SYMPOSIUM: HAEMATOLOGY

Diagnosis and management

of thalassaemia

erythropoiesis are accompanied by changes in the type of haemoglobin produced. Senescent red cells are constantly broken
down and replaced by new red cells derived from haemopoietic
stem cells (HSC).
Haemoglobin synthesis is controlled by two multigene clusters on chromosome 16 (encoding the a-like globins, a and zeta
(z)) and chromosome 11 (encoding the b-like globins, gamma
(g), epsilon (), delta (d) and b).
In humans the genes are set out along the chromosomes in the
order that they are expressed during development:

Jennifer Welch

Abstract
Thalassaemia is the commonest inherited anaemia world wide. There is
wide spectrum of clinical severity spanning from insignificant to transfusion dependence. It is caused by abnormalities in the structure, manufacture or function of the globins that form the tetramers of normal adult
haemoglobin A. The primary changes in erythropoiesis lead to the secondary changes of anaemia, splenomegaly, bone marrow expansion,
extra medullary haemopoiesis, bone deformities and iron accumulation
which in turn lead to long term organ damage. The anaemia itself results
from a combination of ineffective erythropoiesis, peripheral haemolysis
and an overall reduction in haemoglobin synthesis. Optimum management with early detection, appropriate transfusion, iron chelation and
monitoring for complications can offer a good quality of life and a near
normal lifespan. The major threats to this outcome in developed countries
are serious infections and organ damage from iron overload.

Embryonic haemoglobins

Fetal haemoglobin
Adult haemoglobins

Portland
Gower I
Gower II
Fetal
HbA2
HbA

(z2 g2)
(z2 2)
(a2 2)
(a2 g2)
(a2 d2)
(a2 b2)

The b globin gene cluster contains five functional genes, , Gg,

g, d, b.
Whilst the a-like genes undergo a single switch (embryonic to
fetal/adult) the b-like genes undergo two switches (embryonic to
fetal to adult). Expression of the adult b globin gene depends on
lack of competition from the g gene.
More than 200 b thalassaemia mutations have been
described affecting any of the stages from transcription to RNA
processing to translation of b globin mRNA. They are mostly
point mutations, small deletions and deletions of regulatory
elements.
When expression of a globin is completely abolished by
a mutation it is referred to as b0 whereas reduced output
of structurally normal b globin is referred to as b thalassaemia. Additionally some structural variants such as bE
(Haemoglobin E) can lead to a thalassaemic effect because
they are produced at a reduced rate leading to clinically significant conditions.

Keywords Anaemia; iron chelation; iron overload; thalassaemia;

transfusion

Definition
Abnormalities in the structure, manufacture and function of the
alpha (a) and beta (b) globins that form the tetramers of haemoglobin A (a2 b2) lead to thalassaemia.
Defects in the production of the a globin chains lead to a
thalassaemia and defects in production of b globin chains cause b
thalassaemia.

How common is thalassemia?

World wide, thalassaemia is one of the commonest autosomal
recessive diseases, however the incidence of thalassaemia is very
geographically variable with the highest recorded rates in Cyprus
(14%) and Sardinia (12%). It is prevalent in populations from
the Mediterranean, Middle East, Central Asia, Indian Subcontinent, Far East and Africa. The WHO estimates that 1.5% of the
worlds population may be beta thalassaemia carriers and that at
least 60,000 severely affected people are born each year. Population migration means that thalassaemia is seen throughout the
world. The most common mutations are those that are prevalent
in tropical and sub tropical regions where high gene frequencies
are reached due to the associated protection against malaria.

Molecular and cellular pathology

The production of a and b globin chains is normally balanced.
In b thalassaemia there is an excess of a chains which clump in
red cell precursors forming inclusion bodies and causing mechanical damage resulting in premature destruction of the red
cell precursor and thus ineffective erythropoiesis. Anaemia increases production of erythropoietin leading to bone marrow
expansion.

