complications. Rees. Piras. Hypertransfusion is a promising treatment method. 2006). Graziadei. Cerino et al. Ismaeel and Cappellini. Ismaeel and Cappellini. Barella et al. Extramedullary haematopoiesis is a compensatory mechanism where bone marrow activity increases in an attempt to overcome the chronic anaemia of thalassaemia intermedia. Cerino et al.

either alone or in combination with erythropoietin or platelet-derived growth factor. although regular blood transfusions may provide some relief in persistent cases. cause is associated with hypertrophic stones that block the renal tubules and even the calyces. once an ulcer has started to develop it is very painful and difficult to cure. 1982). Zinc Thrombophilia Patients with thalassaemia intermedia have been shown to have an increased Figure 2: Thrombotic mechanism in thalassaemia intermedia 125 . The kidneys are frequently enlarged in thalassaemia. In addition. Wexler and Rachmilewitz. 2006. It is unclear why ulcers develop. Leg ulcers Leg ulcers are more common in older rather than younger patients with thalassaemia intermedia. Ismaeel and Cappellini. Gimmon. due to the presence of extramedullary haematopoiesis. Hydroxyurea also has some benefit.supplementation can help accelerate the healing of ulcers. the use of an oxygen chamber can provide moderate relief since tissue hypoxia may be an underlying cause of the ulceration (Taher. However.

Rachmilewitz. pulmonary embolism (12%) and others (20%). Ismaeel and Cappellini. 2001. AbouMourad. Cappellini. 2002. In a study of 110 thalassaemia intermedia patients (60. Hepatitis Hepatitis due to viral (B and C) infection is less frequent in thalassaemia intermedia than in patients with thalassaemia major. Cappellini. 2006.which is thought to be the primary cause of congestive heart failure in this patient population (Aessopos. Karagiorga et al. although data from large patient numbers are lacking in thalassaemia intermedia (Taher. 2001). Management of thrombophilia has two arms: prevention and treatment. Karagiorga et al. 2006. 2002). Regular transfusion and iron chelation therapy is therefore indicated in thalassaemia intermedia patients who are well-stratified according to the early detection of pulmonary hypertension indices. 2000). Such events mainly occurred in the venous system and comprised deep vein thrombosis (40%). Taher. (See Figure 2 for more on the thrombotic mechanism in thalassaemia intermedia. Farmakis. 126 . Ismaeel. 2006. 2005). portal vein thrombosis (19%). predisposition to thrombosis compared with thalassaemia major patients. Robbiolo. Farmakis. the two conditions are likely to be at the root of the pathophysiology of pulmonary hypertension.9% untransfused or minimally transfused). Abnormal liver enzymes (increased alanine and aspartate aminotransferase) are frequently observed in patients with thalassaemia intermedia. Ismaeel and Cappellini. Mehio. Ismaeel and Cappellini. Marelli and Fiorelli. Sildenafil has also been successfully used to treat pulmonary hypertension. Treatment entails the adequate use of anticoagulation according to the recommendations for hypercoagulable states. Eldor. Normalisation of liver enzyme levels is often observed during appropriate chelation therapy (Taher.1% were shown to have PHT. since blood transfusions are much less common in thalassaemia intermedia. Moreover. Pulmonary hypertension and congestive heart failure Pulmonary hypertension (PHT) is prevalent in patients with thalassaemia intermedia. Abchee et al. Farmakis. 2001). Prevention consists of proper anticoagulation prior to any surgical or other high-risk procedure. 2006. Taher.) As anaemia and iron overload are uncommon in well-transfused and chelated thalassaemia major patients. Deftereos et al. Bignamini et al. stroke (9%). 2000. splenectomised patients have been shown to have a higher risk of thrombosis than non-splenectomised patients (Cappellini. Awareness is important since thromboembolism plays an important role in pulmonary hypertension and right heart failure (Taher. Aessopos. Bottasso et al. Robbiolo. primarily due to hepatocyte damage resulting from iron overload. The mechanism underlying pulmonary hypertension in thalassaemia intermedia is unclear. Cerino. Bottasso et al. Aessopos. 59.

and should be carefully monitored in order to assess the need for transfusion therapy and to avoid haemodynamic compromises (Taher. The chronic anaemia of thalassaemia intermedia can cause an increase in spontaneous abortions. Nassar. although complications during pregnancy may occur. 2006. Initiation of iron chelation depends on the amount of excess iron. Ismaeel and Cappellini. 2001). Usta and Taher. 2006. 2006). TI patients are susceptible to complications of iron overload. Ismaeel and Cappellini. Fiumana et al. low dietary intake or. most significantly. women with thalassaemia intermedia should be given oral folic acid supplementation (around 1 mg/day). an increased demand for folic acid from active bone marrow. hypothyroidism and diabetes mellitus are quite rare in thalassaemia intermedia. Osteoporosis (also see chapter on osteoporosis) There is a high incidence of osteoporosis of the spine and hip in both sexes in thalassaemia intermedia. 1990).However. Fargion. Although patients with thalassaemia intermedia generally experience puberty late. 2006. 2005). and duration of exposure to excess iron. rate of iron accumulation. Management consists of bisphosphonates and calcium supplementation with follow up bone-mass densitometries (Origa. Cerino. pre-term labour and intrauterine growth retardation. The resulting iron overload can lead to a number of serious complications. Rechdan. Ismaeel and Cappellini. Pregnancy in TI Women with thalassaemia intermedia may have spontaneous successful pregnancies. Cappellini. Increased levels of liver iron concentration (LIC) have been observed with small increases in serum ferritin (Fiorelli. they have normal sexual development and are usually fertile. Thus. Pseudoxanthoma elasticum (PXE) Iron overload PXE is a rare hereditary connective tissue disorder. including cardiac failure and endocrine abnormalities such as diabetes mellitus and hypogonadism (Taher. direct assessment of LIC by biopsy or MRI is recommended. 127 . while endocrine complications due to haemosiderosis are common. the mechanism involved in TI is increased absorption from the gut rather than blood transfusions. characterised by generalised degeneration of the elastic fibres with a Just as in thalassaemia major. 2006). 2001). Ismaeel and Cappellini. The severity increases with age and even young patients exhibit a spinal bone mineral density far below that of age-matched controls. Hypothyroidism is sometimes observed late in life (Taher. Chelation therapy should be initiated if LIC ≥ 7 mg/g dry weight of liver (Taher. Marelli and Fiorelli. Folic acid deficiency is common in thalassaemia intermedia and occurs due to poor absorption. Endocrine function Hypogonadism. During pregnancy. Piperno et al. Weatherall.

1979. including failure of growth and development. Cerino. Splenectomy Transfusions are indicated where the following are observed: ñ failure to thrive in childhood in the presence of significant anaemia. to help prevent transfusion-dependency. the main indications for splenectomy include growth retardation or poor health. The decision to initiate therapy should be based on the presence and severity of signs and symptoms of anaemia.broad phenotypic expression. ñ delayed or poor pubertal growth spurt and ñ progressive splenic enlargement. SheikhTaha et al. with secondary calcium deposition. The clinical picture consists mainly of cutaneous. ocular and vascular manifestations. Splenectomy before the age of 5 carries a high risk of infection and is therefore not generally recommended. compared with the regular transfusion regimens implemented in thalassaemia major. including splenectomy. it can afford significant benefits. 2003. This condition has been described as occurring in Ùhalassaemia. Warner and Weatherall. ñ evidence of a clinically relevant tendency to thrombosis. an assessment of liver iron concentration is advisable before initiating transfusion therapy. ñ emergence of bone deformities. Ismaeel and Cappellini. ñ increasing anaemia not attributable to rectifiable factors. Cappellini. skin histopathology involves swollen. Callender. 128 . transfusion therapy. Patients with thalassaemia intermedia may benefit from an individually tailored transfusion regimen. leucopenia. thrombocytopenia. Alloimmunisation is a relatively common observation in thalassaemia intermedia. Marelli and Fiorelli. 2006. As the rate of iron loading is variable in thalassaemia intermedia. Hoffbrand. However. Transfusion therapy and iron chelation Although transfusion therapy is not currently a routine treatment approach for patients with thalassaemia intermedia. although the risk is decreased if transfusion therapy is initiated before the age of 12 months (Pippard. Management of thalassaemia intermedia There are a number of options currently available for managing patients with thalassaemia intermedia. irregularly clumped and multiply-fragmented elastic fibres in the middle and deep reticular dermis. ñ presence of leg ulcers. Cappellini. 2001). ñ development of pulmonary hypertension. Mourad. 2001). modulation of fetal haemoglobin production and bone marrow transplantation (Taher. increased transfusion demand and symptomatic splenomegaly. Splenectomy is no longer a major mode of management.

the degree of its success depends primarily on the health and age of the patient. see Chapter 13: Alternative approaches to the treatment of thalassaemia. Mishra et al. Darzi. Agents including cytosine arabinoside and hydroxyurea may alter the pattern of erythropoiesis and increase the expression of Á-chain genes. ñ aspirin for stroke prevention. M. Dettelbach and Aviado. Dixit. Butyrates are a further experimental category. postsplenectomy and life-long anticoagulation in patients with a history of thrombotic events is a must. 1993. Good responses have been reported. The scheme for adult thalassaemia intermedia patients is as follows: ñ each patient to be reviewed separately and stratified by risk. (For more details. Faller et al. Graziadei. 2006. This is particularly relevant in patients with thalassaemia intermedia. H. 2005. Yavarian. In stable asymptomatic TI patients who do not require transfusions. ñ liver MRI assessment of iron concentration (or liver biopsy if MRI is Bone marrow transplantation Bone marrow transplantation is an established treatment for ‚-thalassaemia. Olivieri. ñ transfusion and iron chelation therapy with deferoxamine subcutaneous infusion and concomitant steroids for protection from alloimmunisation are essential. ñ hydroxyurea introduced as a suitable initial approach. Ciceri et al. bone marrow transplantation is not needed. Ginder.) Recommendations for the management of thalassaemia intermedia Two major issues regarding the management of thalassaemia intermedia are 1) the approach and management of complications in adult thalassaemia intermedia patients and 2) preventing such complications in younger patients. 1997). however. The decision as to which patients are 129 . Ismaeel and Cappellini. Modulation of fetal haemoglobin production Increasing the synthesis of fetal haemoglobin can help to alleviate anaemia and thereby improve the clinical status of patients with thalassaemia intermedia. especially in those who are only mildly affected. Cappellini. Erythropoietin has been shown to be effective. with a possible additive effect in combination with hydroxyurea. 2000. Although marrow transplantation can lead to cure. A stratification of the management of TI between adults and young patients has therefore been established. Further clinical evaluation is required to clarify the value of this approach (Taher. Perrine. 2005. Rees. still unlicensed and with difficult intake. Chatterjee.eligible for transplantation is complex and is related to both quality of life and expected survival time of the transplanted patient. 1985. Karimi. most patients complain of the difficulty of intake orally and intravenously. Ginder et al.

