THALASSEMIA

Mrs. NEERAJA RAJIV

Asst Professor
BNCP
DEFINITION
 The thalassaemias are a diverse group of
hereditary disorders in which there is
reduced synthesis of one or more of the
globin polypeptide chains.
GENETICS AND CLASSIFICATION
 Thalassaemias are genetically transmitted disorders.

 Normally, an individual inherits two β-globin genes

located one each on two chromosomes 11, and two α-
globin genes one each on two chromosomes 16, from
each parent i.e. normal adult haemoglobin (HbA) is α2
β2.

 Depending upon whether the genetic defect or deletion

lies in transmission of α- or β-globin chain genes,
thalassaemias are classified into α- and β-
thalassaemias.

 Thus, patients with α-thalassaemia have
structurally normal α-globin chains but their
production is impaired.
 Similarly, in β-thalassaemia, β-globin chains are
structurally normal but their production is
decreased.
 Each of the two main types of thalassaemias may
occur as heterozygous (called α- and β-
thalassaemia minor or trait), or as homogygous
state (termed α- and β-thalassaemia major).
 The former is generally asymptomatic, while the
latter is a severe congenital haemolytic anaemia.
PATHOPHYSIOLOGY OF
ANAEMIA IN THALASSAEMIA
α-Thalassaemia:
 α-thalassaemias are disorders in which there
is defective synthesis of α-globin chains
resulting in depressed production of
haemoglobins that contain α-chains i.e. HbA,
HbA2 and HbF.
 In α-thalassaemia major, the obvious cause
of anaemia is the inability to synthesise adult
haemoglobin, while in α-thalassaemia trait
there is reduced production of normal adult
haemoglobin.
 The clinical manifestations of α-thalassaemia
depend upon the number of genes deleted.
Accordingly, α-thalassaemias are classified into
4 types:
 1. Four α-gene deletion: Hb Bart’s hydrops
foetalis.
 2. Three α-gene deletion: HbH disease.
 3. Two α-gene deletion: α-thalassaemia trait.
 4. One α-gene deletion: α-thalassaemia trait
(carrier)
HB BART’S HYDROPS FOETALIS
 When there is deletion of all the four α-chain
genes (homozygous state) it results in total
suppression of α-globin chain synthesis
causing the most severe form of
αthalassaemia called Hb Bart’s hydrops
foetalis.
 Hb Bart’s is a gamma globin chain tetramer
(γ4) which has high oxygen affinity leading to
severe tissue hypoxia.
CLINICAL FEATURES.
 Hb Bart’s hydrops foetalis is incompatible
with life due to severe tissue hypoxia.
 The condition is either fatal in utero or the
infant dies shortly after birth.
 If born alive, the features similar to severe
Rh haemolytic disease.
LABORATORY FINDINGS
 1. Severe anaemia (haemoglobin below
6g/dl).
 2. Blood film show marked
anisopoikilocytosis, hypochromia,
microcytosis, polychromasia, basophilic
stippling, numerous normoblasts and target
cells.
 3. Reticulocyte count is high.
 4. Serum bilirubin level is elevated.
 5. Haemoglobin electrophoresis shows 80-90%
Hb-Bart’s and a small amount of Hb-H and
Hb-Portland but no HbA, HbA2 or HbF.
HBH DISEASE
 Deletion of three α-chain genes produces HbH which is
a βglobin chain tetramer (β4) and markedly impaired α-
chain synthesis.
 HbH is precipitated as Heinz bodies within the affected
red cells.
 An elongated α-chain variant of HbH disease is termed
Hb Constant Spring.
CLINICAL FEATURES.
 The features are intermediate between that of β-
thalassaemia minor and major.
 The severity of anaemia fluctuates and may fall to very
low levels during pregnancy or infections.
 Majority of patients have splenomegaly and may
develop cholelithiasis.
LABORATORY FINDINGS:
 1. Moderate anaemia (haemoglobin 8-9 g/dl).
 2. Blood film shows severe microcytosis,
hypochromia, basophilic stippling, target
cells and normoblasts.
 3. Mild reticulocytosis.
 4. HbH inclusions as Heinz bodies can be
demonstrated in mature red cells with
brilliant cresyl blue stain.
 5. Haemoglobin electrophoresis shows 2-4%
HbH and the remainder consists of HbA,
HbA2 and HbF.
Α-THALASSAEMIA TRAIT
 α-thalassaemia trait may occur by the
following molecular pathogenesis: By
deletion of two of the four α-chain genes in
homozygous form called homozygous α-
thalassaemia, or in double heterozygous form
termed heterozygous α-thalassaemia.
HETEROZYGOUS Α-
THALASSAEMIA
 By deletion of a single α-chain gene causing
heterozygous α-thalassaemia trait called
heterozygous α-thalassaemia.
CLINICAL FEATURES.
 Asymptomatic.
 One gene deletion α-thalassaemia trait is a
silent carrier state.
LABORATORY FINDINGS.
 1. Haemoglobin level normal or mildly reduced.
 2. Blood film shows microcytic and hypochromic
red cell morphology but no evidence of
haemolysis or anaemia.
 3. MCV, MCH and MCHC may be slightly reduced.
 4. Haemoglobin electrophoresis reveals small
amount of Hb-Bart’s in neonatal period (1-2% in α-
thalassaemia 2 and 5-6% in α-thalassaemia 1)
which gradually disappears by adult life. HbA2 is
either normal or slightly decreased (contrary to
the elevated HBA2 levels in β-thalassaemia trait).
Β-THALASSAEMIA:

