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Thalassaemia

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Thalassaemia\: group of genetic disorders causing reduced haemoglobin in red blood cells; classi
chain and severity, ranging from asymptomatic to fatal.
Epidemiology\: a
Africa, Middle East, SE Asia; alpha thalassaemia common in West Africa and SE Asia; incidence rising in Northern Europe
and North America due to migration.
Pathophysiology\: mutations in globin genes lead to reduced globin chain production, causing accumulation of unpaired
chains, unstable red blood cell precursors, and increased red cell destruction. Severe forms result in insu
delivery to tissues.
Classi
Alpha thalassaemia\: reduced synthesis of alpha globin chains;
Alpha thalassaemia trait/minor\: 1-2 a
Haemoglobin H disease\: 3 a
supplementation.
Alpha thalassaemia major (hydrops fetalis)\: 4 a
Beta thalassaemia\: reduced synthesis of beta globin chains;
Beta thalassaemia trait/minor\: 1 a
Beta thalassaemia major\: both genes a
overload.
Clinical features of beta thalassaemia major\:
Severe anaemia
Splenomegaly and hepatomegaly
Bone expansion
Iron overload
Diagnosis\:
Full blood count
Blood
Haemoglobin electrophoresis or high-performance liquid chromatography (HPLC)
Genetic testing if indicated
Complications\:
Infection due to hyposplenism
Osteoporosis
Transfusion reactions
Alloimmunisation
Endocrine dysfunction
Cardiovascular complications
Thrombosis
Other\: gallstones, leg ulcers, gout, skin bronzing
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Prognosis\: varies by severity; thalassaemia trait does not a
dependent HbH disease are life-limiting; iron chelation therapy improves outlook, but heart failure from iron-induced
cardiomyopathy remains a leading cause of death.
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A comprehensive topic overview

Introduction

Thalassaemia is a group of genetic disorders that lead to reduced haemoglobin in red blood cells. They are classi
according to the globin chain which is a
asymptomatic to fatal.
The most severe forms of thalassaemia are rare in the UK, but their incidence is rising due to migration.
1

Epidemiology

Genetic disorders of haemoglobin are the most common genetic disorders worldwide. Globally 80-90 million people (1.5%
of the global population) are a
2
Beta thalassaemia is common in countries from the Mediterranean down to Africa and across to the Middle East and
Alpha thalassaemia is common in a similar distribution, most commonly found in West Africa and South
South East Asia. 3
East Asia.
This geographical distribution is thought to result from the thalassaemia trait o
malaria, the so-called 'malaria hypothesis'
. However, this mechanism is not fully established.
4
Migration is causing thalassaemia to become more common in other regions, particularly Northern Europe and North
America.
3
Figure 1. Distribution of alpha and beta
thalassaemia globally.
5

Aetiology

Anatomy

To understand thalassaemia, we
Haemoglobin is a substance found in red blood cells which carries oxygen from the lungs to the body’s tissues.
One haemoglobin molecule consists of four globin chains (chains of protein forming a roughly spherical shape) connected
by noncovalent bonds. These form a structure called a tetramer (one which is made up of four subunits). Each globin chain
is associated with a haem group containing an iron molecule.
The most abundant haemoglobin in normal adults is HbA. This is made up of two globin chains, known as alpha chains,
and two known as beta chains.
6-8
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Figure 2. (a) The structure of
haemoglobin is made up of two alpha
and two beta chains, each of which has
an iron-containing haem group (heme in
the US). (b) Molecular structure of a haem
9
group.
In humans, there are four alpha globin genes located on chromosome 16 used to make alpha chains. There are two beta
globin genes located on chromosome 11 used to make beta chains.
6-8

Pathophysiology

a
In thalassaemia, globin genes are absent or mutated, limiting the ability to produce the globin chains encoded by the
With reduced production in one type of globin chain, excess numbers of the other type of globin chain accumulate within
red blood cell precursors. The accumulation of unpaired globin chains disrupts the cells’ normal function and causes them
to become unstable.
These unstable red blood cell precursors cannot mature correctly and are destroyed by macrophages in the bone
marrow. The body compensates by producing more red blood cells, but each one has a reduced amount of haemoglobin
(leading to hypochromic red cells).
In severe forms of thalassaemia, the de
severe forms of thalassaemia have a greater degree of anaemia, in some cases so severe that they are fatal.
7,8

Classi

The two main types of thalassaemia are named according to the globin chain whose production is reduced\:
Alpha thalassaemia occurs when there is reduced synthesis of alpha globin chains due to a
Beta thalassaemia occurs when there is reduced synthesis of beta globin chains due to a
Alpha thalassaemia will cause an excess of unpaired beta globin chains, and beta thalassaemia will cause an excess of
unpaired alpha globin chains.