The combination of HbE with ‚-thalassaemia spans thalassaemia phenotypes.pregnancy. Haemoglobin E has the clinical phenotype of a mild form of ‚-thalassaemia. infection) Symptomatic anaemia Thrombocytopenia CHF+PHT Increased transfusion demand Leg ulcers Symptomatic splenomegaly (Taher. ‚-thalassaemia/HbE may be classified into three categories. Clinically.unavailable) is important to determine liver iron status for future chelation. Indications for transfusion Indications for splenectomy Growth failure or poor performance at school Growth retardation or poor health Transient stressful conditions Leukopenia (e. 2006) Table 2: Indications for transfusion and splenectomy in thalassaemia intermedia 130 . Ismaeel and Cappellini. prolonged immobilisation and the use of oral contraceptives or an intrauterine device. and is most frequent in southeast Asia. each of which has its own unique clinical management requirements: Mild ‚thalassaemia/HbE Mild ‚-thalassaemia/HbE patients do not require treatment and rarely develop clinical problems. Definition of ‚thalassaemia/HbE There are no clear guidelines for the management of thalassaemia intermedia in the young. poor performance at school or a psychological impact secondary to facial deformities. the authors recommend the following: ñ a guarded approach to the need for splenectomy and delay in initiating transfusion unless considered necessary based on the above mentioned indications. 2005). Thus. Premawardhena et al.g. Care should be taken not to See Table 2 for indications for transfusion and splenectomy. particularly eastern Thailand and Laos. from a condition indistinguishable from thalassaemia major to a mild form of thalassaemia intermedia (TIF. ñ discourage smoking. ñ early initiation of transfusion and iron chelation therapy if there is evidence of growth abnormalities. 2002. Haemoglobin levels may be as high as 9-12 g/dl. ñ regular follow-up with echocardiodoppler for cardiac complications and initiation of therapy at earlier disease onset to prevent progression. ñ regular follow up of liver iron concentration with MRI or liver biopsy.

including iron status and haemoglobin electrophoresis (TIF. Haemoglobin levels can be as low as 4-5 g/dl. 2005). 2005). The clinical management of this group of patients needs to be addressed as in thalassaemia major (TIF. by careful investigation of the red cell morphology. Other complications such as iron overload may occur in these patients. 2002. 2002. Premawardhena et al. these patients manifest symptoms similar to thalassaemia intermedia and normally do not require blood transfusions unless they develop infections precipitating further anaemia. iron chelation therapy should be initiated. Patients in this group often have a somewhat shortened lifespan. Complications and management of ‚-thalassaemia/HbE Complications in ‚-thalassaemia/HbE patients depend on the category they belong to. bone deformities including facial changes. jaundice and hepatosplenomegaly.confuse this group of patients with individuals having iron deficiency or with carriers of ‚-thalassaemia. including defective physical development. Where this is the case. in which the clinical picture is similar to that ‚thalassaemia major. but with careful monitoring and treatment can have an open-ended prognosis (TIF. Moderately severe ‚-thalassaemia/HbE This group encompasses the majority of ‚thalassaemia/HbE patients. anaemia. Clinically. Severe ‚-thalassaemia/HbE Patients present with the clinical symptoms of thalassaemia major. 2002. as indicated above. 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). Premawardhena et al. The worst of the complications occur in the severe group. Most patients have steady haemoglobin levels of 6-7 g/dl. Premawardhena et al. 2005). 131 .

more effective treatment of cytomegalovirus infection. Among Class I children with thalassaemia major transplanted early in the course of the disease. Three patient classes have been identified on the basis of the following risk factors. which have been found to have a significant influence on posttransplant outcome: ñ inadequate iron chelation therapy. (Centres performing transplants in patients with broadly similar characteristics have shown comparable outcomes [Lucarelli 1997]. requiring the physician. However. with a 3% risk of rejection and a 15% risk of non-rejection mortality (see Figure 2). bone marrow transplantation in thalassaemia should be considered for patients at an early age or before complications due to iron overload have developed. a final decision must be based on an assessment of the relative advantages and disadvantages of bone marrow transplantation and conventional therapy. with a 28% risk of rejection and a 19% risk of non-rejection mortality (see Figure 3). ñ presence of liver fibrosis and ñ hepatomegaly Based on these outcomes. 1990).Stem Cell Transplantation Figure 1). Outcome and patient selection Bone marrow transplantation from HLAidentical siblings has been increasingly adopted for the cure of haemoglobinopathies. patient and family to weigh the outcome and risks of each. with a 2% risk of rejection and an 8% risk of transplant-related mortality (see 132 . patients in Class II have one or two. Over that time. the probability of surviving a bone marrow transplant procedure is 66% with a 62% probability of cure. the probabilities of survival and disease-free survival are 93% and 91% respectively. improved aseptic techniques and the evolution of systemic antibiotic therapy – have led to a remarkable improvement in the outcome of bone marrow transplantation procedures (Lucarelli. and patients in Class III exhibit all three characteristics. Class II patients have an 87% probability of survival and an 83% chance of disease-free survival. a number of factors – the use of cyclosporin. Among adults (aged >16). Since 1981.) In the case of Class III patients. while Class III patients have a 79% probability of survival and a 58% chance of disease-free survival. the introduction of conditioning regimens containing less than 200 mg/kg of cyclophosphamide resulted in a significant decrease in transplant-related mortality. a large clinical experience has been gained with more than 1. a 35% chance of transplant-related mortality and a 5% chance of returning to the pre-transplant thalassaemic condition (see Figure 4). but with a concomitant increased risk of graft rejection.500 bone marrow transplants performed in centres around the world. Patients in Class I have none of the above characteristics.

the routine collection of cord blood stem cells from all births would provide a wider pool of donors for BMT therapy. Experience so far is limited. Reduction of the dose of busulfan or cyclophosphamide in the conditioning regimens produced higher rates of mixed chimerism – a risk factor for graft failure.There are several possible advantages to this approach. HLA-matched sibling donors The general applicability of bone marrow transplantation is limited by the availability of a related HLA-matched donor. normally termed mixed chimerism. the quantity of stem cells obtained is insufficient for engraftment in an adult recipient. there is interest in using unrelated but otherwise matched donors. 1998). Nevertheless. Unfortunately. Mixed chimerism Persistence of residual host haematopoietic cells. the evidence of decreased GVHD using cord blood is not persuasive. its overall value in treating the condition has yet to be firmly established. while cord blood transplantation has been successfully used to treat some patients with thalassaemia (Miniero. suggesting that if unrelated donors are from a closely related genetic background the outcome may be improved (Dini. while 29% of patients with mixed chimerism rejected the graft within two years of marrow infusion. it has been suggested that graft versus host disease (GVHD) may be less severe when stem cells are obtained at this early point in life. It is hoped that with continuing improvements in matching techniques. And in many cases. 133 . Thus. Second. however. Matched unrelated donor transplantation Because most patients with thalassaemia do not have a compatible sibling donor. a condition of long-term (> 2 years) persistent mixed chimerism has been observed after successful BMT in thalassaemia. None of the patients showing full donor engraftment rejected the transplant. There is a onein-four chance that any given sibling will be HLA identical. frequently occurs after bone marrow transplantation in ‚-thalassaemia (Andreani. Miano. 2000). the complication rates of transplants using matched unrelated donors are generally much higher than with sibling matched transplants. There has been some application of transplantation using matched unrelated donors in thalassaemia. complication rates will be reduced to acceptable levels. 1999. This Cord blood transplantation The use of stem cells obtained from umbilical cord blood collected at the time of delivery has recently received considerable interest. and often in sufficient quantity for a successful donation – thus avoiding the bone marrow harvest of a donor at a later age. Third. stem cells can be obtained easily at birth. 1998). However. with the likelihood of a thalassaemic patient having an HLA identical sibling donor varying according to family size. First.

cardiac function and endocrine deficiencies can be more easily managed after transplant. Within the first year. infectious complications and graft versus host disease is essential. chronic hepatitis. This can usually be achieved by repeated venesection (6 ml/kg blood withdrawn at 14-day intervals) (Angelucci 1997). careful monitoring of haematological and engraftment parameters. Long-term follow-up is of particular interest with respect to monitoring the evolution of multi-system problems (iron overload. pubertal development. It is particularly important to remove excess iron after transplant. A number of reports indicate that iron overload. sometimes permitting the healing of damaged organs. 134 . Post-transplant follow-up Post-transplant clinical follow-up of BMT is particularly important. growth.observation may have a significant impact on the design of future bone marrow transplant strategies. endocrine deficiencies) related to the primary disease.

event-free survival. . rejection and non-rejection mortality in 115 adult thalassaemic patients (aged more than 16 years).Figure 1: Figure 3: Figure 2: Kaplan and Meier probabilities of survival. rejection and non-rejection mortality in 126 Class III thalassaemic patients aged less than 17 years. rejection and non-rejection mortality in 119 Class I thalassaemic patients aged less than 17 years. Kaplan and Meier probabilities of survival. rejection and non-rejection mortality in 291 Class II thalassaemic patients aged less than 17 years Kaplan and Meier probabilities of survival. Figure 4: 135 Kaplan and Meier probabilities of survival. event-free survival. event-free survival. event-free survival.

in which the number of painful crises was reduced and overall health indicators improved. The lesser benefits in thalassaemia are perhaps due to the fact that the cytostatic effects of hydroxyurea are limited in the disease. as in ‚thalassaemia. have been explored over the past 20-25 years (Pace and Zei. Modulation of fetal haemoglobin The demethylating agents 5-azacytidine and decitabine have been administered to a few ‚-thalassaemia patients with good responses. 1993. 2006. The mutagenic potential and instability of formulations of 5-azacytidine have limited its investigation. Hydroxyurea has been less beneficial in thalassaemia intermedia than in sickle cell disease. but higher oral doses of decitabine have been effective in baboons (Lavelle. other than bone marrow transplantation—an option available only to a small minority of patients that have a suitable donor and are in good clinical condition. when it is typically suppressed and the production of ‚-globin is increased.Alternative Approaches to the Treatment of Thalassaemia recovery from bone marrow suppression after the use of cytotoxic drugs. raising total haemoglobin levels by a mean of 2. attention has focused on the possible role of cytotoxic agents as therapies in the treatment of serious haemoglobin disorders. by re-activating the foetal globin genes. This pattern is the norm even when the genes are mutated. with lower responses but reduced haemolysis (Fuchareon. promising. Patients with ‚-thalassaemia who continue to produce high levels of foetal globin. Another. Zeng.5 g/dl above baseline and clearly prolonging the lives of end-stage patients (Lowrey. Several cytotoxic agents that alter the pattern of erythropoiesis. 1982). have less globin imbalance and less severe anaemia. such as those with Hereditary Persistence of Foetal Haemoglobin. Fathallah and Atweh. Gambari and Fibach. 1996. even eliminating transfusion requirements in some Cytotoxic agents Following observations that foetal haemoglobin synthesis is reactivated during 136 . Hydroxyurea has been studied in HbE/ ‚thalassaemia patients. even rendering some transfusion independent. 1989. Ley. Dunbar. Foetal haemoglobin is the predominant non· globin produced in humans until around six months of age. 1995). 2006). Other agents Erythropoetins (EPOs) have increased haemoglobin levels significantly in some patients with thalassaemia intermedia. The therapeutic stimulation of foetal globin could therefore benefit many patients. 2007). Several candidate therapies now offer the potential to correct or modulate the underlying pathology. There is currently no definitive treatment for any of the serious haemoglobin disorders. favouring the expression of foetal (Á)-globin genes and so increasing the number of red cells containing HbF (F-cells). approach involves the use of therapeutics to definitively correct the globin chain imbalance in ‚-thalassaemia. 2006. and studies are planned in selected patients.

