Thalassemias

HEMOGLOBIN A

Fetal Hemoglobin (2 alpha, 2 gamma)

Hemoglobin A2 (2 alpha, 2 delta)

Small amounts in body

Disorders of Haemoglobin
1. Thalassemia
2. Haemoglobinopathies

What is Thalassaemia ?
Thalassaemia is a group of inherited
disorders of hemoglobin synthesis
characterized by a reduced or absent
one or more of the globin chains of
adult hemoglobin .
Genetic autosomal recessive blood
disease.
The name is derived from the Greek
words Thalasso = Sea" and "Hemia =
Blood" in reference to anemia of the
sea.

Thalassemia
Mediterranean Anemia- 1st published in 1925
May be either homozygous defect or heterozygous

defect.

Thalassemia
Results

in overall decrease in amount of

hemoglobin produced and may induce
hemolysis.
May contribute protection against malaria.

Demographics: Thalassemia

Found
most
frequently in the
Mediterranean,
Africa,
Western
and
Southeast
Asia, India and
Burma

GeneticTypes of Thalassaemia :
There are two basic groups of thalassaemia.

Alpha ( )Thalassaemia

Beta ( )Thalassaemia

Clinical Types of Beta Thalassaemia :

There are 3 types of Beta thalassaemia :
1.

Thalassaemia Minor

2.

Thalassaemia Intermediate

3.

Thalassaemia Major

Genetics of Thalassemia
Adult

hemoglobin composed two alpha and

two beta chains.
Alpha thalassemia usually caused by gene
deletion; Beta thalassemia usually caused
by mutation.
Results in microcytic, hypochromic anemias
of varying severity.
10

Normal Human Haemoglobins

Haemoglobin

Structural
formula

Adult

Hb-A
Hb-A2

2 2 97%
2 2 1.5-3.2%

Fetal
Embryonic

Hb-F
Hb-Gower 1
Hb-Gower 2
Hb-Portland

2 2
2 2
2 2
2 2

0.5-1%

Chromosomes

Gene Structure ( Alpha 1 and Alpha 2 produce identical chains)

ALPHA THALASSEMIA

Alpha Thalassemia: deficient/absent alpha subunits

Excess beta subunits

Excess gamma subunits newborns

Tetramers formed:
Hemoglobin H adults
Hemoglobin Barts newborns

Five types:

Silent Carrier
Trait (Minor)
Hemoglobin H Disease
Major (Hemoglobin Barts)
Hemoglobin Constant Spring

/
/

GENETIC BASIS OF ALPHA THALASSEMIA

Encoding genes on chromosome 16 (short arm)
Each cell has 4 copies of the alpha globin gene

Each gene responsible for production of alpha globin

4 possible mutation states:

Loss of ONE gene silent carrier
Loss of TWO genes thalassemia minor (trait)
Loss of THREE genes Hemoglobin H

Accumulation of beta chains

Association of beta chains in groups of 4 Hemoglobin H

Loss of FOUR genes Hemoglobin Barts

NO alpha chains produced only gamma chains present
Association of 4 gamma chains Hemoglobin Barts

Classification & Terminology

Alpha Thalassemia
Normal
Silent carrier
Minor
Hb H disease
Barts hydrops fetalis

/
- /
-/-
--/
--/-
--/--

CLINICAL OUTCOMES OF ALPHA THALASSEMIA

Silent carriers

asymptomatic
normal

Alpha Thalassemia minor (trait)

no anemia
microcytosis
-unusually small red blood cells due to fewer Hb in RBC
normal

Alpha Thalassemia intermedia (Hemoglobin H)

microcytosis & hemolysis (breakdown of RBC)

- results in severe anemia
bone deformities
splenomegaly (enlargement of spleen)
severe and life threatening

CLINICAL OUTCOMES OF ALPHA THALASSEMIA

Alpha Thalassemia major

Hb Barts
fatal hydrops fetalis
- fluid build-up in fetal compartments, leads to death

occurs in utero

BETA THALASSEMIA

Beta Thalassemia: deficient/absent beta subunits

Commonly found in Mediterranean, Middle East, Asia,

and Africa

Three types:
Minor
Intermedia
Major (Cooley anemia)

May be asymptomatic at birth as HbF functions

GENETIC BASIS OF BETA THALASSEMIA

Encoding genes on chromosome 11 (short arm)
Each cell contains 2 copies of beta globin gene

beta globin protein level = alpha globin protein level

Suppression of gene more likely than deletion

2 mutations: beta-+-thal / beta-0-thal

Loss of ONE gene thalassemia minor (trait)

Loss of BOTH gene complex picture

2 beta-+-thal thalassemia intermedia / thalassemia

major
2 beta-0-thal thalassemia major
beta-+-thal / beta-0-thal thalassemia major

Excess of alpha globin chains

Classification & Terminology

Beta Thalassemia
Normal
Minor
Intermedia

Major

/
/0
/+
0/+
+/+
0/0
+/+
0/+

CLINICAL OUTCOMES OF BETA THALASSEMIA

Beta Thalassemia minor (trait)

Beta Thalassemia intermedia

asymptomatic
microcytosis
minor anemia
symptoms similar to Cooley Anemia but less severe

Beta Thalassemia major (Cooley Anemia)

most severe form

moderate to severe anemia
intramedullary hemolysis (RBC die before full development)
peripheral hemolysis & splenomegaly
skeletal abnormalities (overcompensation by bone marrow)
increased risk of thromboses
pulmonary hypertension & congestive heart failure

Thalassemia major

Thalassemia minor

Pathophysiology
Disturbance of ratio between Alpha &
non alpha globin chain synthesis then
absent or decrease production of one or
more globin chains
Formation of abnormal Hb structures
Ineffective erythropoiesis
Excessive RBCs Destruction
Iron Overload
Extra-medullary hematopoiesis

Signs & Symptoms

Thalassaemia Minor :
Usually no signs or symptoms
except for a mild anemia.
Thalassaemia Major :
1. Paleness, Jaundice or yellow coloured skin.
2. Growth retardation.
3. Bony abnormalities specially of the facial
bones.
4. Enlarged spleen and liver.

Laboratory
Diagnosis of
Thalassemia
36

Laboratory Diagnosis

Thalassemia minor:
Haemoglobin : Haemoglobin level is usually normal
or mildly reduced.
Peripheral blood film : Hypochromia
and
Microcytosis (similar to Iron Deficiency Anemia).
MCV< 75 fl,
RDW < 14%.
Reticulocyte Count increases
Decrease Osmotic Fragility
Haemoglobin electrophoresis
HPLC (High Performance liquid chromatography)

Haemoglobin electrophoresis

A
F
S
C

Other Special Procedures

Globin

Chain Testing - determines ratio of

globin chains being produced.
DNA Analysis - Determine specific defect at
molecular DNA level.

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Course and treatment of thalassaemia

Untreated

thalassemia Major :

Death in first or second

decade of life
Intermedia:

variable life span

Minor/Minima:

Normal life span

TREATMENTS FOR ALPHA THALASSEMIA

Silent Carrier no treatment required
Trait (Minor) no treatment required
Hemoglobin H Disease Folate

avoid iron supplements

Major (Hemoglobin Barts) RBC transfusion while still in

womb, else fetus is stillborn or dies shortly

TREATMENT FOR BETA THALASSEMIA

Trait no treatment required
Intermedia
Major (Cooley anemia)

Regular folate supplementation

RBC transfusion (Splenectomy may decrease need for
transfusions)
to maintain [Hgb] ~9-10g/dL
Blood transfusions iron accumulation iron overload
Iron chelators (diferroxamin)