Thalassemia

Summary
Thalassemias are a heterogeneous group of hereditary blood disorders characterized by
faulty globin chain synthesis resulting in defective hemoglobin, which can lead to anemia.
Based on the defective globin chain, they are classified as either alpha or beta subtypes.
Thalassemias are generally more frequent in areas where malaria is endemic; alpha
thalassemias occur most commonly in patients of Asian or African origin, whereas beta
thalassemias are predominant in patients of Mediterranean descent. Beta thalassemia can
be further divided into a heterozygous minor and a homozygous major variant. The minor
variant features only a low risk of hemolysis; however, the major variant presents with
severe anemia as early as infancy and often causes growth retardation. The severity of
alpha thalassemias varies as well, with significant anemia generally first arising with a
deletion of three of the four alleles (HbH disease). Deletion of all four α-globin alleles (Hb
Bart disease) is usually fatal in utero or shortly after birth. In all forms of thalassemia,
insufficient erythropoiesis can lead to extramedullary hematopoiesis as well as bone
marrow hyperplasia. The latter frequently results in periosteal reactions that are observed
as the classic "hair-on-end" sign on skull radiographs. Diagnosis is confirmed
via electrophoresis or DNA analysis. If a patient with thalassemia
requires transfusion therapy, it is important to consider the possible development of
secondary iron overload, which should be treated with chelating
agents (e.g., deferoxamine).
Epidemiology
 Beta thalassemia: most commonly seen in people of Mediterranean descent
 Alpha thalassemia: most commonly seen in people
of Asian and African descent

Alpha thalassemia is common in Asia and Africa!

Epidemiological data refers to the US, unless otherwise specified.

Etiology
General
 Cause: gene mutations

Beta thalassemia
In a normal cell, the β-globin chains are coded by a total of two alleles Thus, there are two
forms of the disease.

 Beta thalassemia minor (trait): one defective allele

 Beta thalassemia major (Cooley anemia): two defective alleles

 Alpha thalassemia
In a normal cell, the α-globin chains are coded by a total of four alleles.

 Silent carrier (minima form): one defective allele (-α/αα)

 Alpha thalassemia trait (minor form)

o Two defective alleles (-α/-α or --/αα)

 Hemoglobin H disease (intermedia form): three defective alleles (--/-α) → results

in excessive production of pathologically altered HbH

 Hemoglobin Bart disease (major form): four defective alleles (--/--) → results in

excessive production of pathologically altered Hb Bart (consists of four γ-chains

Pathophysiology
Anemia results from a combination of inefficient erythropoiesis and increased hemolysis

 Inefficient erythropoiesis → anemia

o Beta thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-

chains→ ↑ γ-,δ-chains → ↑ HbF and ↑ HbA2.

o Alpha thalassemia major (HbH disease) and Bart disease: faulty α-globin chain

synthesis → ↓ α-chains → ↑ β-, γ-chains → ↑ HbH, ↑ Hb-Bart's

 Increased hemolysis: One of the chains (either α or β) is reduced →

compensatory overproduction of other chains → excess globin chains precipitate
and form inclusions within RBCs → erythrocyte instability with hemolysis

 Anemia → ↑ erythropoietin → bone marrow hyperplasia and skeletal deformities

Clinical features
Beta thalassemia
 Minor variant (heterozygous): unremarkable symptoms (low risk of hemolysis,
rarely splenomegaly)

 Major variant (homozygous)

o Severe hemolytic anemia that often requires transfusions; secondary iron

overload due to hemolysis, transfusion, or both → secondary hemochromatosis

o Hepatosplenomegaly

o Growth retardation

o Skeletal deformities

Alpha thalassemia
 Silent carrier: asymptomatic

 Alpha thalassemia trait: mild hemolytic anemia with normal RBC and RDW

  Hemoglobin H disease

o Jaundice and anemia at birth

o Chronic hemolytic anemia that may require transfusions → secondary iron

overload due to hemolysis, transfusion, or both → secondary hemochromatosis

o Hepatosplenomegaly

 Hb-Bart's hydrops fetalis syndrome (most severe variant of alpha thalassemia)

o hydrops fetalis; hepatosplenomegaly

o Incompatible with life (death in utero or shortly after birth)

Diagnostics
Laboratory tests
 Blood sample

o Microcytic hypochromic anemia

 thalassemia minor or thalassemia trait usually have a normal RDW and a

higher RBC, and a relatively low MCV

o hemolysis (↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes)

 Blood smear: target cells; teardrop cells; anisopoikilocytosis

 Confirmatory tests

o Hb-electrophoresis

 Abnormal pattern depends on the exact subtype (see table

with hemoglobin variants).

o DNA analysis

Hemogl Globin ch Beta thalassemia Alpha thalassemia

obin ains
Minor (t Majo Silent Trait Hb H Hb
rait) r carrie (min disease Bart
(Cool r or) (interme disea
ey (mini dia) se
anem ma) (maj
ia) or)

HbA ααββ ↓ Abse Norma ↓ ↓↓ Abse

nt l nt

HbA 2 ααδδ ↑ ↑↑ Norma ↓ ↓↓ Abse

l nt

HbF ααγγ ↑ ↑↑ Norma ↓ ↓↓ Abse

l nt
 Hemogl Globin ch Beta thalassemia Alpha thalassemia
obin ains
Minor (t Majo Silent Trait Hb H Hb
rait) r carrie (min disease Bart
(Cool r or) (interme disea
ey (mini dia) se
anem ma) (maj
ia) or)

HbH ββββ Absent Abse Absent ↑ ↑↑ ↑↑

nt

Hb Bart γγγγ Absent Abse Absent Abse ↑ ↑↑

nt nt

HbS ααββ Absent

HbC ααββ Absent

Imaging
 Skeletal deformities; high forehead, prominent zygomatic
bones and maxilla, referred to as “chipmunk facies”

 X-ray: hair-on-end (“crew cut”) sign

Family history plays an important role in diagnosing patients with clinically silent
thalassemia. The possibility of thalassemia in these patients may only be investigated once
a family member is diagnosed with a more severe form!

Suspect thalassemia in a patient with microcytic anemia that is nonresponsive

to iron supplementation!

Treatment
Minor and minima variants
 Usually no therapy required

Major variants and hemoglobin H disease

 Symptomatic treatment

o Transfusion of erythrocyte concentrate

o Chelating agents (e.g., deferoxamine)

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