1996 and 1997. The mechanisms by which short chain fatty acids stimulate Á-globin production are being elucidated. 2006). Oral derivatives that persist for many hours after a single dose and which also stimulate erythroid cell proliferation and survival. Isobutyramide has induced foetal globin and reduced transfusion requirements in thalassaemia intermedia and major (Cappellini. Rachmilevitz. Combination therapy Although pharmacological induction of fetal haemoglobin in transfusion-dependent patients with thalassaemia will require highpotency induction of foetal globin. 1995.g. could result in complimentary effects and render even severe patients transfusion- The most effective compound thus far is arginine butyrate. sodium 2. children. Phenylbutyrate and butyrate cause general histone hyperacetylation. 1998. 2003). will enter clinical trials soon 137 . 2005). 2005). Short chain fatty acid derivatives Short chain fatty acid derivatives induce activity from the foetal globin gene promoter. 1997. and are counter-productive in thalassaemia. New generation agents which promote erythroid survival. review Perrine. Several preliminary trials with intravenous butyrate and oral phenylbutyrate compounds have shown increases in foetal and total haemoglobin levels in patients with thalassaemia intermedia. Perrine. 2001. 2005).2-dimethybutyrate) (Boosalis. 2000). Some new derivatives displace a repressor complex and cause acetylation specifically of the foetal globin gene promoter (Mankidy et al. 2005). requiring limited exposure (Pulse therapy). Butyrates have induced fetal globin production in approximately twothirds of patients with diverse molecular mutations and raised total haemoglobin levels an average of 2-3 g/dl above baseline when given intermittently to avoid antiproliferative effects (review Perrine. these will certainly apply in the highly diverse thalassaemia syndromes. resulting in two-to-six-fold higher foetal globin mRNA in some patients. weaning of transfusions to allow renewal of patients’ own erythropoiesis. EPOs may thus be particularly helpful in patients with relatively low levels of endogenous erythropoietin for their degree of anaemia (Bourantas. EPO promotes survival of red blood cells and may counteract the rapid cell death (apoptosis) caused by precipitation of excess ·-globin chains in ‚-thalassaemia (review Silva. which inhibits cell proliferation. used in combination or properly scheduled. while a few previously transfusion-dependent thalassaemia major patients have been maintained transfusion-independent on home therapy for 5-7 years. Their acceptable toxicity profiles add to their potential as long-term therapeutic agents. and can be given daily. Select hydroxamic acid derivatives have had high activity in transgenic mice (Cao. 1996. As differences in drug metabolism contribute significantly to responsiveness to any drug. Perrine. Singer. similar to EPO.(e. although this has the disadvantage of requiring intravenous infusion due to its rapid metabolism. 2000. offer significantly more potential benefit than the first generation prototypes. Reich. adequately high EPO levels to promote eyrthroid cell survival and iron availability for erythropoiesis. 2005). Nisli. there is expectation that some of the agents. especially those who have at least one ‚0thalassaemia mutation and EPO levels >140 mU/ml (Collins.

much higher than additive effects. in experimental studies (Constantoulakis. 138 . An approach to rational combinations can now be based on a patient’s baseline HbF. a demethylating agent and butyrate had synergistic activity. Such combinations offer excellent potential for patients with diverse syndromes. Clinical trials should be planned to find optimal drug combinations for different patient subsets. For example. total haemoglobin and EPO levels (review Perrine.independent. 1989). 2005).

The smallest version of the LCR-‚-globin gene LV vector has included only LCR elements HS2 and HS3 in its design. The idea of using gene therapy to treat the haemoglobinopathies (thalassaemia and sickle cell disease) is. if reproduced in a gene therapy context (Levings and Bungert. 1999). 2000. 2004. the stable transfer of a normal functioning copy of a ‚globin therapy gene unit into the patient’s own HSC would result in the generation of normal rather than diseased RBC for life. von Kalle C et al. 139 . 2006). Therefore.Gene Therapy: Current Status and Future Prospects vector. at long last. which is then retained for life. The stable introduction of the LCR-‚-globin therapy gene unit into the patient’s HSC is via a retrovirus delivery vector. However. Stamatoyannopoulos. However. a major breakthrough occurred in 2000. In addition. 2000). (Note: no donor bone marrow is needed). 2004). the LCR-‚-globin therapy gene units that could be incorporated into this vector system were ineffective at producing a consistent and sufficiently high level of ‚-globin protein to be of therapeutic value (Antoniou and Grosveld. May et al. who in the meantime has undergone chemotherapy (as in a donorderived bone marrow transplant) to partially or completely destroy their diseased bone marrow (Persons and Tisdale. Sadelain et al. The corrected cells are then returned to the patient. the gene therapy protocol employs an ‘ex vivo’ procedure. It was found that linking the LCR to a ‚-globin gene unit enables the gene to be efficiently and reproducibly switched on. 2004. a number of groups in the US and Europe have built their own versions of the LCR-‚-globin gene LV vector (Persons and Tisdale. HS4). it proved very difficult to accommodate LCR-‚-globin gene units within MoLV retroviral vectors and manufacture them. 2003). Red blood cells (RBC) are continuously replenished by bone marrow haematopoietic stem cells (HSC). HSC are isolated from the patient’s bone marrow and infected or transduced with the LCR-‚-globin retroviral Since then. a group led by Prof Frank Grosveld discovered the master regulator of the ‚globin gene family. Rivella et al. 2005). known as the ‘locus control region’ (LCR). gene therapy for the haemoglobinopathies looks a serious possibility in the not too distant future. and that application of this vector in an ex vivo bone marrow transplant procedure could completely cure or rescue the ‚-thalassaemia condition in mouse models of this disease (May et al. In 1987. particularly since 2000. Overall. provided good proof of principle. in principle. straightforward. 2002. Early studies with LCR-‚-globin gene retroviral vectors based on the mouse MoLV virus and using an ex vivo procedure in animal models. when the laboratory of Prof Michel Sadelain reported work involving the testing of an LCR-‚-globin therapy gene unit within a class of retrovirus known as an HIV lentiviral (LV) vector (Figure 1. mean that. HS3. Prof Sadelain showed for the first time that the LV vector can readily accommodate a larger and more efficient version of the ‚-globin therapy gene linked to the three most powerful LCR elements (HS2. resulting in the permanent splicing or integration of the therapy gene into the HSC DNA. A number of major discoveries and technical advances in gene therapy over the last 20 years. and to produce a sufficiently high level of ‚-globin protein to be of therapeutic benefit.

Some researchers have which has significantly improved the ease of vector manufacture (Miccio et al. Structure and gene organisation of wild-type HIV virus. (ii) insertional mutagenesis: the integration of the LCR-‚-globin gene LV vector into the HSC DNA has the potential to disrupt host cell gene function causing.Figure 1: Illustration of how a lentiviral vector containing a b-globin therapy gene unit is constructed from the normal (wild-type) HIV virus. a leukaemia-type condition (von Kalle C et al. which also targets the HSC of the patient. researchers have shown good efficacy in rescuing disease in mouse models of ‚-thalassaemia or of sickle cell disease. 2006). Roselli et al. see May et al. Sadelain et al. von Kalle C et al. at present there is significant variability in the expression of the LCR-‚-globin therapy gene (including its complete switching off). Han et al. 2006). as has been observed in clinical trials using retroviral vectors for gene therapy of X-linked severe combined immune deficiency (SCID-X1. 2000. In addition. Remaining problems that need to be addressed in order to improve both the effectiveness and safety of the LCR-‚-globin 140 . 2007). which is dependent upon the site where the LV vector has integrated within the HSC DNA (e. transduction of human HSC derived from bone marrow of severe ‚-thalassaemia major patients with the LCR-‚-globin gene LV vector can correct the globin chain imbalance in resulting RBC (Persons and Tisdale. Replacement of the normal genes of the wild-type HIV virus with the Locus Control Region-‚globin therapy gene unit produces the lentiviral vector. in the extreme situation. 2004. see Nienhuis et al. 2006. gene LV vector include: (i) reproducibility of function of the vector.g. B. 2004). under laboratory conditions. some groups have shown that. 2004. A. 2006). Miccio et al. Note: combinations of locus control region elements HS2/HS3/HS4 or HS2/HS3 have been employed. 2006. In all these cases.

it has been suggested that the cHS4 element may act to shield host genes within the HSC from interference by the LCR-‚-globin therapy gene unit and therefore promote safety. We eagerly await the outcome of these studies. The protocol. von Kalle C et al. 2005). involves an ‘ex vivo’ approach. let alone in relation to what is currently achievable with a sibling-donor bone marrow transplant. mainly related to the use of a high-risk full chemotherapy-conditioning programme as part of a protocol whose success is still far from certain. as expected. which has led to some improvement in the reproducibility of functioning (Persons and Tisdale. These studies led to the commencement of the first Phase I/II gene therapy clinical trial for the haemoglobinopathies in 2006. two patients with ‚-thalassaemia had been treated. as well as the commencement of future trials with LV vector designs with higher efficacy and safety profiles. Sadelain et al. therefore included the chicken b-globin LCR element cHS4 in their LV vector design to try and ‘insulate’ the LCR-‚-globin gene unit. 2004. The trial is led by Prof Philippe Leboulch in Paris and aims to treat five ‚-thalassaemia and five sickle cell disease patients within the age range of 5-35 years. with patients receiving a full chemotherapyconditioning programme with Busulfex to destroy their diseased bone marrow (Bank et 141 . although this has yet to be formally demonstrated. The trial has not been without controversy. 2006). Up to the end of 2006.al. 2004. It is too early in the trial to know if any benefit has been derived. In addition.

Taken together. as transfusion and chelation therapy require repeated invasive procedures and hospital visits. Because of the disease-oriented emphasis of medical education. which is vital to successfully coping with thalassaemia. the difficulties of lifelong transfusion and chelation therapy will not be faced. A key role for treating physicians and other health care professionals is to help patients and families to face up to the difficult demands of treatment. implies a sense of guilt that may interfere with the primary parent-infant relationship.Psychological Support in Thalassaemia The success of management of thalassaemia is based. many health professionals find it difficult to come to terms with the psychological demands of treating chronic inherited diseases. regardless of its aetiology. including general attitude and well-being. has important psychological implications. Moreover. the disease can have also a negative impact on the parent-child relationship. emotional and social development. Why is psychological support so important? It is now universally recognised that thalassaemia. extremely difficult to maintain. Chronicity is a powerful source of emotional problems that intensify at each significant 142 . As its clinical manifestations develop in the first year of life. The psychology of inherited chronic disease Adherence to treatment is a basic goal. leading to an increased risk of disease complications and poorer survival. these factors can make honest. in-depth communication. Furthermore. the treatment is emotionally demanding. after many years of treatment. This can be made more difficult in thalassaemia because patients often express strong negative feelings. this regular interaction provides to the whole staff. Monthly contact with a local thalassaemia centre from the first years of life allows doctors and other members of the team to act as a reference point for the patient’s overall state of health. but a general acceptance by the patient of his/her own condition constitutes the key to normal development from childhood to adulthood. In addition. which can hamper communication. and in particular to the treating physician a good opportunity to promote the patient’s physical. to a great extent on the establishment of a therapeutic alliance between caring staff and the patient throughout the course of the disease. Every genetic disease. Without an understanding and acceptance of the disease and its implications. while maintaining a positive role. patients and family may be better informed about the illness than non-skilled health professionals— a factor that can undermine the health professionals’ perceived role. like other chronic diseases. The way in which the family and the patient come to terms with the disease and its treatment will have a critical effect on the patient’s survival and quality of life. taking on several characteristics of the traditional ‘family doctor’ as guardian of the patient’s overall wellness.

