The Thalassemias

Dr. Bulan Ginting Munthe., Sp.A (K)

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Thalassemia
Thalassemia is a disease due to a
genetic abnormality leading to
decrease or no synthesis of one of the
globin polypeptide chains without
alteration in its primary structure

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Thalassemia
Heritable, hypochromic anemias-varying
degrees of severity
Genetic defects result in decreased or absent
production of mRNA and globin chain
synthesis
At least 100 distinct mutations
High incidence in Asia, Africa, Mideast, and
Mediterrenean countries
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2 2 4

2 2 = 97 %
(Hb A)

2 2 (Hb F)< 1 %

2 2 4
(Hb H)

2 2 4 (Hb Bart`s)

2 2 (Hb A2) 2-3 % 2 2 4 ?

Normal

2 2 (Hb F)
2 2 (Hb A2)
- Thal

- Thal
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Hemoglobin Review
Hemoglobin is a complex compound of hem and globins
Hem is complex consist of one Fe atom in the midle of
porphyrin complex
Globins is a kind of protein consist of polypeptide chain.

One molecule of hemoglobin consists of :

Four polypeptide chains, non-covalently bound
Four heme complexes with iron bound
Four O2 binding sites
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Globin Chains
Alpha Globin
141 amino acids
Coded for on Chromosome 16
Found in normal adult hemoglobin, A1 and A2

Beta Globin
146 amino acids
Coded for on Chromosome 11, found in Hgb A1

Delta Globin
Found in Hemoglobin A2--small amounts in all adults

Gamma Globin
Found in Fetal Hemoglobin

Zeta Globin
Found in embryonic hemoglobin

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Hemoglobin Types

Hemoglobin Type Globin Chains

Hgb A192%---------
Hgb A22.5%--------
Hgb F <1%---------
Hgb H ------------------
Barts Hgb--------------
Hgb S-------------------- gluval
Hgb C------------------- glulys
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Genetics
Alpha globins are coded on chromosome 16
Two genes on each chromosome
Four genes in each diploid cell
Gene deletions result in Alpha-Thalassemias

Also on chromosome 16 are Zeta globin genes

Gowers hemoglobin (embryonic)
Beta globins are coded on chromosome 11
One gene on each chromosome
Two genes in each diploid cell
Point mutations result in Beta-Thalassemias

Also on chromosome 11 are Delta (Hgb A2) and

Gamma (Hgb F) and Epsilon (Embryonic)
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Clinical Manifestation of
Thalassemia Syndrome
There is a wide spectrum of manifestation
of thalassemia syndromes stretching from
normal clinical and hematologic findings to
the totally lethal Hb in Bart`s hydrops
fatalis on the other.

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Severity of clinical manifestation

in thalassemia is determined by :
(1) Types of the thalassemia genes
(2) Gene combination (genotypes)
(3) Non genetic factors

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1. Types of the thalassemia genes

1-1. -thalassemia
(1)

-thalassemia 1 Complete suppression of

- chain synthesis

(2) -thalassemia 2 Partial suppression

of - chain synthesis
(3) Nondeletion -thalassemia
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1.2. - thalassemia

(1) 0- thalassemia :

complete suppression of - chain

synthesis.
(2) +-thalassemia : partial suppression of -chain
synthesis.
(3) Silent -thalassemia : normal hematologic
findings in the heterozygotes
(4) - thalassemia : and chain are suppressed
(5) HPFH : Hereditary Persistence of Fetal hemoglobin.
(6) Hb Lepore : structural mutant equivalent to a
- thalassemia gene.
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2. Gene Combinations
2.1 Trait or heterozygosity or carrier state
2.2 Homozygosity
2.3 double heterozygosity
2.3.1 Between thalassemia genes
Thal1 / Thal 2
0 Thal / + Thal
0 Thal / Thal
+ Thal / HPFH
2.3.2 Between a thalassemia gene and an allelic
hemoglobin variant.
An -chain variant is allelic to an thalassemia
gene, while a -chain variant is allelic to a thalassemia gene
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2.4 Association : Non alllic genes may be inherited

together in the same individuals.
For example;