Pathology, pathogenesis and applied physiology

Phenotypic diversity in beta thalassaemia

In health the globin genes are expressed sequentially at each

stage of embryonic and fetal development. Changes in the site of

As severity is directly related to globin chain imbalance

factors that reduce this imbalance will improve the phenotype.
Coinheritance of a thalassaemia reduces the amount of a
globin excess, whilst extra a globin genes will have an adverse
effect. A capacity to produce g globin which combines with
excess a globin to form fetal haemoglobin has an ameliorating
effect.

Jennifer Welch BMBS (Nottingham) MRCP MRCPCH FRCPath is a Consultant

Haematologist in the Department of Paediatric Haematology at
Sheffield Childrens NHS Foundation Trust, Sheffield, UK. Conflict of
interest: none declared.

PAEDIATRICS AND CHILD HEALTH 25:8

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SYMPOSIUM: HAEMATOLOGY

As b globin synthesis is controlled by the two b genes a mutation affecting one gene (b thalassaemia trait) is not usually
clinically significant, but if both genes are affected (by the same
or different mutations) leading to absent or reduced production
of the globin the result is often severe anaemia.
Deletions causing beta thalassaemia are rare. Some are associated with an unusually high Haemoglobin F and A2 in heterozygotes as gamma and delta gene expression is increased.

and neonate and excess b chains in later life which form tetramers. Both g4 (Haemoglobin Barts) and b4 (Haemoglobin H)
have high oxygen affinity and are unstable and lead to ineffective
erythropoiesis and haemolysis.
Both a0 and a can occur as the homozygous or heterozygous
state or there may be compound heterozygosity (a/a0). The
rarer non deletional forms are written aT and their severity
varies.

Dominantly inherited beta thalassaemia

Clinical effects of alpha thalassaemia

This term describes the inheritance of a single beta thalassaemia

allele in the presence of a normal alpha globin genotype resulting
in clinical disease. The described mutations result in synthesis of
highly unstable b chain variants. There is ineffective erythropoiesis and peripheral haemolysis. These mutations are rare and
do not follow malarious areas. Spontaneous mutations occur, so
this should be suspected in a clinically appropriate case where
both parents are unaffected.

Four a gene deletion is not compatible with life as the a genes are
expressed early in fetal life. This is referred to as Hb Barts
Hydrops fetalis. An affected embryo can only make the normal
embryonic haemoglobins Portland and Gower 1. By 16 weeks
gestation the fetus is oedematous (hydropic). The mother will
often have severe pre eclampsia and the fetus usually dies in
utero by 30 weeks of gestation.
Deletion of three of the four a genes results in the condition
Hb H disease which arises from a number of genetic abnormalities, the most common being compound heterozygosity for a
and a0 thalassaemia. These children usually have a Thalassaemia
Intermedia (TI) phenotype, with splenomegaly and moderate
anaemia (70e80 g/l) requiring occasional transfusions. Some
more severe transfusion dependent forms exist, this tends to be
the case when the a gene mutations are non deletional.
Rare non-deletional a thalassaemia is caused by a mutation on
the X chromosome (ATR-X syndrome). The clinical features are
mild anaemia, short stature, microcephaly, facial dysmorphism,
abnormal external genitalia and mental retardation presenting in

Alpha thalassaemia
There are four a genes, two on each copy of chromosome 16.
There are more than 100 mutations known to cause a thalassaemia, most are deletional and can be divided into:
 Those where two genes are deleted on the same chromosome (alpha zero, a0)
 Those where only one gene has been deleted from the
chromosome (alpha plus, a).
0
a deletions cause a greater reduction of globin synthesis than
a ones. Alpha thalassaemia leads to excess g chains in the fetus

Clinical and practical points in thalassaemia

Ethnic groups with a0
genotypes

Symptoms and signs of

anaemia in an infant

Consequences of iron overload

Calculation of transfusion volume in paediatric

patients

Common
Chinese
South East Asian
Cypriot
Greek
Turkish
Sardinian
Occurs infrequently
United Arab Emirates
Iranian
Yemeni
Kuwaiti
Jordanian
Kurdish Iraqi
Occurs Rarely
African
Indian
Pakistani
Bangladeshi