Clinical severity

Thalassaemia is also classi
a
People with thalassaemia trait (also known as thalassaemia minor) produce a reduced amount of globin chains and thus
have increased numbers of small red blood cells, but are asymptomatic with mild/no anaemia seen in their full blood
count.
Patients with thalassaemia major produce very little or no relevant globin chains, leading to profound anaemia.
Patients with thalassaemia intermedia have an intermediate clinical picture.
10

Alpha thalassaemia

Alpha thalassaemia is caused by deletions of alpha globin genes located on chromosome 16. The clinical severity of the
condition is proportional to the number of the four alpha globin genes a

Alpha thalassaemia trait/minor

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In alpha thalassaemia trait, one or two genes are a
microcytic hypochromic red cells on peripheral blood
Alpha thalassaemia trait is asymptomatic. Haemoglobin electrophoresis or high-performance liquid chromatography
(HPLC) is normal. These tests measure the relative amounts of di
charges.
In alpha thalassaemia trait, the percentage of each haemoglobin is unchanged because all the haemoglobins found in the
normal adult (HbA, foetal haemoglobin/HbF and HbA2) contain alpha chains, so the production of each of them is a
to the same extent.
Alpha thalassaemia trait can be mistaken for iron de. Accurate documentation of alpha thalassaemia trait
is essential to avoid unnecessary investigations and treatment.
When two genes are a
thalassaemia. When both alpha globin genes on the same copy of chromosome 16 are a
zero thalassaemia.
This is important because if two carriers of alpha thalassaemia zero produce a child, there is a one in four chance that the
resulting foetus will have alpha thalassaemia major and have no alpha globin genes, a condition which is fatal i n u t e r o
from hydrops fetalis (see below).
10
Figure 3. Image depicting the di
in genetics between alpha plus
thalassaemia trait (shown on the left) and
alpha zero thalassaemia trait (shown on
the right) – the clinical
identical but only alpha zero
thalassaemia trait can lead to a
pregnancy a
thalassaemia major

Haemoglobin H disease

When three alpha globin genes are a
haemoglobin H (a tetrameter of beta globin chains).
Patients with HbH disease have moderate anaemia and microcytic, hypochromic red cells on a blood
anisopoikilocytosis (red blood cells of varying and abnormal sizes and shapes), teardrop cells and basophilic stippling.
Patients with HbH disease may experience symptoms of anaemia or those related to increased red cell turnover (e.g.
pigment gallstones or splenomegaly). On haemoglobin electrophoresis or HPLC, a reduced amount of HbA will be seen
alongside large amounts of HbH.
Patients should receive folic acid supplementation due to the high turnover of red cells, and subsequent erythropoiesis,
depleting folate stores.
The severity of HbH disease varies. Some patients with HbH will need regular transfusions and iron chelation therapy,
whilst others may be largely asymptomatic.
10
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Figure 4. RBC morphology in

Alpha thalassaemia major (hydrops fetalis)

haemoglobin H disease. Hypochromic
When four alpha globin genes are a
RBCs displaying anisopoikilocytosis and
produced beyond the embryonic stage of development, and severe anaemia ensues. This is incompatible with life and
target cells are seen.
11
leads to death in utero by hydrops fetalis (heart failure of the foetus).
On haemoglobin electrophoresis or HPLC, no HbA or HbF is seen. Instead, only Hb Barts (tetramers of gamma chains which
in health would pair up with alpha chains to make HbF) are seen.
6,7,10

Summary of alpha thalassaemia

Table 1. Summary table of alpha thalassaemia.
7,10
Condition
No. of a
alpha genes
Clinical features Electrophoresis
Una
Alpha
thalassaemia
minor/trait
1 or 2
Usually
asymptomatic
Normal
Reduced HbA
Haemoglobin H
disease
3
Mild-moderate
anaemia
Presence of
HbH
Alpha
thalassaemia
major (hydrops
fetalis)
Absence of HbA
4 Death in utero
Presence of Hb
Barts