 β-Thalassaemia:
 In β-thalassaemia major, the most important
cause of anaemia is premature red cell
destruction brought about by erythrocyte
membrane damage caused by the
precipitated α-globin chains.
Other contributory factors are:
 shortened red cell lifespan
 ineffective erythropoiesis
 haemodilution due to increased plasma
volume.
 A deficiency of β-globin chains in β-thalassaemia
leads to large excess of α-chains within the
developing red cells.
 Part of these excessive α-chains are removed by
pairing with γ-globin chains as HbF, while the
remainder unaccompanied α-chains precipitate
rapidly within the red cell as Heinz bodies.
 The precipitated α-chains cause red cell
membrane damage.
 During their passage through the splenic
sinusoids, these red cells are further damaged
and develop pitting due to removal of the
precipitated aggregates.
 Thus, such red cells are irreparably damaged
and are phagocytosed by the RE cells of the
spleen and the liver causing anaemia,
hepatosplenomegaly, and excess of tissue
iron stores.
 Depending upon the extent of reduction in β-chain
synthesis, there are 3 types of β-thalassaemia:

1. Homozygous form: β-Thalassaemia major. It is the most

severe form of congenital haemolytic anaemia. It is further
of 2 types

 i) β° thalassaemia major characterised by complete absence

of β-chain synthesis.
 ii) β+ thalassaemia major having incomplete suppression of
β-chain synthesis.

2. β-Thalassaemia intermedia: It is β-thalassaemia of

intermediate degree of severity that does not require
regular blood transfusions. These cases are genetically
heterozygous (β°/β or β+/β).