Poor feeding, failing to

wake for feeds
Irritability
Recurrent infections
Lethargy
Pallor
Failing to reach normal
milestones

Pituitary damage
Hypogonadism
Poor Growth
Endocrine damage
Diabetes
Hypothyroidism
Hypoparathyroidism
Osteoporosis
Liver Disease
Fibrosis
Cirrhosis
Cardiac Disease
Arrhythmias
Cardiac Failure

To calculate the volume of packed cells

needed in transfusion dependence use the
formula:
Rise in haemoglobin required (g/l)
x
Childs weight (kg)
x
0.4
e.g. in a 20 kg child with pre-transfusion Hb of
98 g/l and target of 140 g/l
42 x 20 x 0.4 336 mls packed cells
Whilst the volume to transfuse is in mls, units
of blood usually contain 250e300 mls.
Common sense should be used to avoid using
only small amounts from a second unit to
reduce donor exposure and wastage. Normally
transfuse at 5 ml/kg/h. Take all the normal
precautions to ensure safe transfusion.

Table 1

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SYMPOSIUM: HAEMATOLOGY

usually predictable from the genotype and most dont need

regular transfusions. Long term complications include
pulmonary hypertension, hypersplenism, gallstones and
chronic ankle ulceration.

a young boy. One and two gene deletion a thalassaemia is clinically insignificant but carriership in two parents is important
since HbH disease or Hydrops fetalis is possible in the next
generation. Genetic risk relates to whether parents with two gene
deletion a thalassaemia are a0 or a compound heterozygote or
homozygote for a where the risk of Hb Barts Hydrops fetalis is
absent. Ethnic groups with a0 genotypes are shown in Table 1
although sporadic cases can occur anywhere.

Thalassaemia minor (thalassaemia trait)

Thalassaemia trait is usually associated with the inheritance of a
single beta thalassaemia allele (b0 or b). The person is often
asymptomatic but may have a slightly reduced haemoglobin
concentration.

Clinical course
Transfusion dependent thalassaemia (thalassaemia major TM)
Transfusion dependent patients are usually homozygous or compound heterozygous for one of the 200 b thalassaemia mutations.
Occasionally people with non-deletional HbH disease are transfusion dependent. If not diagnosed early affected children present
with pallor, hepatosplenomegaly and failure to thrive in the first
year of life when in the case of the b thalassaemias the change from
fetal to adult (g to b chains) is complete. Without intervention
(regular blood transfusion) these children remain anaemic with
progressive hepatosplenomegaly, poor growth, experience feeding
problems, irritability, diarrhoea, recurrent fevers and infections
and are hypermetabolic. They will die in the 1st or 2nd decade of life.
If regular transfusions are established keeping the haemoglobin 95e105 g/l, growth and development will be normal until
age 10 or 11 years when the complications of iron overload will
manifest with growth retardation, failure of sexual maturation,
liver fibrosis and cirrhosis, endocrinopathies hypoptiuitarism,
cardiomyopathy with death in the 2nd or 3rd decade. The classical
clinical picture of untreated thalassaemia major is now only seen
in countries where resources for transfusion and chelation are
not available or where there has been persistent non compliance.

Diagnosis of thalassaemia
In the UK this usually made on the Newborn Screening blood
spot in the light of antenatal test results. Newborn screening is
not capable of detecting all new cases as it aims to detect the
most clinically important structural haemoglobin variants.
Newborns with <1.5% Haemoglobin A are reported as Haemoglobin F only and this will detect a considerable number
but not all babies with b thalassaemia. Haemoglobin H and
Haemoglobin Barts are not specifically sought on screening.
Infants of parents found antenatally to be at risk of Haemoglobin H should be offered clinical follow up. Initially the
differentiation between TM and TI may be difficult and only
careful observation, in tandem with mutation analysis will give
the answer.

