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The Thalassaemia Syndromes
• The thalassaemia are heterogeneous group of
inherited disorders, which are characterized by
reduced or absent synthesis of one or more
globin chain type.
• The imbalance of globin chain synthesis, which
result leads to ineffective erythropoiesis and a
shortened red cell lifespan.
• In contrast to the structural
haemoglobinopathies, the affected globin chain
is structurally normal; it is only the rate at which
it is synthesized which is affected.
• The thalassaemia are most common in part of the world where
malaria is, or was recently, endemic: the result of positive selection
for a gene, which affords some protection against malaria.
• The distribution of the different forms of thalassaemia is not uniform:
each is most commonly found in certain populations.
• β Thalassaemia is most common in people from the Mediterranean,
Africa, India, SE Asia and Indonesia. The incidence of mutations,
which lead to β thalassaemia, reaches almost 10% in some parts of
Greece. The disorder is relatively rare in Northern and Western
Europeans and in native Americans.
• The clinically mild forms of α thalassaemia (α +
most common in American blacks, Indonesia, SE Asia, the Middle
East, India, and the Mediterranean. 30% of American blacks are
silent carriers of α +
heterozygous, while 3% are homozygous.
Homozygous express minimal symptoms of disease.
• The clinically sever a thalassaemia (α0
thalassaemia) are common
in people from the Philippines, SE Asia and S China. The population
incidence of deletions, which leads to this form, reaches 25% in
some parts of Thailand.
The thalassaemias are classified according
to three criteria:
1- The affected globin gene(s) e.g. α , β , dδ , etc.
2- Whether the reduction in synthesis in the
affected gene is partial (β+
) or absolute (β0
3- The genotype e.g. homozygous β 0
Normal α α / α α
heterozygote α − / α α
homozygote α − / α −
heterozygote − − / α α
homozygote − − / − − (Barts hydrops foetalis)
Double heterozygote − − / α − (hemoglobin H disease)
More than 95% of a thalassaemias result from the deletion
of one or both of a globin genes located on chromosome
16. This gives rise to five possible genotypes:
Most β thalassaemia result from a point mutation within the β
globin gene complex. Each mutation can result in a reduction
or abolition of β globin gene function and so to β+
thalassaemia. Therefore, the classification of β thalassaemia is
similar to that for α thalassaemia:
Normal β / β
• The myriad manifestation of this complex
group of disorders result from the
imbalanced synthesis of α-like and non- α
-like globin chains.
• Under normal circumstances, the rate of
synthesis of α globin must be more or
less matched by the total synthesis of β, δ
and γ globin chains.
• Impaired synthesis of α globin results in
the accumulation of unpaired non- α
globins within the developing erythroblasts
and vice versa.
• Unpaired globin chains are unstable: they
form aggregates and precipitate within the
cell, causing decreased deformability,
membrane damage and selective removal
of the damaged cell by reticuloendothelial
• Unpaired α globin chains are extremely
insoluble and causes sever damage to the
• Unpaired β globin chains, on the other hand,
form haemoglobin H, which is relatively stable
and only precipitate as the red cell ages. Thus
moderate impairment of β globin synthesis is
associated with a greater degree of ineffective
erythropoiesis and haemolysis than an
equivalent impairment of α globin synthesis.
• The affected individuals in this disease are
belonging to one of four groups according to
the increasing severity of their symptoms:
1- "silent" carriers
2- α thalassaemia trait
3- haemoglobin H disease
4- haemoglobin Barts hydrops foetalis
• The groups correspond approximately to the
functional equivalent of the deletion of 1, 2, 3
or 4 a globin genes respectively.
1- "Silent" carriers
• Deletion of a single a globin gene has no
significant effect on the affected individual.
• As adults, no haematological abnormality can be
demonstrated using standard laboratory
techniques (excluding DNA analysis).
• Umbilical cord blood of newborns may contain
1% of haemoglobin Barts (γ4
• Such individuals can only be defined with
complete reliability by DNA analysis.
2-α Thalassaemia Trait
• Individuals with deletion of two α globin
genes may be:
homozygous (α-/α-) or α0
(- -/ α α). It's important to know to which
group a given individual belong to give
accurate genetic counseling.
• The two groups are clinically
indistinguishable and present identical
Laboratory findings of Thalassaemia Trait
Affected individuals typically show:
1- Mild microcytic hypochromic anaemia
with no significant symptoms.
2- Precipitated haemoglobin H (- - /α -) can
be demonstrated by supravital stain in
small minority of red cells.
3- Umbilical cord blood contains up to 10%
of haemoglobin Barts.
3-Haemoglobin H Disease
• It's arises from the deletion of three α globin
• The severity of Hb H is highly variable.
• It's characterized by a moderately sever
anaemia and hepatosplenomegally.
• Typically, the haemoglobin level is maintained
around 8 g/dl, and transfusion support is
• Extramedullary haemopoiesis and skeletal
abnormalities are uncommon.