It can also be extremely rewarding for the healthcare professional. young patients begin to ask crucial questions about the duration of care and possibilities of a cure. Separate interviews with patient and with parents are recommended in the approach to adolescence. good treatment facilitates personal development and achievement of targets in life. From as early as three to five years of age. These should be dealt with sensitively and honestly. helping him/her to cope better with thalassaemia and to maintain a sense of 143 . Good communication with healthcare professionals can be extremely beneficial for the patient. Overall. Healthcare professionals should seek. but are mandatory at crucial milestones in the patient’s and parents’ experience: At the onset and during the first period. s/he will often discover in patients with thalassaemia skills that greatly surpass those of their peers when facing the great challenges of life such as birth/death. Their state of mind can shift rapidly from depression to anger and vice versa. love/loneliness. while in adulthood individual interviews with the patient are essential. as far as possible. limited or isolated. but the child has to be included as soon as possible.balance. opportunities/limits. but keeping in mind his/her role as a physician Communication of diagnosis As exemplification. Health workers must be prepared to accept this shift and to help patients deal with these feelings. while poor care makes such development difficult or unpredictable. both in medical and emotional terms. communication work is carried out with parents. Where a healthcare professional manages to maintain a constant dialogue with his/her patients. Caring for a ‘normal’ development Communication: healthcare professionals with patients Settings and methodology for discussion are important all along the course of the disease. to: ñ Listen – to be interested in the patient’s emotional and real experiences ñ Accept – to respect the patient’s point of view and be sensitive to the timing of personal communication ñ Share – to be consistently close to the patient’s positive and negative feelings ñ Understand – at an emotional and not simply an intellectual level ñ Maintain boundaries – to give help and relief. it is useful to focus on communication of diagnosis. finding a way to their own ‘normalisation’ that implies different individual styles in adult life. developmental stage of the patient’s life. Patients can feel that they are different. because it is the natural starting point of the whole course of disease and may mark permanently (positively or negatively) the therapeutic relationship.

fears of being contaminated are ever-present and may be intense for real reasons (high risk of transmission) or due to the patient’s emotional state. The weight of negative emotions may be so great that parents may appear confused even after complete information has been given more than once. such as gratitude for receiving life. worries and concerns. the discussion must be renewed. However. giving life and well-being but also (even if safe from infection) causing iron overload. which necessitates additional treatment that is also lifelong. and preferably with the same doctor to preserve continuity. with the same attention given to the setting. allowing ample time to listen to their concerns and to respond to their questions. Regularly transfused patients can experience positive feelings. limiting personal development. The same attention to setting must be provided at any significant step. Psychological impact of anaemia and transfusion Psychological aspects of chelation therapy Serious anaemia will cause the patient to feel weak and vulnerable. it merely provides a monthly “patch” for the anaemia. and negative ones such as fear and anger at being ‘ruined’. 144 . the need for periodic transfusions testifies that vital energy comes from other people. transfusion therapy does not cure. Moreover. This gives the patient the experience of instability and doubt about his/her physical capabilities. This fact helps to sustain ambivalence towards therapy. ñ Information must be sincere. the following points should be considered: ñ The room chosen and time allocated aim to provide an atmosphere that will sustain hope and optimism.transfusion interval may allow these symptoms to recur. In trying to establish an ideal setting. ñ The diagnosis should be discussed with both parents together. implying a dependence at the physical level that can invade the mental level. In any case. and not make the patient feel depressed or misled. the decrease in haemoglobin during the Treating staff should be very familiar with the emotional aspects of chelation. This combination of advantages and disadvantages of transfusion finds a parallel in patients’ psychological reactions to their treatment. in order to better support patient/parents in coping with distressing information. In addition. Maintaining an adequate haemoglobin level through optimal transfusion therapy (see Chapter 2: Blood Tranfusion Therapy in ‚-thalassaemia Major) eliminates these symptoms and reduces the patient’s anxiety about death. because of the risk of transfusiontransmitted diseases. ñ In the months following diagnosis. complete and repeated as often as needed. as compliance with therapy determines prognosis (see Table 1).

Subcutaneous chelation Parenteral treatment implies a small act of aggression. ñ Effectiveness of the drug cannot be checked quickly and directly by the patient. and even more on a daily basis. it is a reminder of one’s illness. Physicians may: ñ ‘Bargain’ with the patient. so trying to reduce the body image damage. ñ Optimal chelation starts during the first years of life. So compliance is a function of trust. it reflects the quality of the treating staff-patient relationship and a belief in long-term benefits. Skin punctures from the needles cause body image damage. underprescribing desferrioxamine. ñ Like transfusion. Parents may: ñ Not yet have overcome the shock of diagnosis. Administering the infusion can be painful since they feel responsible for their child’s discomfort. more for psychological reasons than on the rationale of iron balance. The patient may feel ‘as full of holes as a colander’. because: ñ Iron chelation does not cure but rather treats the main complication of the basic therapy (transfusion). Patients may: ñ Adopt attitudes of out-and-out refusal. In general. ñ Use chelation as a control tool when the child reaches adolescence.Psychological aspects Subcutaneous chelation Oral chelation + - Aggression ‘Patch’ + + Body image damage + - Daily reminder + + ++ + Feeling different Lack of check + + Constant commitment + + Table 1 Time and movement restrictions related to the use of the pump generate feelings of being different and restricted. either self-directed or inflicted by the patient’s loved ones. 145 . ñ Repeatedly select the same sites for needle insertion. feeling ‘tortured’ instead of cared for. that is to say. chelation is a psychologically demanding therapy. ñ Exploit any opportunity or excuse to skip a day’s infusion. as ‘the patch of another patch’.

Many patients with thalassaemia can begin to take control of their medication regimen from six years of age. Table 2 outlines the impact of the most common complications (at moderate/severe stage) on patient emotional balance. Patients taking oral chelators must still face the daily feeling of being different and will still lack the means to immediately and quickly assess the impact of treatment and in this context it will remain difficult for some patients even on oral chelation to maintain adequate compliance. asymptomatic complications do not require medication and do not interfere heavily with quality of life. the long-term effects of such behaviour are harmful for the patient’s physical health and emotional well-being. ñ Tacitly encourage non-compliers to treatment in order to avoid the development of negative psychological states. oral chelation only helps with the issues of daily ‘holes’ to the skin and consequent damage to body image. While the underlying motivation for all the above reactions or attitudes is generally a desire to provide relief from the patient’s discomfort and to make him/her feel better.ñ Promote the shift from parent to patient management as early as possible. ñ Pay due attention to the psychological aspects of the disease. In general. Psychological impact of complications During adolescence or young adulthood various complications may occur. S/he has to integrate the hopes. instead of simply insisting or prescribing. The early initiation of self-management limits overprotection and stimulates autonomy in the young patient. 146 . Oral chelation Oral administration simplifies significantly many practical aspects of chelation management with Deferrioxamine. the inadequately supported patient may feel ‘hopelessly ruined’. as underestimating these undermines the effectiveness of the treating staff-patient relationship with an increased risk of treatment failure. ñ Encourage patients to feel a sense of reward for achieving mutually agreed therapeutic goals. a shift to oral chelation may seem ‘the solution to every problem’. The psychological implications of such complications lie in their degree rather than their onset. reprimanding or threatening the patient. when a serious complication such as heart disease or diabetes appears. enthusiasm and wishes typical of youth with a damaged physical state and medical features typical of old age. In fact. In such a situation. Recommendations: ñ Define and resolve the practical aspects of optimal chelation (see Chapter 3: Iron Overload). however. However. ñ Remember that long-term high compliance fosters good capability and self-reliance and is a key positive factor in maintaining emotional well-being. ñ Be involved in supporting. For some patients (and some healthcare professionals). the patient undergoes a period of psychological readjustment. ñ Avoid judging. It also gives relief to parents and ultimately improves the quality of life of the whole family. giving up on health and continued therapy.

Treating staff should accompany the patient along his/her life path. however. and generally in improving quality of life. Challenges for the adult patient Summary of psychological goals If the disease is fully compensated. In terms of the psychological care of the patient. healthcare professionals should aim to: ñ Provide information that promotes understanding of the illness ñ Help patient and parents to talk and to express feelings about the illness 147 . while respecting his/her fragilities. On the other hand. special care should be taken in preventing intrusions into the patient’s privacy. Sometimes an emotional crisis occurs and psychological support may be required. it is still possible to deal with suffering by sharing and working together to find ways of accepting new limits inherent to a given situation. Treating staff must maintain a positive perspective and support a patient’s sense of hope. Even in this ideal state.Complication Treatment burden Influence on daily life Feeling of difference Dependence Feeling of damage Death anxiety Hypogonadism +++ ++ +++ + ++ - Hypothyroidism + - + - ++ - Hypoparathyroidism ++ ++ + + ++ - Osteoporosis ++ ++ ++ + ++ - +++ +++ +++ +++ ++ + +++ +++ +++ ++ +++ +++ -/+++ ++ ++ + +++ + Diabetes Heart disease Hepatitis Table 2 Beginning a new job or an important loving relationship can increase feelings of inadequacy and fragility. In contrast to the past. Even in very serious cases. recent advances in iron chelation therapy have led to a dramatic progress in survival. at a psychological level young adults with thalassaemia can run into more difficulties than peers in coping with the tasks of adult life. particularly those implying independence and responsibility. sensitivity. in saving patients from acute life-threatening heart failure. physical conditions allow the patient with thalassaemia to make his/her choices of adult life without any restrictions or limitations. The most common mistakes on the part of healthcare professionals is that they are being overprotective or disinterested. and supporting resources.

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

openness Home Splenectomised patients should be warned about the risk of having pets at home. However. teaching parents to decide with the child. hospital and official bodies). due to the possibility of bites and this increased risk of septicaemia (Capnocytophaga The patient should have the right to decide if. Where the haemoglobin level is allowed to fall too low. school. from the age of 6. ñ Help parents to be aware of diseaserelated issues early on in the patient’s life (e. trying to be compliant with local. those of parents. an individual with thalassaemia major can enjoy a near-normal lifestyle and experience regular physical and emotional development from childhood to adulthood. including parenthood. Confidentiality vs. if and how to communicate with the school about thalassaemia) ñ Help the patient to build up a realistic and balanced position between being open and being secretive about the disease Treating staff should promote such a progression by trying to reduce as far as possible the degree to which the disease interferes with the patient’s personal and social life. relatives. treating staff should: ñ Manage treatment and monitoring schedules so as to minimise any unnecessary impact on normal daily activity ñ Be aware of the particular psychological aspects of health care for this chronic condition (see Chapter 15: Psychological Support in Thalassaemia) Although normal transfusion and follow up schedules many require a number of absences. the obstacles to a normal lifestyle should be taken into account with a realistic but positive approach. individual variability is wide. School If the patient’s haemoglobin levels are maintained close to the values recommended in this book. Lifestyle If the disease is fully compensated by ideal treatment. if not against patient’s rights.General Health Care and Lifestyle in Thalassaemia This right should be considered before other points of view (i.e.g. based on informing and encouraging the patient. no relevant interference with academic performance should be seen. and reviewing limitations on time and treatment schedule. International laws and rules on privacy. when and with whom to talk about the disease. 149 . Staff should: ñ Assure confidentiality of patient identity and data in all circumstances. From a practical point of view. Where the disease cannot be fully compensated with proper transfusional schemes. the patient may have difficulty in school. these should not be to the extent where the patients’ school performance is negatively affected.

Carriers of a viral infection must also address additional uncertainties as regards safe sexual behaviour. treating staff. with resulting benefits and special employment facilities. care should be taken that these entitlements do not interfere with a positive attitude to normality. means it is now possible for them to have children spontaneously or by induction of pregnancy. patient association and patients themselves). particularly in industrilized high income (HDI) countries. The decision as to whether to induce pregnancy medically can be difficult. thalassaemia may be recognised as causing a certain degree of disability. Depending on the country. In adolescence. Patient attitudes to parenthood may range from unnecessary feelings of psychophysical inadequacy to an underestimation of the risks and difficulties involved. Exhaustive counselling is necessary to explore these issues in a sensitive but thorough manner. and skin colour) may affect selfconfidence and participation in social life. While these may help the family and the patient from a practical viewpoint. the absence or delay of sexual development is regarded by patients as particularly stigmatising. Sexual and reproductive life Differences in appearance (facial features. well-treated patients generally do not face difficulties in performing work as a direct result of their disease. the risks of pregnancy and the long-term prognosis of the patient must be seriously taken into consideration. Symptomatic heart disease and osteoporosis may cause difficulties for patients in performing certain physical tasks and specific advice in limiting at-risk activities should be provided. The general improvement in the health of patients with thalassaemia. Treating staff should help the patient and his/her partner to achieve a balanced position. self-esteem and the ability to work (see Chapter 15: Psychological Support in Thalassaemia). Work In general. Patients with active viral hepatitis or other viral infections should take general measures to minimize or prevent the risk of transmission to the family. Additional care in preventive measures may be required in some areas due to specific infection risk (see the example of Pythiosis in Thailand in Chapter on Infections). and the patient’s and partner’s expectations. it is important for patients to have a positive attitude towards their ability to work. height. Timely optimal treatment of hypogonadism limits these effects. However. 150 .canimorsus-associated). In chronic diseases a shift to overprotection is a frequent problem for all people involved (parents. This may be partially useful when treatment possibilities are scarce and the physical conditions of the patient are poor.