History and physical examination

There may be a family history of thalassaemia and antenatal results
may be available. Consanguinity may be relevant. The child may
have symptoms of anaemia. For those not detected by screening
then clinical findings may include pallor, jaundice, lethargy and
irritability with hepatosplenomegaly and skeletal changes.

Thalassaemia intermedia (TI)

TI describes patients with thalassaemia who do not have an
absolute requirement for regular blood transfusions. It encompasses a wide spectrum of severity and numerous genotypes.
Those affected are also usually homozygotes or compound heterozygotes for b or b0 mutations, or have HbH Disease. TI
usually presents later (2e6 years). The haemoglobin is usually
between 70 and 100 g/l and the child may need intermittent or
occasional transfusion. They will develop pallor, jaundice, gallstones, liver and spleen enlargement, skeletal changes of marrow
expansion, leg ulcers, extra medullary masses, osteopenia and
osteoporosis, thrombotic events and iron overload even without
transfusion from increased intestinal absorption.
The aim for these patients is to maintain good health, normal
growth and development and a good quality of life, using
transfusion where needed. TI is further subdivided into mild and
moderate/severe subtypes.
 Moderate/severe Thalassaemia Intermedia. This includes
the majority of children with Haemoglobin E/b thalassaemia, around 10% of those with homozygous b thalassaemia and a very small number of those with Haemoglobin
H disease. Most benefit from intermittent transfusion.
 Mild Thalassaemia Intermedia. This group includes the
majority of children with haemoglobin H disease, some
with Haemoglobin E/b thalassaemia and a small number
with homozygous b thalassaemia. The clinical severity is

PAEDIATRICS AND CHILD HEALTH 25:8

Investigation of suspected thalassaemia

A GP confronted with the above clinical picture can arrange for
an FBC which will reveal a severe microcytic hypochromic
anaemia. If hypersplenism has developed there may be leucopenia and thrombocytopenia. The child should be referred to the
haemoglobinopathy clinic for further management where
parental and patient blood tests should include:
 FBC with red cell indices, reticulocytes and blood film
 HPLC or equivalent to report Hb A2%
 Molecular Genetics for b thalassaemia mutations and
Xmn1 e Gg polymorphism
 Molecular genetics for a thalassaemia mutations according
to the history, blood film, indices and ethnic group
 Group and antibody screen and extended red cell phenotype of the child
 Bilirubin, LDH, and HbH preparation in suspected a
thalassaemia
In clinically significant thalassaemia the abnormalities will be
more marked the later the child presents.

Beta thalassaemia
Typical late findings include reduced haemoglobin (30e70 g/l),
haematocrit, red blood cell count, mean cell volume (MCV) (50

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SYMPOSIUM: HAEMATOLOGY







e60 fL), Mean Cell Haemoglobin (MCH) (12e18 pg). Typically

the blood film will show microcytosis, hypochromia, anisopoikilocytosis, basophilic stippling, pappenheimer bodies, target
cells and nucleated red blood cells (NRBCs).

Beta thalassaemia trait

Typically the individual may have mild hypochromic microcytic
anaemia with a raised Hb A2%. The blood film may be normal or
may show anisopoikilocytosis and hypochromia, basophilic
stippling and target cells. One third to a half will have an elevated
HbF%. In people with thalassaemic indices but a normal A2%,
dbthalassaemia, Hb Lepore and Hb E should be excluded. If these
are excluded the most common reason for thalassaemic indices is
a thalassaemia.

Ongoing management for transfusion dependent thalassaemia

(see Table 1)
Transfusion may need to start any time in the first year of life,
usually when the Haemoglobin is <70 g/l but before the longer
term complications of anaemia are seen. The aim is to achieve a
pretransfusion haemoglobin of 100 g/l with 3e6 weekly transfusion. In children this usually means aiming for a posttransfusion haemoglobin of 140 g/l. Sometimes an acute event
(such as an infection) can precipitate the need for a single
transfusion and it should not be assumed that the child is
transfusion dependent from then on. Monthly monitoring with
FBC and clinical assessment will establish the phenotype.
Those with TI not requiring regular transfusion still need
lifelong follow up for the complications of chronic haemolysis
and iron overload.