Beta thalassaemia

Beta thalassaemia is caused by deletions or mutations of the beta globin gene on chromosome 11.
Beta thalassaemia is divided broadly into two groups of diseases depending on the number of genes a
If one copy of the beta globin gene is a
If both copies of the beta globin gene are a
intermedia if there is some function of the beta gene and some beta chains are still produced, resulting in a less
clinically severe condition)

Beta thalassaemia trait/minor

In beta thalassaemia trait/minor, only one copy of the beta globin gene is a
beta chains. Beta thalassaemia trait is asymptomatic. This is because the other copy of the beta globin gene can
compensate for the missing copy.
The full blood count will show microcytosis with mild or no anaemia. Investigations in these patients include a blood
showing hypochromic, microcytic red blood cells and target cells. Haemoglobin electrophoresis or HPLC shows a raised
level of haemoglobin A2 (HbA2) which is a haemoglobin consisting of two alpha and two delta chains, which is present in
small amounts in the normal adult.
As seen in alpha thalassaemia trait, the implications of a diagnosis of this condition are to prevent misdiagnosis of iron
de
6,7,10

Beta thalassaemia major

In beta thalassaemia major, both beta globin genes are a
Clinical features
Clinical features of beta thalassaemia major include\:
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Severe anaemia\: becomes apparent at 3-6 months after birth when the switch from foetal haemoglobin (HbF) to adult
haemoglobin (HbA) occurs. If the diagnosis has not been made at birth, and a transfusion programme started, the infant
will present with typical features of anaemia (e.g. failure to thrive, pallor)
Splenomegaly and hepatomegaly\: occur due to excessive red blood cell destruction and extramedullary (outside the
bone marrow) red blood cell production in an attempt to correct the anaemia. In infants, this presents as a swollen
abdomen.
Bone expansion\: the bone marrow (where red blood cells are produced) expands into the cortical bone. This occurs
because the bone marrow increases in size to produce more red blood cells in response to anaemia.
Iron overload\: occurs due to regular blood transfusions used to treat thalassaemia and enhanced absorption of dietary
iron in response to anaemia-induced tissue hypoxia. If iron overload is left untreated, it can lead to organ failure as iron
accumulates in various parts of the body (e.g. liver, pancreas, bones and heart).
6,12
Features of bone marrow expansion
Bone marrow expansion is prevented by initiating a blood transfusion programme in infancy, but historically
presented with the following\:
Thalassaemic facies\: occurred when bone expansion a
Predisposition to fractures\: due to an impairment of bone structural integrity
Bossing (overgrowth) of the skull with a ‘hair on end’ appearance on X-ray (Figure 5)
Figure 5.
‘ H a i r o n e n d’ a p p e a r a n c e a s
s e e n i n b e t a t h a l a s s a e m i a m a j o r .
1 4
Investigations
Most people in the UK will have thalassaemia major detected at or before birth with antenatal or newborn screening, so
these investigations are usually not required to make the diagnosis.
Relevant investigations include\:
6,12
Full blood count\: microcytic anaemia
Liver function tests\: isolated hyperbilirubinemia (the rest of the liver function tests are normal)
Ferritin or iron studies\: normal iron levels, di
Blood
basophilic stippling
Haemoglobin electrophoresis or HPLC\: absence of HbA, both HbF and HbA2 are elevated
Management
Management of beta thalassaemia major includes\:
Regular red cell transfusions. Patients usually require 2-3 units every 4-6 weeks to maintain haemoglobin levels over
100g/L and suppress erythropoiesis (the production of red blood cells).
Splenectomy can be considered to reduce blood requirements. If performed, then appropriate vaccinations and
antibiotics need to be given.
Monitoring of iron status and iron chelation therapy (e.g. desferrioxamine) is essential to avoid iron overload. Iron
chelation has side e
careful monitoring by a thalassaemia specialist.
13
Folic acid (5mg daily) to replace folate stores which are used up more quickly because of increased red cell turnover.
Regular monitoring of other organ systems (e.g. thyroid function, pulmonary function, cardiovascular function, bone
density). Viral serology is also undertaken regularly for HIV, hepatitis B and hepatitis C due to the high number of blood
transfusions these patients need.
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Future therapies for beta thalassaemia major
Allogeneic stem cell transplantation o
precursors. However, it is associated with a high risk of morbidity or mortality.
Gene therapies, which involve adding functional genes to stem cells, are also currently in clinical trials.
6,8,12