The degree of osteoporosis of maxillary bone should guide the treatment schedule. Particular attention should be paid to the prevalence of malaria (see below). in order to avoid receiving transfusions elsewhere. treating staff should. Routine Health Care Vaccinations There is no reason for patients with thalassaemia to skip or delay standard recommended vaccinations. particularly if visiting areas where blood supplies carry a high risk of infection. sepsis or animal bites. Orthodontic schedule must take account of the peculiar characteristics of bone disease in thalassaemia in order. Dental care Patients who are untransfused.in the country to be visited should be obtained. an adolescent planning the first camp holidays with peers). and appropriate vaccination and prophylaxis obtained in advance. s/he can be flown home immediately. Splenectomy The splenectomised patient should always travel with antibiotics. unless they have special 151 . which increases if the patient cannot receive expert local treatment. with provision of any necessary medical assistance. detailed advice about infection risks Nutrition General Patients with thalassaemia do not have specific dietary requirements. and relational aspects (i. a patient should always receive blood transfusions at the same place. Travelling Travel carries a degree of risk. secrecy or open communication about the disease). undertransfused or who begin transfusion at a later stage in the disease may have some malformations of the facial bones due to marrow expansion. If the patient plans a trip. Additional vaccinations for patients with thalassaemia are discussed in the Chapter on Infections. Travel plans should be coordinated with the patient’s transfusion schedule. As for any traveller. to assure prompt medication in case of fever. as this disease may be more serious in splenectomised subjects. to prevent tooth instability or loss. Blood Ideally. Orthodontic care may be successful in improving masticatory function and/or correcting unaesthetic dental appearances. However. give information about the closest hospital with services and experience in the management of thalassaemia. requests to comply with adjustments in the chelation schedule to minimise interruptions must also take into account some practical aspects (e. Chelation Travelling and holidays should be organised so as not to interfere with regular chelation and treating staff should not indulge the ‘poor guy’ attitude. This can affect growth of the teeth and cause malocclusion.e. it is vital that adequate travel insurance is obtained so that if serious complications develop. Treating staff should discourage travel where the risk of malaria is significant.g. If a patient is travelling to a remote country. as far as possible.

the haemoglobin level and other potential independent factors. However. In general. Vitamin D may also be required to stabilise calcium balance. careful monitoring is required in order to prevent toxicity. leading to vitamin C deficiency in some patients. Supplements (1mg/day) may be given if this occurs. During adolescence and adult life. A diet containing adequate calcium (e. soft drinks. The patient should therefore make a habit of reading labels carefully. 1979). a restrictive diet is easy to be prescribed but difficult to be maintained over the long term. 152 . The amount depends on the degree of erythropoiesis. However. During growth. However. unless at late stages. nephrolithiasis is seen in some adults with thalassaemia major. Patients on high transfusion regimens rarely develop this condition. breakfast cereals and multivitamin preparations contain added iron. However. and usually have no need for supplements. Vitamin C Iron overload causes vitamin C to be oxidised at an increased rate. milk. In case of liver disease. cheese. Iron Increased iron absorption from the intestinal tract is characteristic of thalassaemia. a normal energy intake with normal fat and sugar content is recommended.g. Drinking a glass of black tea with meals reduces iron absorption from food. In thalassaemia. only foods very rich in iron (such as liver and some ‘health drinks’ or health vitamin cocktails) should be avoided. snacks) may be useful in preventing or delaying the onset of impaired glucose tolerance or diabetes.prescriptions. Patients with thalassaemia should not take additional calcium or vitamin D unless prescribed by their medical practitioner. dairy products and kale) is always recommended. there is no evidence that iron-poor diets are useful in thalassaemia major. if supplements are used. Many baby foods. a diet low in highly refined carbohydrates (sugar. particularly if hypoparathyroidism is present. Folic acid Patients with thalassaemia who remain untransfused or are on low transfusion regimens have increased folate consumption and may develop a relative folate deficiency. particularly in thalassaemia intermedia (de Alarcon. Calcium Many factors in thalassaemia promote calcium depletion. Vitamin C may increase the ‘chelatable iron’ available in the body. the activated form should be preferred. along with other vitamin supplements. instead a low oxalate diet should be considered. and calcium supplements should not be given unless there is a clear indication. the patient already has a heavy treatment schedule and it is counterproductive to add further restrictions without the likelihood of clear benefit. seeking expert advice if necessary. Patients with thalassaemia should never be given iron supplements. thus increasing the efficacy of chelation with desferrioxamine. There is no clear evidence that a diet is beneficial in preventing or managing liver disease.

dose and duration. vitamin C ingestion may increase iron absorption from the gut. drug abuse is common among adolescents and young adults. depending on the chelator. A key danger is that— as with many adolescents—drug abuse may be seen as a compensatory way to be popular among peers or to ‘fit in’. supplements should only be considered for patients on desferrioxamine (see Chapter on Iron Overload). Treating staff should aim to help the patient maintain such a position. Smoking Cigarette smoking may directly affect bone remodelling which is associated with osteoporosis and is related to adverse effects on the general health. as well as certain ‘health foods’. upsetting the delicate balance of factors affecting physical and mental health. Alcohol A transparent discussion of these issues may help the patient to gain insight into the associated risks. For young people with thalassaemia. Therefore. may contain vitamin C and should be avoided. Indeed. Zinc supplementation requires close monitoring. However. deferasirox or combination treatment. Treating staff should recommend a regular intake of vegetable oils as part of a balanced diet. bearing in mind the challenges an adolescent patient is likely to face. including citrus fruits and vegetables. difference and anxiety can push patients to seek ‘normality’ through an abuse habit. physical activity must always be encouraged in patients with a chronic Substance abuse Physical activity 153 . is recommended. For an individual with a chronic disease. Patients with thalassaemia should be discouraged from consuming alcohol. the effectiveness and safety of vitamin E supplementation in thalassaemia major has not been formally assessed and it is not possible to give recommendations about its use at this time. drug abuse can be a serious threat to an already challenging condition. as it can facilitate Recreational activities the oxidative damage of iron and aggravates the effect of HBV and HCV on liver tissue. feelings of dependence. labile iron and hence iron toxicity. alcoholic drinks may have unexpected interactions with medication. there is currently no evidence supporting the use of vitamin C supplements in patients on deferiprone. the probability of developing cirrhosis and In general. Some drugs. A diet rich in fresh fruits. Where all three factors are present. In addition. Zinc Zinc deficiency may occur during chelation. Excessive alcohol consumption also results in decreased bone formation and is a risk factor for osteoporosis. Vitamin E Vitamin E requirement is high in thalassaemia. Drug abuse In many countries.hepatocarcinoma is significantly raised. such as aspirin and throat lozenges.

unless there is a precise secondary medical condition. the more rigorous treating staff must be in recommending avoidance of those sports and physical activities with significant risk of abdominal trauma. Conditions requiring special attention include: ñ Splenomegaly: the more enlarged the spleen.disease. Driving No special attention is needed. In some countries. Patients with thalassaemia should have a quality of life and range of life experiences as much like those of others as possible. ñ Osteoporosis or back pain in adults may limit physical activity. the presence of diabetes mellitus requires special checks and limitations. 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. Osteoporosis carries an increased fracture risk and contact sports should therefore be avoided if osteoporosis is present. ñ Heart disease: moderate physical activity is beneficial. 154 . if is matched to the clinical condition and its treatment.

oncology patients. The staff must include a charge nurse/nurse practitioner who supervises the nursing staff. and overnight transfusion help minimise inconvenience to the patient’s social life. transfusion. night. otherwise. This requires an approach more like that of adult internal medicine. Attempting to manage many patients with thalassaemia in big multi-purpose units (such as paediatrics. Staff most commonly involved are: ñ Nurse specialist(s) ñ Cardiologist ñ Endocrinologist ñ Diabetes specialist ñ Reproduction endocrinologist ñ Andrologist or gynaecologist ñ Psychiatrist/psychologist ñ Social worker ñ Hepatologist ñ Transplant specialist Each patient’s transition from paediatric to adult care must be accurate and smooth: ñ transmission of complete clinical records ñ shared discussion of past and current clinical problems ñ Ideally. a clinician with continued care as patients progress from paediatric to adult stages Programming of treatment The unit should be dedicated but not isolated. The staff requires a career structure with promotion possibilities and regular contact with other branches of medicine. The importance of a dedicated thalassaemia unit The thalassaemia unit should operate on an outpatient basis: facilities for evening. accumulate more experience and are closer to prevention of genetic disease. and as a result they may be unwilling to work in the unit. In a dedicated thalassaemia unit. more patients reach adulthood (Figure 1). organisation of a thalassaemia unit is useful both in terms of functionality and cost. a treating physician specially trained in thalassaemia oversees all aspects of treatment. oncohaematology and transfusion centres) without dedicated facilities is often counterproductive. referring to specialists when indicated. Paediatric vs. Paediatric centres. adult care The choice between a paediatric or adult medicine setting may be crucial.Organisation and Programming of a Thalassaemia Centre as possible. in order to provide continuity of care. doctors and nurses can be afraid of losing skills and missing promotion opportunities. It is essential that staff turnover of the unit is kept as low Transfusion therapy is ideally conducted according to the procedure outlined in Chapter 2: Blood Tranfusion Therapy in ‚Thalassaemia Major. etc). as most resources are used for the main activity of the unit (acute patient. with a growing number of risk factors and complications. This often includes: 155 . As treatment opportunities improve. The day of transfusion should be utilised as effectively as possible – ideally providing all treatment and other medical services the patient needs during one visit. Unless the number of patients is minimal. mainly in thalassaemia major.

which runs all specific procedures used in the diagnosis.cy).thalassaemia. Interaction of the thalassaemia unit with other hospital facilities The unit must be closely connected with: ñ A blood bank ñ A general laboratory ñ If available. ñ Clinical discussion of the case record ñ Individual conversation to set goals. renew critical information.org. Some of them have been computerised and can be distributed to the interested centres upon request (TIF’s website: www. ñ The clinical resources of the departments of paediatrics. 156 .Figure 1: Changing pattern of age distribution in patients with thalassaemia ñ Physical examination ñ Clinical and laboratory tests. and listen to the patient (see Chapter 15: Psychological Support in Thalassaemia) ñ Ideally the patient should leave the hospital after every transfusional event with updated documentation. follow-up and monitoring treatment of thalassaemia. a special laboratory unit. Several programmes for thalassaemia patient data have been set up. scheduled by the treating physician on the basis of guidelines and individual need. internal medicine and haematology/oncology critical for thalassaemia (see specialists).

in order to minimise the risks involved in transfusion (e. but also to secure the ideal blood for the patient. The doctor from the Thalassaemia Unit must keep blood bank staff sensitised to the needs of chronically transfused patients The organisation of a Thalassaemia Unit The supervising physician should schedule regular meetings of the staff for the purpose of: The organisation of the Thalassaemia Unit in this fashion optimises treatment. alloimmunisation and infections).Figure 2: An example of organisational interaction of the thalassaemia unit with other hospital facilities [Kattamis 1989] ñ Updating staff on new aspects of thalassaemia and its treatment ñ Discussing and resolving organisational aspects of the unit’s activities ñ Renewing staff motivation to work in the field of thalassaemia. while 157 .g. so as to prevent professional burnout The well-functioning blood bank is of primary importance for the management of thalassaemia. Its functions are not only to find the huge amount of blood needed for the treatment of thalassaemia.