Three gene deletion a thalassaemia

The typical late findings in three gene deletion alpha thalassaemia include a moderately reduced haemoglobin (70e100 g/l
but can be lower), raised reticulocytes, reduced MCV (50e65 fL),
MCH (15e20 pg) and Haemoglobin A2%, raised bilirubin and
LDH. The blood film is usually bizarrely abnormal with anisopoikilocytosis, poor haemoglobinisation, microcytes, macrocytes, fragmented cells, target cells, teardrop cells,
polychromasia and occasional NRBCs.HPLC shows Haemoglobin
H 2e40% (usually around 10%), Haemoglobin Barts is seen in
some.

Iron chelation
Iron overload results from iron intake that surpasses the bodys
ability to utilize or remove it. Intake can be from transfusion or
increased gut absorption. Both occur in thalassaemia. In
untransfused patients gut iron absorption increases. Iron is a
reactive metal which forms free radicals which damage lipid
membranes, organelles and DNA causing cell death and tissue
fibrosis. Normally iron is locked up safely by binding to molecules such as transferrin, but in iron overload the capacity for
binding is exceeded. The resulting free iron damages many organs and is eventually fatal usually through cardiac complications in the second decade of life unless treated by chelation.
Chelation is usually needed in TM after 10e15 transfusions or
when the serum ferritin is consistently around 1000 micrograms/
l. If started too early the chelation agents themselves can cause
toxicity to bone growth, vision and hearing.
Reliance on ferritin estimations alone may lead to inaccurate
assessment of body iron burden, particularly in TI. Liver biopsy
is the gold standard but this is not without risk. It may be
informative and necessary in some cases but the ideal is to be
able to assess iron loading with non invasive MRI techniques e.g.
(Ferriscan) which have been shown to correlate with liver biopsy results. Cardiac iron loading can be assessed with T2* MRI.
Complications of thalassaemia in developed countries are not
now those of under transfusion, but those of iron overload (Table
1). Chelation is vital. The iron chelators available are compared
in Table 2.

One or two gene deletion alpha thalassaemia

The diagnosis here is one of exclusion. If a person has hypochromic microcytic red cell indices with raised RBC, normal A2%
and iron deficiency has been excluded, a thalassaemia is likely.
The definitive diagnosis is made only if needed (for example for
genetic counselling in a couple at risk of a fetus with Hb Barts
Hydrops) by DNA analysis.

Outpatient management
It may not be clear initially whether the child has TM or TI so
clinical monitoring is needed. The aim is to prevent the primary
manifestations of the disease by early detection and intervention.
At the first clinic visit important information to impart and actions to take are:
 Confirmation of the diagnosis including the genetic
mutation
 Other tests e FBC, G S, Red Cell phenotype, G6PD
screen
 Explanation that it is an inherited lifelong anaemia
 Implications for future pregnancies
 Possible/likely transfusion dependence, starting at a variable age
 The need for Hepatitis B immunisation
 Need for close monitoring to judge if/when transfusion
should start
 Parental recognition of signs of anaemia
 Information about blood transfusion
 The concept of ineffective erythropoiesis and the need to
switch off red cell production

PAEDIATRICS AND CHILD HEALTH 25:8

The pivotal importance of iron chelation

Possible need for venous access device
Brief description of sibling stem cell transplant
Plan for normal growth, development and life
Give written information about all the above, contact details for clinical advice, support groups and the National
Haemoglobinopathy Registry (UK)

Caring for thalassaemia patients in the community

In the UK the care of children with thalassaemia is directed by a
haemoglobinopathy centre. The childs transfusions (if needed)
may be carried out at a more local hospital with communication
between the two sites. The family will be encouraged to contact

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PAEDIATRICS AND CHILD HEALTH 25:8

Comparison of iron chelators in transfusional iron overload

Chelator
Feature

Desferrioxamine

Deferiprone

Deferasirox

Route/Frequency

Sub. cut. over 8e12 hours or IV continuous

through Hickman line or port-a-cath
20e40 mg/kg/d (may be divided over 5 nights
per week) sub. cut. infusion
Yes
At time of infusion. Start a few weeks after
chelation has begun. Do NOT use Vitamin C in
cardiac failure
3 monthly LFTs, bone profile, U&E, Ferritin,
growth, annual ophthalmology and audiology
assessment
Local skin reactions

Oral tablets t.i.d.