Beta thalassaemia intermedia

In beta thalassaemia intermedia, both beta globin genes are mutated, but the body can still make some functional HbA.
This clinical diagnosis is between the asymptomatic beta thalassaemia trait and the transfusion-dependent beta
thalassaemia major. These patients should be o
during increased physiological stress (pregnancy, surgery).
15

Di

Whilst thalassaemia major is unmistakable, di
10,12
Iron de
Anaemia of chronic disease

Screening

Both alpha and beta thalassemia is inherited in an autosomal recessive fashion. However, there are twice as many alpha
genes as beta genes.
If both parents have beta thalassemia trait (only one gene), the following outcomes for the baby exist\:
One in four chance of not having the disease and not carrying the gene
Two in four chance (i.e. one in two) of having beta thalassaemia trait
One in four chance of having beta thalassaemia major
Figure 6. Autosomal recessive
inheritance.
17
Babies with severe disease can arise from parents who are both silent carriers of thalassaemia.
The NHS has a screening programme for all pregnant women in the UK. Pregnant women are o
they reach 10 weeks gestation to identify carriers of thalassaemia.
If the mother is found to be a carrier, the father is o
diagnostic test (chorionic villus sampling or amniocentesis) to establish the baby's thalassaemia status.
Testing for thalassaemia is also included in the newborn blood spot for babies 5-8 days old.
16

Complications

The majority of thalassaemia complications are transfusion-related. Complications include\:
Infection\: hyposplenism increases the risk of pneumococcal, Haemophilus and meningococcal infection. Iron overload
predisposes to bacterial infections such as klebsiella, yersinia and fungal infections. Viruses can also be very rarely
transmitted via blood transfusion.
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Osteoporosis\: presents earlier than the general population due to thalassaemia or iron overload. Vitamin D and calcium
can be used to prevent osteoporosis.
Transfusion reactions\: including febrile reaction, acute haemolytic reaction and transfusion-related acute lung injury
(TRALI).
Alloimmunisation\: with repeated transfusions, there is also the risk of alloimmunisation, where the transfused patient
develops antibodies against red cell antigens, which can lead to di
reactions.
Endocrine complications\: due to iron overload, patients can develop delayed sexual maturation, infertility, thyroid
dysfunction and parathyroid dysfunction.
Cardiovascular complications\: iron overload increase the risk of arrhythmias and heart failure due to iron-induced
cardiomyopathy.
Thrombosis\: thalassaemia increases the risk of thrombosis.
Other complications\: gallstones, leg ulcers, gout and skin bronzing due to iron overload.
10-12

Prognosis

This varies depending on the severity of thalassaemia. Thalassaemia trait does not a
Beta thalassaemia major (and transfusion-dependent HbH disease) are life-limiting conditions, with most patients dying in
their 50s and 60s. However, the long-term outlook improves dramatically when iron overload is managed with good
chelation therapy. The leading cause of death in these diseases remains heart failure, secondary to iron-induced
cardiomyopathy.
6,10,12

References

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b e t a t h a l a s s a e m i a i n E n g l a n d \: e s t i m a t i n g a n d v a l i d a t i n g e t h n i c-s p e c i
Kattamis A, Forni GL, Aydinok Y, Viprakasit V. C h a n g i n g p a t t e r n s i n t h e e p i d e m i o l o g y o f β-t h a l a s s e m i a . Pubmed Published in
2020; 105(6)\:692-703
Galanello R, Ra
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[LINK]
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Redhouse white, Vanbergen, C r a s h C o u r s e H a e m a t o l o g y a n d I m m u n o l o gy , F i f t h E d i t i o n . Published Tidy C, T h a l a s s a e m i a- P a t i e n t U K . Published in 2018. Available from\: [LINK]
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Reviewer

Dr Angela Collins
Consultant Haematologist
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Contents

Introduction
Aetiology
Classi
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