The Peripheral blood film includes:
• Microcytosis, hypochromasia, fragmented red
cells, poikilocytosis, and polychromasia and
• Multiple haemoglobin H inclusions are seen in
most of the cells; these bodies cause haemolytic
anaemia, which characterizes the condition.
• Umbilical cord blood contains up to 40%
• Adult's blood contains between 5-35% of
4-Haemoglobin Barts Hydrops Foetalis
• The most sever form of a thalassaemia
results from the deletion of all four a globin
genes and so is associated with a
complete absence of a globin synthesis.
4-Haemoglobin Barts Hydrops Foetalis
• Because of the absence of a globin synthesis, no
functionally normal haemoglobins are formed after the
cessation of ζ globin synthesis at about 10 weeks
• Instead, functionally useless tetrameric molecules such
as haemoglobin Barts (γ4
) and haemoglobin H (β4
• Thus, although the haemoglobin concentration at
delivery typically is about 6 g/dl, functional anaemia is
much more sever.
• The severity of anaemia causes gross oedema
secondary to congestive cardiac failure and massive
• Pregnancy usually terminates in a third trimester
stillbirth, often after a difficult delivery.
• The peripheral blood smear shows
marked microcytosis, hypochromasia,
poikilocytosis, fragmentation and
numerous nucleated red cells.
Haemoglobin electrophoresis confirms this
• β Thalassaemia usually results from
point mutations within the β globin
gene cluster, β thalassaemia can be
classified according to the severity of
their symptoms into three groups:
1- β thalassaemia minor (or trait)
2- β thalassaemia major
3- β thalassaemia intermediate
1- β Thalassaemia minor
• It's the mildest form, which arises from the
inheritance of a single abnormal β globin
gene. Typically, the affected individual
exhibits no significant signs of the disease,
and may be unaware of the condition, and
generally live a normal lifespan.
• Microcytic hypochromic anaemia, with
target cells a prominent feature in the
peripheral blood film.
• Red blood cell count is high to
compensate for the generated
• Haemoglobin level is around 10-11 g/dl.
• Reticulocyte is slightly increased.
• White blood cells is normal
• Bone marrow :
Generally shows some degree of erythroid
hyperplasia and mild ineffective
erythropoiesis. Iron storage is slightly
• Haemoglobin Electrophoresis:
Hb F(2 - 6 % ) Hb A2
( 3 - 7 %) Hb A (87 - 95 %)
Beta thalassemia - heterozygous
(minor or trait)
2-β Thalassaemia major
• β Thalassaemia major results from the inheritance of
two b thalassaemia genes. Affected individuals are
either homozygous or double heterozygous for two
• In the absence of treatment, the condition is
characterized by :
1- sever anaemia
2- gross splenomegally
3- Frequently hepatomegally
4- Retarted growth
5- Facial mongoloid appearance
6- Rarely live beyond the second decay.
1. peripheral blood
• Sever haemolytic anaemia with Hb< 7.0 g/dl
• Microcytic hypochromic due to decrease globin synthesis.
• Marked anisocytosis and poikilocytosis.
• Increased polychromatophilia.
• Numerous target cells.
• Howell-jolly bodies and sedrocyte are common.
• Increased NRBC's ( 200 or more / 100 WBC's)
• Increased reticulocyte.
• WBC is slightly increased with occasional immature
• Platelets are slightly increased
2- Bone Marrow:
The bone marrow shows erythroid
hyperplasia, and excess blood
transfusion & haemolysis will lead to
precipitation of iron in spleen and liver.
3- Biochemical tests:
• Haptoglobin is decreased.
• Bilirubin is increased.
• Analysis of the haemoglobins present reveals a marked
increase in Hb F, the precise value of which is
dependent on the genetic defect(s) present. for example:
• In homozygous β0
thalassaemia: Hb F accounts for up to
98 % of the total.
• In double heterozygous β+
thalassaemia: Hb F accounts
for 40-60 %
• Hb A2 is increased in both defects.
• The increase in d and g chains is a compensatory
mechanism due to the decrease in the production of β
Beta thalassemia major
• Iron chelation
• stem cell transplant
3-β Thalassaemia intermedia
Typically, thalassaemia intermedia arise from one
of three circumstances:
• Inheritance of mild β thalassaemia
• Co-inheritance of a gene which increases the
rate of γ globin synthesis.
• Co-inheritance of α thalassaemia. Reduction
in a globin synthesis reduces the imbalance
in α: non-α globin synthetic ratio.
3-β Thalassaemia intermedia
• Thalassaemia intermedia encompass all cases of β
thalassaemia with significant symptoms of disease which do
not require regular transfusion to maintain their haemoglobin
level above 7 g/dl.
• The laboratory and clinical features of this condition mirror
those of the more sever phenotype. The major cause of
morbidity is due to iron overload as a result of increase
gastrointestinal absorption of dietary iron in anaemic patients;
these results in increase total body iron.
• The bone marrow is massively imposed by erythroid
hyperplasia, this leads to increase demand of iron, which
exceeds the supply capacity of the reticuloendothelial system.
Thus functional iron deficiency is present, despite raised in
Stepwise approach to the diagnosis of thalassemia