Oral
Once a day drink
20 mg/kg/d to stabilise iron load
30 mg/kg/d to reduce iron overload
No

Dose for Children

Use Vitamin C for
maximum iron loss?

Monitoring

Frequent side effects

75 mg/kg/d
No

364
Dose related adverse
reactions

Practical issues

Advantages
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Disadvantages

Rickets e like irreversible bony changes

High frequency hearing loss
Night blindness/impaired colour vision
Reduced visual fields and visual activity
Growth retardation (if exceed 40 mg/kg/day)
RARE e renal impairment, pneumonitis
a
Calculate therapeutic index (see foot of table)
Need infusor device. Use 10% solution and
rotate skin sites. Need to prepare or have
fridge for ready-made supply. Omit dose if
fever or abdominal symptoms
Longest experience. Proven to work. Parents
sure child is receiving prescribed dose
Prolonged infusion
Effects on QOL
Yersinia infection
Inconvenient
Need for sub. cut. needle

Ataxia
Dystonia
RARE Ophthalmic and auditory complications

After initial introduction, monthly U&E, LFT,

urine dipstick for protein
Abdominal pain, nausea, vomiting and
diarrhoea (usually resolve even with continued
use)
Rashes 15%
Non progressive rise in creatinine
Deranged LFTs
Metabolic acidosis due to renal leakage of
electrolytes

Needs weekly FBC. Patient and parent need to

be alert to possible infections, bruising and
bleeding. Stop if cytopenias

Suspended in water or apple juice (at least

100ml)
Best before food.

Oral, improved QOL, useful to chelate cardiac

iron
Needs weekly blood test monitoring
t.i.d. dose e difficult compliance
Arthropathy
20e30% unable to tolerate long term (double
that of Deserrioxamine)

Oral, once a day, improved QOL.

Raised creatinine
Difficult for small children to take reliably

QOL Quality of life; LFT liver function tests; Sub cut sub cutaneous UEs urea and electrolytes; IV intravenous; NSAIDS non steroidal anti inflammatory drugs; t.i.d. 3 times per 24 hours FBC full blood count.
daily dose mg=kg
a
Therapeutic index for Deserrioxamine Mean
Ferritin micrograms=l . Must be less than 0.025 at all times.

Table 2

SYMPOSIUM: HAEMATOLOGY

Weekly FBC for cytopenias. Fortnightly LFTs. 3

monthly zinc levels (for deficiency), annual
ophthalmology and audiology
Arthropathy in 4e40%, Reduce or stop if not
helped by NSAIDs. Abnormal LFTs

PAEDIATRICS AND CHILD HEALTH 25:8

Out patient monitoring of thalassaemia patients

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Examination

Tests

Education

In addition
Annual review for transfusion dependent
Patients

Well being
School attendance
Pre-transfusion dip?
Compliance with
chelator and any
other medication
Symptoms of cardiac
disease
Bone pains or fracture
with minimal trauma
Symptoms of hypothyroidism
or diabetes

General physical examination

Growth plotted on centile chart
Puberty - delayed or arrested?
Jaundice?
Splenomegaly?
Hepatomegaly?
Skin, nails, hair healthy?
Check Desferrioxamine
infusion sites
Check Port-a-cath if present

Pre-transfusion
haemoglobin levels
Ferritin e look at
trend and aim for
<1000 microgram/l
Liver function
Bone Profile
Renal Function
FBC especially if
on Deferiprone
Urine dipstick for
protein/glucose

