Transcript Slide 1

Thalassemia
Dr.Alireza Nikanfar
Hematology and oncology research center of
Tabriz University of Medical Sciences
Hemoglobin Structure
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tetramer of globin polypeptide chains: a pair of
α -like chains 141 amino acids long and a pair of
ß -like chains 146 amino acids long
The major adult hemoglobin, HbA, has the
structure α2 ß2. HbF (α2 γ2) predominates during
most of gestation, and HbA2 (α2δ2) is a minor
adult hemoglobin.
Hemoglobin Structure
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Each globin chain enfolds a single heme moiety,
consisting of a protoporphyrin IX ring
complexed with a single iron atom in the ferrous
state (Fe2+),
Each heme moiety can bind a single oxygen
molecule; every molecule of hemoglobin can
thus transport up to four oxygen molecules.
Thalassemia Syndromes
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inherited disorders of α- or ß-globin
biosynthesis
The reduced supply of globin diminishes
production of hemoglobin tetramers, causing
hypochromia and microcytosis.
Unbalanced chain accumulation dominates the
clinical phenotype
α-Thalassemia Syndromes
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α-thalassemia-2 trait, in which one of the four αglobin loci is deleted
α -thalassemia-1 trait, with two deleted loci
HbH disease, with three loci deleted
hydrops fetalis with Hb Bart's, with all four loci
deleted
Nondeletion forms
α-Thalassemia Syndromes
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α -Thalassemia-2 trait is an asymptomatic, silent
carrier state.
α -Thalassemia-1 trait resembles -thalassemia minor
Heterozygosity for a deletion that removes both genes
from the same chromosome (cis deletion) is common in
Asians and Mediterranean individuals, as is
homozygosity for -thalassemia-2 (trans deletion). Both
produce asymptomatic hypochromia and microcytosis.
α-Thalassemia Syndromes
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In HbH disease, HbA production is only 25 to 30%
of normal
In adults, unpaired chains accumulate and are soluble
enough to form ß4 tetramers called HbH
Patients with HbH disease have thalassemia intermedia
characterized by moderately severe hemolytic anemia
but milder ineffective erythropoiesis
Survival into midadult life without transfusions is
common.
α-Thalassemia Syndromes
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The homozygous state for the α-thalassemia-1
cis deletion (hydrops fetalis) causes total absence
of α-globin synthesis
Excess γ globin forms tetramers called Hb
Bart's (γ4), which has an extraordinarily high
oxygen affinity
It delivers almost no O2 to fetal tissues, causing
tissue asphyxia, edema (hydrops fetalis),
congestive heart failure, and death in utero.
ß -Thalassemia Syndromes
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Mutations causing thalassemia can affect any
step in the pathway of globin gene expression:
Hypochromia and microcytosis
In heterozygotes (ß -thalassemia trait), this is the
only abnormality seen; anemia is minimal.
ß -Thalassemia Syndromes
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In homozygous states accumulation of highly insoluble
unpaired α chains, which form toxic inclusion bodies
that kill developing erythroblasts in the marrow
ineffective erythropoiesis
The few surviving red cells bear a burden of inclusion
bodies, detected in the spleen, shortening the red cell
life span and producing severe hemolytic anemia.
Erythroid hyperplasia can become exuberant and
produce extramedullary erythropoietic tissue in the liver
and spleen
ß -Thalassemia Syndromes
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Massive bone marrow expansion deranges
growth and development.
"chipmunk" facies
thinning and pathologic fracture of long bones
and vertebrae due to cortical invasion by
erythroid elements,
profound growth retardation
ß -Thalassemia Syndromes
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Hemolytic anemia causes hepatosplenomegaly,
leg ulcers, gallstones, and high-output congestive
heart failure.
The conscription of caloric resources to support
erythropoiesis leads to inanition, susceptibility to
infection, endocrine dysfunction, and, in the
most severe cases, death during the first decade
of life.
ß -Thalassemia Syndromes
Severity is highly variable
 Alleles associated with milder synthetic defects
and coinheritance of
α-thalassemia trait reduce clinical severity
 HbF persists to various degrees in thalassemias.
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ß -Thalassemia Syndromes
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ß-thalassemia major
ß-thalassemia intermedia can survive without
transfusion
ß-thalassemia minor and ß-thalassemia trait
describe asymptomatic heterozygotes for ß
thalassemia
Diagnosis
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The diagnosis of ß-thalassemia major is readily
made during childhood on the basis of severe
anemia accompanied by hepatosplenomegaly;
profound microcytosis; a characteristic blood
smear ; and elevated levels of HbF, HbA2, or
both.
Patients with ß-thalassemia intermedia exhibit
similar stigmata but can survive without chronic
hypertransfusion.
Diagnosis
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ß-Thalassemia minor (i.e., ß thalassemia trait) usually
presents as profound microcytosis and hypochromia
with target cells but only minimal or mild anemia
The mean corpuscular volume is rarely >75 fL; the
hematocrit is rarely <30 to 33%.
Hemoglobin electrophoresis classically reveals an
elevated HbA2 (3.5 to 7.5%), but some forms are
associated with normal HbA2 and/or elevated HbF.
Diagnosis
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Persons with α-thalassemia trait may exhibit mild
hypochromia and microcytosis, usually without
anemia
HbA2 and HbF levels are normal.
HbH disease resembles ß-thalassemia
intermedia, with the added complication that the
HbH molecule behaves like a moderately
unstable hemoglobin.
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