Long-term management implies collaboration of the patient and the family with the well-organised thalassaemia unit team. such as: 158 .ñ Capacity for expert diagnosis ñ Expert clinical management ñ The use of outcome measures and quality control. mainly due to distance. quality of life measures and other measures of patient interest ñ Sufficient activity – which means a minimum number of patients to ensure adequate staff experience for quality care ñ High level expertise and experience of staff ñ Epidemiological surveillance. the centre will provide support to local physicians treating patients with limited access to expert centres. and that the medical staff have the patients’ best interests as top priority. which could be used as a standard in organising or running an expert or Reference Centre. including patient registers ñ Collaboration with national and international centres ñ Close links with patient associations ensuring the greatest possible level of comfort and convenience for patients with thalassaemia and their families. with the aim of improving both survival and quality of life. As such. The European Union has established criteria for such centres of expertise (Rare Disease Task Force Criteria). it should be in a position to provide multidisciplinary knowledge. to ensure continuous. In addition. A Thalassaemia Unit is expected to be a centre of expertise for the management of a chronic disorder. It is essential that patients with thalassaemia feel that the unit is their own place. In such a system. as described above. including survival and complication rates. the patient is fully supported for self-management and is considered a partner in the decisions affecting his/her treatment. a fact that may assist in patient adherence to long-term treatment protocols. appropriate treatment and a long and productive life for the patient with thalassaemia.

with all its attendant side effects. to maintain the pretransfusion haemoglobin level above 9-10. who often struggle to resolve competing complaints that together pose diagnostic dilemmas.Osteoporosis and microfractures B . chest pain.Infection with HPV-B19 virus A . back pain.Chest Pain Thalassaemia is an extremely demanding disease.Increased transfusion requirements VII .Cholelythiasis B . allows normal physical activities. The following chapter addresses some of those dilemmas.Pump failure D .Back Pain A .Hypoparathyroidism Diagnostic Dilemmas in Thalassaemia III . This transfusion regimen promotes normal growth.Alloantibody C .Rib fracture (extramedullary expansion) C .Dysrhythmia B .5 g/dl. Increased transfusion requirements IV .Hepatic capsule distension F . While shorter intervals between transfusions may reduce overall A . fever.Hypocalcaemia B .Delayed transfusion reaction A .Worsening jaundice A . dyspnoea.Delayed Transfusion reaction G .Pancreatitis C .End plate degeneration D .Unexplained Abdominal Pain A .Pulmonary embolism I.Hypersplenism B .Yersinia VI .Pulmonary hypertension 159 .Klebsiella D . abdominal pain.Infection due to Bacterial B . worsening jaundice and leg cramps.Liver failure II .Autoantibody D .Pericarditis and myocarditis B . thalassaemia poses considerable challenges to treating physicians.Portal vein thrombosis D .Prolapse in disc C .Dyspnoea The recommended treatment for thalassaemia major involves regular blood transfusions.Yersinia C .Prolapse V .Leg cramps A . usually administered every two to five weeks.Outline of Diagnostic Dilemmas in Thalassaemia I .Gilberts B .Renal stones E . A .Increased haemolysis C .Drug Reaction D . At the same time. including increased transfusion requirements.Fever VIII . Patients must commit themselves to a lifetime of transfusion and chelation therapy. adequately suppresses bone marrow activity and minimises transfusional iron accumulation.

leading to the premature destruction of red cells. constitute factors that influence the clinical picture. Splenectomy should be considered when annual blood requirements exceed 1. although they may give little benefit. its optimal binding temperature. immunosuppressive drugs and intravenous immunoglobulin are used for the clinical management of this situation. Enlargement of the spleen is accompanied by symptoms such as left upper quadrant pain or early satiety. (Reasons for increased blood requirements include new alloantibodies. infection and changes in the haematocrit of transfused units. and haemoglobin concentration may fall well below the usual pre-transfusion level. However. and whether complement is fixed.anti-Kell alloantibodies are most common. haemolysis) and. new alloantibodies. such as the patient’s work or school schedule. provided that they are on the same transfusion scheme and have no other reasons for increased consumption. Thus it is important to carefully monitor patients for the development of new antibodies and to eliminate donors with corresponding antigens. the choice of interval must take into account other factors.e. infection and changes in the haematocrit of transfused units.. to anaemia and its attendant signs and symptoms. by ultrasonography. I-B. Destruction both of the donor red cells and of the recipient’s red cells occurs. blood requirements. Alloantibody The development of one or more specific red cell antibodies (alloimmunisation) is a common complication of chronic transfusion therapy. Autoimmune haemolytic anaemia is a very serious complication of transfusion therapy usually combined with underlying alloimmunisation. I-A. Steroids. 5-10% of patients present with alloantibodies against rare erythrocyte antigens or with warm or cold antibodies of unidentified specificity. anti-C and 160 . in all cases of AIHA the autoantibody leads to a shortened red blood cell survival (i. Hypersplensism Throughout the care of the patient with thalassaemia. trapping and destruction of red blood cells in an enlarged spleen.5 times those of splenectomised patients. as needed. or when massive splenomegaly causes concern about possible splenic rupture. Autoantibody Autoimmune haemolytic anaemia (AIHA) refers to a collection of disorders characterised by the presence of autoantibodies that bind to the patient's own erythrocytes. Autoimmune haemolytic anaemia may occur more frequently in patients beginning transfusion therapy later in life.) I-C. However. the size of the spleen should be carefully monitored on physical examination and. when the rate of haemolysis exceeds the ability of the bone marrow to replace the destroyed red cells. Anti-E. Physicians should be on the look out for hypersplenism with stasis. Specific characteristics of the autoantibodies (especially the type of antibody). Reasons for increased consumption include hypersplenism. Even red cells from seemingly compatible units may have markedly shortened survival.

A wide differential exists. milk or water. Iron chelation should not be restarted until the patient has been asymptomatic for over a week. although it is commensal in healthy individuals. II. Infection with HPV-B19 II-B. nephritis or splenic abscess. II-C. but also to other clinical problems such as myocarditis.I-D. or other bacterial pathogens and delayed transfusion reactions. the causes may include other infections with Klebsiella and Yersinia. even in the nonsplenectomised patient. spanning all types of infections from bacterial to viral to fungal. sickle-cell anaemia. If this occurs. such as arthralgia and skin rashes. Complications may include abdominal abscess (right iliac fossa). B 19 infection may cause an acute. Fever is the most common presenting feature. INFECTION DUE TO BACTERIA In patients with thalassaemia. The Yersinia organism is most commonly transmitted by the ingestion of contaminated food.y investigated and treated swiftly and aggressively. meat. be thorough. Klebsiella species should be addressed as a potential pathogen. Klebsiella Of the multitude of bacteria described in association with iron overload. along with a multitude of syndromes and organic diseases leading to fever. Yersinia Parvovirus B 19 . The cessation of erythropoiesis lasts for 5-7 days and haematologically complicates chronic haemolytic anaemia. are sometimes seen. life-threatening red cell aplasia. In vitro Klebsiella species have been shown to have increased virulence in 161 . It can also be transmitted through blood. Generally antibiotics are continued for at least two weeks after proven infection. It is recommended that iron chelation be stopped while the cause of unidentified fever is investigated. a longer period of oral antibiotics may be necessary to eradicate the infection. commonly referred to as “transient aplastic crisis”. Yersinia enterocolitica makes no siderophores of its own and therefore lives most efficiently in an iron-rich environment such as that found in unchelated patients with thalassaemia or uses the DFO in chelating patients which is a siderophore to obtain iron and thrive. Iron chelation can be recommenced after the infection has been eliminated. Extra gastrointestinal manifestations. Iron overload and infection are common causes of death. Relapse after restarting desferrioxamine has been noted in some cases. which may indicate infection with the virus. Attention must thus be given not only to aplastic crises. Fever Fever is an elevation of body temperature that exceeds the normal daily variation. Unlike most other bacteria. autoimmune haemolytic anaemia and thalassaemia. often associated with abdominal pain and diarrhoea or vomiting. Hence clinical experience mandates that fever and infection. II-A.In patients with an already shortened red cell lifespan (15-20 days) and a low haemoglobin level due to haematological disorders such as spherocytosis.

microfarctures. In addition. delayed pneumatisation of the sinuses and marked overgrowth of the maxillae. malaise and jaundice. disc prolapse and end plate degeneration II-D. trauma with sprains and strains. Marrow expansion causes dramatic widening of the diploic spaces and produces a characteristic ‘hair-on-end’ radiographic appearance of the skull. disc prolapse and end plate degeneration. 162 . lumbar disk disease and organic causes such as osteoporosis. particularly the arms. only limited information is available regarding the effects or functions of mononuclear phagocytes in relation to micro-organisms and the influence of iron overload and iron chelation on their activity and pathogenicity. Of equal concern is the thinning of the cortices due to marrow expansion. Infection with Klebsiella can be fatal in patients with thalassaemia. Delayed transfusion reactions occur 5-10 days after transfusion and are characterised by anaemia. spondylolisthesis). The ribs and bones of the extremities become box-like and eventually convex. there is prominent frontal bossing.the presence of excess iron. III. Microfractures. Premature fusion of the epiphyses can result in characteristic shortening of the limbs. As a result. due to expansion of the bone marrow. The differential spans congenital anomalies of the lumbar spine (spondylolysis. III-A. Delayed transfusion reaction Patients with thalassaemia may exhibit dramatic skeletal abnormalities. A sample should be sent to the blood bank to look for a new antibody and to recrossmatch the last administered units. Osteoporosis There is a high incidence of osteoporosis of the spine and hip in both sexes in thalassaemia. which often results in pathologic fractures. Although there is evidence of altered host immunity in thalassaemia syndromes. Back Pain Back symptoms are the most common cause of disability in patients and account for a huge portion of primary care physician visits. frequently leading to marked changes in the facial structure and body habitus and delayed skeletal maturation. producing malocclusion and the characteristic faces. attenuate the cortex and produce osteoporosis. Even young patients exhibit a spinal bone mineral density far below that of agematched controls. Patients with thalassaemia experience myriad bone complications. These reactions may be due to an alloantibody that was not detectable at the time of transfusion or to the development of a new antibody. III-C & III-D. III-B. which widen the marrow spaces. with severity increasing with age. Skeletal changes are due largely to the expansion and invasion of erythroid bone marrow. The differential diagnosis includes osteoporosis. The skull and facial bones are often strikingly abnormal. the upper incisors are ‘jumbled’ and the malar eminences are especially prominent.

portal vein thrombosis. In the absence of clearcut symptoms. true episodes of cholecystitis or cholangitis are rare. 163 . vascular. Cholelithiasis Venous thrombo-embolism (VTE) is increasingly recognised in paediatrics as a complication of improved treatment strategies for previously lethal childhood diseases. have been reported in children with thalassaemia. endothelial injury and hypercoagulability). Compression fractures and paravertebral expansion of extramedullary masses often become particularly prominent in the second decade of life. However. Although a number of situations can precipitate acute pancreatitis in humans. mechanical obstruction. gall bladder removal is thus rarely indicated. Portal vein thrombosis IV-A. hepatic capsule distention and kidney stones. Unexplained abdominal pain Correctly interpreting abdominal pain constitutes a particular challenge in thalassaemia. The list includes pain originating in the abdomen (peritoneal. 10 percent of alcoholics and a few patients with hypercalcemia. the pathogenesis of this disorder is not fully understood. A prominent feature of children with chronic haemolytic anaemia is the development of premature bilirubin gallstone disease and biliary tract inflammation. pancreatitis. pain referred from extra abdominal sites (thorax. In patients with thalassaemia. Of the multiple complaints patients with thalassaemia present with. CVCs are resorted to when frequent transfusions are required. IV-C. twothirds of which have multiple calcified bilirubin stones by the age of 15. often with spinal cord compression and neurologic deficits. leading to increased turnover of red blood cells and hence further precipitation of gallstones. which present a foreign intravascular surface. spine. A number of conditions are known to induce this disorder with varying degrees of certainty.Compression fractures of the spine. genitalia). This is particularly true of children with ‚-thalassaemia. With regard to patients with thalassaemia. pancreatitis is caused by myriad factors. porphyria) and neurogenic causes. only a small fraction of patients with these predisposing factors develop the diseases—3 to 7 percent with gallstone. damage vessel walls and disrupt blood flow. Fortunately. The basic pathological process underlying VTE is Virchow's triad (stasis. unexplained abdominal pain spans a wide differential diagnosis including chloelythiasis. First and foremost is increased transfusion requirement. IV-B. Central venous catheters (CVCs). abdominal wall). are responsible for approximately 60 percent of VTEs in children. metabolic causes (uremia. IV. Pancreatitis Acute pancreatitis is an inflammatory condition of the pancreas characterised clinically by abdominal pain and elevated levels of pancreatic enzymes in the blood.