Importance of transfusion to switch off

ineffective erythropoiesis
Diet, especially calcium and Vitamin D
Exercise e helps bone strength
Schooling e very important to keep up
Avoid smoking and alcohol
Chelation e VITAL
Dangers of not chelating effectively
Port-a-cath care and management
Vigilance re infections
Staying up to date with immunisations
(including Hepatitis B)
Genetic risk, contraception
Travel advice
Possible HSCT if donor available
Working towards transition

Red cell consumption*

Hepatitis B antibodies
Hepatitis B, C, HIV I II, parvovirus serology
Vitamin D level
Serum copper, zinc and selenium
Audiology review
Ophthalmology review
Random blood glucose from age 10 with
glucose tolerance test if indicated.
Thyroid function tests from age 10
Parathyroid hormone from age 10
Bone Age from age 10
Dexa scan from age 10
LH/FSH, testosterone/oestradiol, random
cortisol from age 10
Cardiology assessment and
Cardiac Echo, ECG from age 10
Cardiac T2* MRI
Aim for Cardiac T2* >20ms
Liver MRI (FerriScan) (both when able to
achieve without anaesthetic)
Aim for Liver iron <7 mg/g dry weight liver
Review chelation regime
Discuss HSCT
*Annual red cell consumption ml/kg/year of
red cells transfused
If more than 275 ml/kg/year of SAG-M buffy
coat depleted, Hct 60%, splenectomy may be
indicated.

Table 3

SYMPOSIUM: HAEMATOLOGY

365

Consultation

SYMPOSIUM: HAEMATOLOGY






Discriminatory pairing
Choosing not to have children
Adoption
Prenatal diagnosis with selective abortion of affected
fetuses
 Artificial insemination (unrelated/unaffected donor)
 Ovum transfer (GIFT) from an unaffected woman
 Pre implantation genetic diagnosis (this can allow the selection of an unaffected embryo)
Acceptability of each of these options will vary according to
culture and religion.

the Haemoglobinopathy team in the first instance if they have

any questions or clinical concerns. However staff working in the
community must be aware of the condition and possible emergencies that can arise in this group of patients. Briefly these are
major sepsis (especially if the patient has had a splenectomy, is
taking Deferiprone, or has a Port-a Cath). Sepsis is now the
leading cause of death in UK thalassaemics. Presentation may be
with collapse, fever and abdominal pain. Iron chelation should
be temporarily suspended and broad spectrum antibiotics
commenced. In a paediatric cohort in the UK it would be unusual
to see acute cardiac complications, liver failure or acute endocrine presentations as regular out patient monitoring is designed
to prevent this but a child new to the UK may present with one of
these life threatening events.
Acute anaemia in TI may be precipitated by an infection such
as (but not limited to) Parvovirus B19.

Prevention e of disease complications

This relies on accurate early diagnosis, appropriate transfusion
management, effective consistent chelation, good education and
motivation of the patient and their carers. Early recognition
of problems allows intervention before irreversible damage is
done.

Care of thalassaemia patients in hospital

Children with transfusion dependency attend as day cases for
their transfusions and ideally this should be at a time that causes
least disruption to their school life.
In addition to 3e6 weekly transfusion attendances children
should be reviewed in clinic three or four times per year so
strategic decisions can be made and an annual review
completed (See Table 3). Out patient monitoring should aim to
detect possible complications of the treatment or the condition at
an early stage so that they can be effectively managed.

Stem cell transplant (HSCT)

HSCT is the only current treatment that offers a potential cure
for thalassaemia. It relies on high-dose chemotherapy to
eliminate thalassaemia-producing cells in the marrow and replaces them with healthy donor cells from bone marrow or
umbilical cord blood of an HLA matched sibling. This therapy
should be considered for all patients who have a suitable
donor. HSCT has a better outcome in younger patients, usually
performed between 2 and 6 years. The overall thalassemia-free
survival of low-risk, HLA-matched sibling stem cell transplantation patients is 85e90 percent, with a 95 percent overall
survival.