3. Heterozygous form: β-Thalassaemia minor (trait).

Β-THALASSAEMIA MAJOR
 β-thalassaemia major, also termed
Mediterranean or Cooley’s anaemia is the
most common form of congenital haemolytic
anaemia.
 β-thalassaemia major is a homozygous state
with either complete absence of β-chain
synthesis (β° thalassaemia major) or only
small amounts of β-chains are formed (β+
thalassaemia major).
 These result in excessive formation of
alternate haemoglobins, HbF (α2 γ2) and
HbA2 (α2 δ2).
CLINICAL FEATURES.
 1. Anaemia starts appearing within the first 4-6
months of life
 2. Marked hepatosplenomegaly occurs due to
excessive red cell destruction, extramedullary
haematopoiesis and iron overload.
 3. Expansion of bones occurs due to marked
erythroid hyperplasia leading to thalassaemic
facies and malocclusion of the jaw.
 4. Iron overload due to repeated blood
transfusions causes damage to the endocrine
organs resulting in slow rate of growth and
development, delayed puberty, diabetes mellitus
and damage to the liver and heart.
LABORATORY FINDINGS.
 The haematological investigations reveal the
following findings:
 1. Anaemia, usually severe.
 2. Blood film shows severe microcytic hypochromic
red cell morphology, marked anisopoikilocytosis,
basophilic stippling, presence of many target cells,
tear drop cells and normoblasts .
 3. Serum bilirubin (unconjugated) is generally raised.
 4. Reticulocytosis is generally present.
 5. MCV, MCH and MCHC are significantly reduced.
 6. WBC count is often raised with some shift to left of
the neutrophil series, with presence of some
myelocytes and metamyelocytes.
 7. Platelet count is usually normal but may be reduced in
patients with massive splenomegaly.

 8. Osmotic fragility characteristically reveals increased

resistance to saline haemolysis i.e. decreased osmotic
fragility

 9. Haemoglobin electrophoresis shows presence of increased

amounts of HbF, increased amount of HbA2, and almost
complete absence or presence of variable amounts of HbA.
The increased level of HbA2 has not been found in any other
haemoglobin abnormality except β-thalassaemia. The
increased synthesis of HbA2 is probably due to increased
activity at both δ-chain loci.

 10. Bone marrow aspirate examination shows normoblastic

erythroid hyperplasia with predominance of intermediate
and late normoblasts which are generally smaller in size
than normal. Iron staining demonstrates siderotic granules
TREATMENT
 Treatment of β-thalassaemia major is largely
supportive.
 1. Anaemia is generally severe and patients require
regular blood transfusions (4-6 weekly) to maintain
haemoglobin above 8 g/dl.
 2. In order to maintain increased demand of
hyperplastic marrow, folic acid supplement is given.
 3. Splenectomy is beneficial in children over 6 years
of age since splenic sequestration contributes to
shortened red cell lifespan.
 4. Prevention and treatment of iron overload is done
by chelation therapy (desferrioxamine). Oral chelation
with kelfer or deferiprone is also available now.
 5. Bone marrow transplantation from HLA-
matched donor that provides stem cells
which can form normal haemoglobin is being
done in many centres with fair success rate,
especially when done at an early stage
before end-organ damage has supervened.
 6. Some workers have found success with
cord blood transfusion
 7. Gene therapy of thalasaemia involving
genetic manipulation in haematopoieitc stem
cells may become an option for future.
Β-THALASSAEMIA MINOR
 The β-thalassaemia minor or β-thalassaemia
trait, a heterozygous state, is a common
entity characterised by moderate reduction
in β-chain synthesis.
CLINICAL FEATURES.
 Usually asymptomatic and the diagnosis is
generally made when the patient is being
investigated for mild chronic anaemia.
 The spleen may be palpable..
LABORATORY FINDINGS.
 1. Mild anaemia; mean haemoglobin level is about 15% lower

than in normal person for the age and sex.

 2. Blood film shows mild anisopoikilocytosis, microcytosis

and hypochromia, occasional target cells and basophilic
stippling.

 3. Serum bilirubin may be normal or slightly raised.



 4. Mild reticulocytosis is often present.

 5. MCV, MCH and MCHC may be slightly reduced.

 6. Osmotic fragility test shows increased resistance to
haemolysis i.e. decreased osmotic fragility.

 7. Haemoglobin electrophoresis is confirmatory for the

diagnosis and shows about two-fold increase in HbA2 and a
TREATMENT
 Patients with β-thalassaemia minor do not
require any treatment. But they should be
explained about the genetic implications of the
disorder, particularly to those of childbearing
age.
 If the two subjects of β-thalassaemia trait
marry, there is a 25% chance of developing
thalassaemia major in offsprings.
 Patients with β-thalassaemia minor have normal
life expectancy but those who are treated
under the mistaken diagnosis of iron deficiency
may develop siderosis and its complications.