The differential diagnosis includes conditions affecting organs throughout the thorax and abdomen. In the liver. cardiac arrhythmia. aortic dissection. In addition. The urine is frequently dark. extramedullary causes and pulmonary embolism. In thalassaemics. or be asymptomatic for long periods of time until symptoms reflecting chronic vascular obstruction (portal hypertension) occur (e. tension pneumothorax or pulmonary embolism can lead to serious complications. In the absence of effective iron chelation therapy. Hepatomegaly is prominent early on in thalassaemia. Thrombosis of the hepatic venous system usually occurs within the portal venous system. including death. potentially. Heart complications are the leading causes of death and one of the main causes of morbidity. with prognostic implications that vary from benign to life-threatening. Even in the 164 . end-stage liver disease. hepatomegaly becomes fixed and non-reducible by blood transfusion. Hepatic capsule distension Cardiac symptoms and premature death from cardiac causes are still major problems in thalassaemia. sudden death or a distressing slow death from progressive congestive cardiac failure. many patients develop evidence of iron-induced myocardial damage with cardiac failure. Renal stones The kidneys are frequently enlarged in thalassaemia. resulting in a chronic state of iron overload. Later in the first decade of life. infections. iron first infiltrates Kupffer cells and then engorges hepatocytes. Less well understood is the tendency for the renal tubules to be dilated. the accelerated rate of iron turnover enhances dietary iron absorption from the gut. Older children may develop portal vein thrombosis (PVT) secondary to liver transplantation. large amounts of urate. splenomegaly or gastrointestinal bleeding secondary to oesophageal varices). the differential diagnosis spans pericarditis and myocarditis.. particularly in adolescents. Liver enlargement tends to be somewhat more prominent in children with thalassaemia than in those with congenital haemolytic anaemia. ultimately provoking fibrosis and. particularly after spelenctomy. Failure to recognise potentially serious conditions such as acute ischemic heart disease. V-A.g. Pericarditis and myocarditis IV-E.absence of transfusion. V. due to increased red cell destruction as well as extramedullary erythropoiesis in the liver. sickle cell disease or the presence of antiphospholipid antibodies. Chest pain Chest discomfort is one of the most common challenges faced by physicians treating thalassaemia patients. due to development of cirrhosis secondary to increased iron deposition. PVT may manifest acutely with symptoms of an acute abdomen. in a manner analogous to that seen in idiopathic haemochromatosis. the debris released from intravascular destruction of red blood cells may accumulate and plug the portal vein. uric acid and oxalate are also seen. due to the presence of extramedullary haematopoiesis. IV-D. due to increased concentrations of bile pigments. splenectomy.

pump failure. pulmonary hypertension and delayed transfusion reaction lead the list of probable causes of dyspnoea in thalassaemia. Classically. mostly occurring without any other risk factors. defined as an abnormally uncomfortable awareness of breathing. Rib fracture (extramedullary expansion) Extramedullary haematopoiesis (EMH) is a compensatory mechanism where bone marrow activity increases in an attempt to overcome the chronic anaemia of thalassaemia intermedia (TI). pulmonary vascular occlusive diseases. VI. Dyspnoea A cardinal symptom of diseases affecting the cardiorespiratory system is dyspnoea. In TI patients. pulmonary embolism (12%) and others (20%). especially following splenectomy. leading to the formation of erythropoietic tissue masses that primarily affect the spleen. fibrosis and cardiac functional impairment. The regular assessment of cardiac status can identify the early stages of heart disease. and intrathoracic masses. dysrhythmia. 165 . Iron distribution in the heart is relatively uneven. Extramedullary haematopoiesis can be managed by radiotherapy. with associated myofibrillar fragmentation and diminished mitochondrial volume per myocyte. However. comprising deep vein thrombosis (DVT) (40%). The characteristic lesion in the heart is caused by iron deposition in the myofibres. Such an extensive differential necessitates meticulous work up to reach a diagnosis. pulmonary thromboembolism and recurrent arterial occlusion have been described in patients with TI. as well as transfusion therapy and hydroxyurea. it has been suggested that there is a poor correlation between myocardial iron content. and heart diseases. stroke (9%). It is important to be aware of these complications since thromboembolism plays an important role in cardiac failure. as it is thought that RBC remnants expose negatively charged phosphatidyl-serine through the ‘flip-flop’ phenomenon and subsequently initiate thrombosis. There are several possible reasons for this. diseases of the chest wall or respiratory muscles. including the procoagulant activity of circulating damaged red blood cells. Pulmonary embolism Patients with TI have an increased risk of thrombosis compared with a normal age and sex-matched population and with thalassaemia major patients. splenectomised patients have been shown to have a higher risk of thrombosis than nonsplenectomised patients. V-C. enabling prompt intervention. The differential covers general topics of obstructive disease of airways. since haematopoietic tissue is highly radiosensitive. Deep vein thrombosis. V-B. They may cause neurological problems such as spinal cord compression and paraplegia. Data indicate that thrombotic events primarily occur in the venous system. portal vein thrombosis (19%). These masses can be detected by magnetic resonance imaging (MRI).pulmonary embolism occurs as part of the full picture of thrombosis. It has also been suggested that viral myocarditis is a contributing factor to acute cardiac deterioration. diffuse parenchymal lung diseases. Moreover. liver and lymph nodes.

gradual and less severe than in the case of acute reactions. whereas patients with ventricular arrhythmias should be warned as to the potential severity of their condition. Classically. VI-A.response occurring after re-exposure to a foreign red cell antigen previously encountered by transfusion. A falling hematocrit. syncopes. Sudden death is likely to be arrhythmic in origin and is more likely to be due to ventricular arrhythmia than atrial. Delayed transfusion reaction Delayed haemolytic transfusion reactions (DHTRs) are due to an anamnestic antibody 166 . This fact may not be widely appreciated by physicians and cardiologists unaccustomed to dealing with VI-B. bearing in mind that iron toxicity is the primary cause of this complication. Intensive chelation treatment has been demonstrated to reduce arrhythmias. These delayed reactions are seen generally within 2 to 10 days after transfusion. the arrhythmias are supraventricular. Pump failure The characteristic lesion in the heart is caused by iron deposition in the myofibres. cardiac arrhythmias are more common. Once the ventricles have enlarged. The development of arrhythmia may be associated with a deteriorating ventricular function and can be improved by addressing the latter problem. Iron distribution in the heart is relatively uneven. is undetectable on pretransfusion testing but increases rapidly in titer following the transfusion. In the majority of instances. and spherocytosis on the blood smear may be noted. Arrhythmias require very careful assessment. reassurance of the patient is generally appropriate. The development of symptoms of heart failure implies advanced disease with a poor prognosis. Haemolysis is usually extravascular. with associated myofibrillar fragmentation and diminished mitochondrial volume per myocyte. now have become positive. they include palpitations. The antibody. An important distinguishing feature of cardiac dysfunction due to iron overload is the capacity of patients. The diagnosis is often made by the blood bank when ordering more blood for another transfusion. but ventricular tachycardia is also occasionally seen. transplantation or pregnancy. VI-C. slight fever. often of the Kidd or Rh system. but rapid haemolysis can occur. mild increase in serum unconjugated bilirubin. shortness of breath. These tend to be of atrial origin. to make a complete recovery with appropriate chelation therapy. the direct antiglobulin test and antibody screen which were previously negative. The decision to treat arrhythmias in patients with thalassaemia must be carefully considered. However. fibrosis and cardiac functional impairment. It has also been suggested that viral myocarditis is a contributing factor to acute cardiac deterioration. decreased exercise tolerance and peripheral oedema. although ventricular tachycardia may occur in seriously ill individuals. if detected early. Dysrhythmia Significant cardiac disease from iron overload typically occurs in the absence of symptoms. For most supraventricular arrhythmias. it has been suggested that there is a poor correlation between myocardial iron content. epigastric pain. when symptoms do occur.

VII. patients with thalassaemia. cholestatic conditions and drugs. and is thought to be the primary cause of congestive heart failure (CHF) in this patient population. possibly due to their relatively higher level of daily bilirubin production. except for icterus. Gilbert’s syndrome The most common inherited disorder of bilirubin glucuronidation is Gilbert's syndrome. or icterus. Gilbert's syndrome. Nevertheless. ampullary and cholangiocarcinoma. although large-scale data for TI patients are lacking. Malignant causes should not be missed. Jaundice. pulmonary haemosiderosis and local thrombosis. It must be emphasised that supporting the failing circulation in these patients for several weeks may be required in order to achieve recovery. Regular transfusion and iron chelation therapy is. physicians should suspect any of the following: unconjugated hyperbilirubinemia. It is rarely diagnosed prior to puberty when alterations in sex steroid concentrations affect bilirubin metabolism. The mechanism underlying PHT in TI is unclear. although evidence indicates a local pathophysiological response in the pulmonary vascular bed that is independent of thromboembolism due to DVT. As anaemia and iron overload are uncommon in well-transfused and chelated patients with thalassaemia major. Suggested mechanisms include endothelial dysfunction with increased inflammation and apoptosis. predominantly unconjugated hyperbilirubinemia. they are likely to be at the heart of the pathophysiology of PHT. a haemolytic disorder. Worsening jaundice Gilbert's syndrome is usually diagnosed in young adults who present with mild. including pancreatic. haemolytic. which has also been called "constitutional hepatic dysfunction" and "familial nonhaemolytic jaundice". the condition is known to run in families.1%). gallbladder. patients with TI often have an increased cardiac output and left ventricular wall dimensions proportional to the dilutional volume overload secondary to chronic anaemia. In patients with thalassaemia.deposition of bilirubin. The disorder is more commonly diagnosed in males. Sildenafil has also been successfully used to treat PHT. indicated in TI patients who are well-stratified according to the early detection of PHT indices. VII-A. therefore. worsening jaundice is another way of presenting to the clinic. However 167 . VI-D. leading to increased plasma bilirubin concentrations. is a yellowish discoloration of tissue resulting from the The physical examination is usually unrevealing. conjugated hyperbilirubinemia. Crigler-Najjar type II. Although many patients present as isolated cases. Pulmonary hypertension Pulmonary hypertension (PHT) is prevalent in patients with TI (59. less frequently. decreased nitric oxide and nitric oxide synthase production. hepatocellular conditions. Tissue deposition of bilirubin occurs only in the presence of serum hyperbilirubinemia and is a sign of liver disease or. Several echocardiographic studies have confirmed that cardiac ejection fraction is rarely affected in TI. Hence the following discussion will shed light on the differential of worsening jaundice in thalassaemics. Of the many diseases presenting with icterus.