Providing information and support

The child has to manage their condition for life. Every opportunity must be taken to educate and support the child and their
family so that transfusion, chelation and management of other
complications are optimal.

Summary
Thalassaemia is the commonest cause of inherited anaemia
world wide. Many areas where it is prevalent do not
have the health resources available to provide optimal management. If children are diagnosed and managed appropriately
according to their phenotype a long and productive life is
achievable.
Under-transfusion leads to anaemia, splenomegaly, haemolysis, hypersplenism, extra medullary haemopoiesis, poor growth
and bony changes. Transfusion without adequate chelation leads
to the problems of iron overload. In order to achieve the best
results affected people are managed by a specialist healthcare
team and are encouraged to become an Expert Patient positively
contributing to their own management plan.
A

Prognosis and explanation to the patient

Thalassaemia is a lifelong condition. Its symptoms can be
managed by careful appropriate transfusion and excellent chelation. Regular monitoring allows early intervention for possible
problems. Only a minority of people with thalassaemia major
have a suitable matched related donor to allow stem cell transplant to achieve a cure and freedom from transfusions. Young
people should achieve regular schooling, higher education and
employment and a family of their own (if that is their wish). True
life expectancy with lifelong effective chelation is not yet known,
but in theory a normal lifespan could be within reach. Sadly this
goal is not currently realised with infection and iron overload
claiming the lives of many in their 3rd and 4th decade. It is hoped
that oral chelators, stem cell transplant and availability of practical and psychological support for those affected will improve
the outlook for children born with this condition today.

FURTHER READING
Bain BJ. The a,b,d and g thalassaemias and related conditions. In: Bain BJ,
ed. Haemoglobinopathy Diagnosis. Blackwell Science Ltd, 2001;
49e112.
Cao A, Galanello R. Beta-thalassemia. Gen Med February 2010; 12: 61e76.
Gibson BES, Todd A, Roberts I, et al. British Committee for Standards in
Haematology Transfusion Task Force. Transfusion guideline for neonates and older children. B J Haem 2004; 124: 433e53.
Guidelines for the clinical management of thalassaemia. 2nd revised edn.
Nicosia Thalassaemia International Federation, 2008.

Prevention e of the primary disease

Thalassaemia major is generally a recessive condition and carrier
status may first come to light during a couples first pregnancy.
Support groups such as the Thalassaemia Society and community groups in high prevalence areas encourage screening prior to
this. Options for couples are:

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2015 Elsevier Ltd. All rights reserved.

SYMPOSIUM: HAEMATOLOGY

Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassemia. Lancet 2012;

379: 373e83.
Ryan K, Bain BJ, Worthington D, et al. Significant haemoglobinopathies:
guidelines for screening and diagnosis. B J Haem 2010; 149: 35e49.
Thein SL. The genetics and multiple phenotypes of beta thalassaemia,
and Stephens A D. The diagnosis and significance of alpha thalassaemia. In: Okpala Iheanyi, ed. Practical Management of Haemoglobinopathies. Blackwell Publishing Ltd, 2004. 26e39 and 40e44.
Wood JC. Guidelines for quantifying iron overload. In Hematology 2014
American society of Hematology Education Program. Am Soc Hematol
2014; 210e6.
Yardumian A, Telfer P, Darbyshire P. Standards for the Clinical Care of
Children and Adults with Thalassaemia in the UK. 2nd edn. United
Kingdom Thalassaemia Society, 2008.

PAEDIATRICS AND CHILD HEALTH 25:8

Practice points
C

C
C

367

Thalassaemia is the commonest cause of inherited anaemia world

wide
Near normal lifespan and activity is possible for many affected
individuals
In TM the problems in the developed world are from iron overload
rather than from under-transfusion
Iron chelation is vital
Major sepsis is now the leading cause of death in UK populations
with thalassaemia

2015 Elsevier Ltd. All rights reserved.