Abnormal liver enzymes (e. Leg cramps Electrolyte disturbances such as hypocalcemia. Injury to the RBC membrane due to the production of excess ·. Increased haemolysis Patients with thalassaemia are more susceptible to haemolysis. The differential diagnosis includes hypocalcemia and hypoparathyroidism. producing methemoglobinemia that may be so profound as to induce coma. and some drug-induced haemolytic anaemias. muscle wasting and weakness. Liver failure Hepatitis due to viral (B and C) infections is less frequent in TI than in patients with thalassaemia major. endocrine deficiencies and neuromuscular and vascular issues may all result in leg cramps. alloimmune haemolytic anaemia. VIII. Thalassaemia patients with inherited Gilbert’s syndrome are at increased risk for haemolysis and. VII-D. is also part of extracorpuscular haemolysis.haemolysis even in normal subjects. Extracorpuscular causes of haemolysis. Drug reactions A variety of drugs have been implicated as causes of drug-induced oxidant haemolysis. VII-C. whether intracorpuscular (intrinsic) or extracorpuscular (a distinction made here because the causes of intrinsic RBC defects are all hereditary). Although any defect in the antioxidant defence mechanisms. are almost always acquired conditions that lead to the accelerated destruction of otherwise normal RBCs.. such as G6PD deficiency. Nitrites bind to haemoglobin. Normalisation of liver enzyme levels is often observed during appropriate chelation therapy. primarily due to hepatocyte damage resulting from iron overload. would present with clinical manifestations of icterus and elevated bilirubin. situations that exaggerate hyperbilirubinemia may bring the patient to medical attention and have corresponding physical findings. such as autoimmune haemolytic anaemia. One-third of patients with thalassaemia major suffer from leg cramps. since blood transfusions are much less common in TI. Amyl nitrite and butyl nitrite. Examples include antibodies directed against RBC membrane components. which includes stasis. increased alanine and aspartate aminotransferase) are frequently observed in TI patients. primarily via inhalation. trapping and destruction of RBC in an enlarged spleen. Hypersplenism. on the other hand.or ‚-globin genes in thalassaemia is an example of an intrinsic defect leading to haemolysis. as a result. The resulting methemoglobinemia and haemolysis may be more pronounced in patients who are G6PD deficient. usually within hours to days after the onset of exposure to the agent. Hypocalcaemia Several acquired causes of hypoparathyroidism have been identified in 168 . substantially increases susceptibility to haemolysis. VII-B. delayed (haemolytic) transfusion reaction. the drugs referred to below can produce oxidative VIII-A. The possible presence of the latter disorder should be suspected if methylene blue infusion does not quickly turn the chocolate colour of blood back to normal. have been used to increase sexual arousal.g.

suggesting either an individual sensitivity to iron toxicity or early damage of the parathyroid gland before chelation. Hypoparathyroidism In the past two decades. 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. No clear relationship between HPT and serum ferritin levels was established. The onset of HPT was preceded or followed in most patients by other endocrine and/or cardiac complications.children. HPT is thought to be mainly the consequence of iron deposition in the parathyroid glands. 169 . including thyroid surgery and iron deposition in the parathyroid gland as a result of frequent transfusions (as in ‚thalassaemia major). several cases of hypoparathyroidism (HPT) in ‚-thalassemia major have been observed. VIII-B.

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Management of HIV in Pregnancy (39) .uk 187 . http://www.April 2004.rcog. http://www.WEBSITES National Evidence-Based Clinical Guidelines Fertility: assessment and treatment for people with fertility problems_.uk RCOG Clinical Green Top Guidelines.rcog.org.org. February 2004.

GROWTH CHARTS 188 .

189 .

190 .

191 .

161 164 127. 73. 94. 89 88 58. 152 . 137 87 84. 144-146. 85. 126 87. 162 75. 76. 162 154.Azacytidine Alchohol consumption Aplastic crisis Antioxidants Agranulocytosis Arthropathy Anticoagulants ACE inhibitors Amiodarone Abdominal pain 101. 25. 88. 56. 40. 81. 166 19. 128.85. 105 14 81 70 84. 112. 83. 56. 69. 153 108. 59 52. 88. 129. 192 99. 161 39 52. 104. 33. 160 60. 59 49. 163 B Blood donation Bone marrow expansion Back pain Bisphosphonates Butyrates Bumetanide Beta blocking agents 20. 127 129. 114.Index Description Page Number A Adefovir Adult Haemoglobin (Hb A) Alendronate Assisted reproduction techniques ART Arrhythmias Alloimmunisation Allergic transfusion reactions Acute haemolytic reactions Autoimmune haemolytic anaemia Arrested puberty Amenorrhoea Acarbose 5 . 30 30 30. 117. 79. 65 66 69 136 86. 81. 54. 151. 32 16. 103. 160 22. 89 C Chimerism Cirrhosis Chelaton Cardiac disease Calcium 133 93. 74. 159. 102. 29. 21. 164 128.

81. 79 80. 50. 41. 153 12 65. 124. 67 40. 136 F Ferritin Fetal haemoglobin (Hb F) Fractures Fertility Folic acid 35. 105 80. 108. 165 85 38. 162 82. 57 14. 85 84 129. 127. 52. 136 80. 162. 65.Circulatory overload (transfusion) Calcitriol Cytotoxic agents Confidentiality Cytomegolovirus (CMV) Chagas disease Chemoprophylaxis 31 69 136 149 111. 92. 151-153 58. 51. 162 70 74. 54. 132 115 119 D Diabetes mellitus Deferiprone DNA Delayed puberty Desferioxamine DFO DEXA scan Disc prolapse Diet Deferasirox Delayed transfusion reactions Decitabine Dental care Drug abuse Driving Dengue fever Digoxin Diuretics 43. 152 193 . 112 74. 147 50. 60. 166 136 151 153 154 114 87 87 E Entecavir Extramedullary haemopoiesis Echocardiography Ejection fraction (LVEF) Electrocardiogram (ECG) Erythropoietin (EPO) 101. 68. 63 30. 74. 123. 73.

133 31. 29 22 G GVHD Growth Growth velocity Glucose tolerance Gene therapy Gallstones (cholelithiasis) Gilbert's syndrome GM CSF 31. 121. 169 38. 125. 81. 109-111 116. 129. 169 69. 67. 74. 131 18 18 19 19 19 65. 101 33. 97. 98-105 31. 81 124. 83. 128 95. 51. 126 93. 126. 92 139 117. 97 36. 92-99. 150 74. 74. 133 45. 58. 160 67. 124.Filtration (Leukoreduction) Frozen red cells 22. 107. 89. 70. 74. 136 69. 127. 152 69 151 194 . 99 31. 77. 163 167 52 H HLA Hepatitis C (HCV) Hepatocellular carcinoma Hepatitis B (HBV) HIV Hypersplenism Hypothyrodism Heart failure Haemoglobin E (Hb E) Haemoglobin Lepore Haemoglobin S (Hb S) Haemoglobin H (Hb H) Hb Constant Spring Hb Bart's Hydrops Fetalis Hypogonadic hypogonadism Hormone replacement therapy (HRT) Hydroxyurea Hypoparathyroidism Hypocalcaemia Heart function 31. 83 I Iron load (haemosiderosis) Interferon (pegylated) Iron absorption Insulin Insurance (travel) 33-40. 42. 166 18. 79. 56. 64 64 68.

84. 92. 51. 165 118 J Jaundice 167 K Klebsiella 113. 80. 105 149 35. 151 38. 42. 85 115. 128 M Matched unrelated donors (MUD) MRI MRI cardiac Malaria Myocarditis 133 37. 50. 95 23 29 124. 42. 86. 52. 124.Immune function Influenza virus vaccine Indwelling intravenous lines Intensive chelation Immunoprophilaxis 107. 152. 56. 127 39. 117 101. 168 37. 92. 94. 57. 59. 116 118 48 48. 92 38. 164 N Neutropenia Neocytes Nonhaemolytic febrile transfusion reactions Nephrolithiasis (kidney or renal stones) Non transferring bound iron (NTBI) 52. 161 L Liver fibrosis Liver failure Liver biopsy Lamivudine Lifestyle Liver iron concentration (LIC) Labile plasma iron (LPI) Leg cramps Leg ulcers 36. 164 39 195 . 132 93. 57 168 125.

29. 160 137 149 153 124. 79. 154. 128. 77. 97. 127.O Osteoporosis Ovulation Oxidative damage 69. 73 71 66 153 108. 127. 132-135 31 196 . 71 39. 70-78.74. 107. 124. 150 70. 116. 72 29. 166 127 81 S Survival SQUID Spermatogenesis Splenectomy Short chain fatty acids School Smoking Splenomegaly Splenic embolisation 43. 166 164 163 163 165 90. 162 70. 97. 154 117 T Thrombocytopenia Transfusion requirement Transplantation (Stem cells) Transfusion related acute lung injury (TRALI) 52. 126. 153 P Puberty Pregnancy Pre pregnancy counselling Preimplantation genetic diagnosis (PGD) Pubertal staging Physical activity Parvovirus B19 Palpitations Pericarditis Pancreatitis Portal vein thrombosis Pulmonary embolism Pulmonary hypertension Pseudoxanthoma elasticum Pamidronate 65-67 47. 116 129. 128 23. 28. 135 37 70. 161 84. 116.

V Vaccinations Vitamin D Vitamin C Vitamin E Vision 98. 99. 161 Z Zolandronic acid Zinc deficiency 81 53. 101. 53 W Washed red cells Work 22 150 Y Yersinia enterocolitica 31. 118. 46. 64. 54. 65. 81. 151 69. 153 197 . 108. 44. 152 153 45. 152 35. 111-113. 41.

and has developed an extensive network of collaboration with scientific and medical professionals from more than 60 countries around the world. regional and international workshops. magazines and books for health professionals and patients/parents. EB118.R1 (29 May 2006) “THALASSAEMIA AND OTHER HAEMOGLOBINOPATHIES” 198 . as well as with other national and international health bodies. a Federation “umbrella”. translation and free distribution of leaflets. representing hundreds of thousands of patients worldwide. and the preparation. publication. It includes the organisation of local. national. TIF. pharmaceutical companies and other disease-orientated patients’ organisations. conferences and seminars. in every affected country of the world. to more than 60 countries.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. TIF has been in official relations with the World Health Organisation (WHO) since 1996. is comprised of 98 national thalassaemia associations from 60 countries. TIF’s educational programme is one of its most important and successful activities. MISSION: “EQUAL ACCESS TO QUALITY HEALTH SERVICES FOR ALL WITH THALASSAEMIA” MOTTO: “UNITY IS OUR STRENGTH” WORLD HEALTH ORGANIZATION (WHO) RESOLUTION: no.

Italian. the carrier of and the patient with a Haemoglobin disorder.1. French 13. Italian.In English.In English 10. “Compliance to Iron Chelation therapy with Desferrioxamine” 2000 – Reprint 2005 . “Blood Safety Kit” (1999) In English 2. French 12. “Guidelines to the Clinical Management of Thalassaemia” Second Edition .thalassaemia” – 2007 .In English 11. “About . “About sickle cell disease” – 2007 . 4.2007 .thalassaemia” – 2007 . Educational Folder Information for the community. French 14. “A guide to the establishment and promotion of nongovernment patients/parents’ organization” 2007 . Italian. “Guidelines to the Clinical Management of Thalassaemia” 2000 Translated into 6 languages 3.In English. 7.Translated into 4 languages 8. 5.In English. “About . “About Thalassaemia” 2003 . 6.In English “Patients’ Rights” 2007 .In English 199 . “Thalassaemia Major and Me” – Children’s Book – 2007 .In English 9.‚ .· .Translated into 11 languages “Prevention of Thalassaemias and Other Haemoglobinopathies” Volume I (2003) Translated into 2 languages “Prevention of Thalassaemias and Other Haemoglobiopathies” Volume II (2005) .