- Thal with - Thal

Hb S
with - Thal
Hb E
with - Thal

As a rule, Association between nonallelic genes are

harmless
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3. Non genetic factors

Environmental (nongenetic) factors interact with thalassemia
and abnormal hemoglobin genes in determining expression.
Such as :
Ion deficiency decreases the levels of Hbs A2. E and H
Megalobastic anemia increases Hb A2.
Pregnancy befalls Hb levels of thalassemia heterozygotes
and patients more then normal persons.
Splenectomy infections
Poverty more severe anemia
Hypersolenism leukopenia and thrombocytopenia
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Alpha Thalassemias
Result from gene deletions
One deletionSilent carrier; no clinical
significance
Two deletions Thal trait; mild
hypochromic microcytic anemia
Three deletionsHgb H; variable severity,
but less severe than Beta Thal Major
Four deletionsBarts Hgb; Hydrops
Fetalis; In Utero or early neonatal death
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Alpha Thalassemias
Usually no treatment indicated
4 deletions incompatible with life
3 or fewer deletions have only mild anemia

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Beta Thalassemias
Result from Point Mutations on genes
Severity depends on where the hit(s) lie
0-no -globin synthesis;
+ reduced synthesis

Disease results in an overproduction of globin chains, which precipitate in the cells

and cause splenic sequestration of RBCs
Erythropoiesis increases, sometimes
becomes extramedullary
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-Thal--Clinical
-Thalassemia Minor
Minor point mutation
Minimal anemia; no treatment indicated

-Thalassemia Intermedia
Homozygous minor point mutation or more severe
heterozygote
Can be a spectrum; most often do not require chronic
transfusions

-Thalassemia Major-Cooleys Anemia

Severe anemia
Transfusion dependent

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Beta Thalassemia Major

Reduced or nonexistent production of -globin
Poor oxygen-carrying capacity of RBCs
Failure to thrive, poor brain development

Increased alpha globin production and precipitation

RBC precursors are destroyed within the marrow

Increased splenic destruction of dysfunctional RBCs

Anemia, jaundice, splenomegaly

Hyperplastic Bone Marrow

Ineffective erythropoiesisRBC precursors destroyed
Poor bone growth, frontal bossing, bone pain

Increase in extramedullary erythropoiesis

Iron overloadincreased absorption and transfusions

Endocrine disorders, Cardiomyopathy, Liver failure
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-Thalassemia MajorLab findings

Hypochromic, microcytic anemia
Target Cells, nucleated RBCs, anisocytosis

Reticulocytosis
Hemoglobin electrophoresis shows
Increased Hgb A2delta globin production
Increased Hgb Fgamma globin production

Hyperbilirubinemia
LFT abnormalities (late finding)
TFT abnormalities, hyperglycemia (late
endocrine findings)
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-Thalassemia Major--Treatment
Chronic Transfusion Therapy

Maximizes growth and development

Suppresses the patients own ineffective erythropoiesis and
excessive dietary iron absorption
PRBC transfusions often monthly to maintain Hgb 10-12

Chelation Therapy
Binds free iron and reduces hemosiderin deposits
8-hour subcutaneous infusion of deferoxamine, 5 nights/week
Start after 1year of chronic transfusions or ferritin>1000 ng/dl

Splenectomy--indications
Trasfusion requirements increase 50% in 6mo
PRBCs per year >250cc/kg
Severe leukopenia or thrombocytopenia
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Treatment
The treatment of thalassemia is directed to :
1. Maintain Hb level at 12 g% (hypertranfusion)
2. Minimize the effect of transfusion :
- Transfusion reaction
- Disease transmission from transfusion
- Iron over load
3. Psycho social problem
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-Thalassemia Major
Complications and Emergencies
SepsisEncapsulated organisms
Strep Pneumo

Cardiomyopathypresentation in CHF
Use diuretics, digoxin, and deferoxamine

Endocrinopathiespresentation in DKA
Take care during hydration so as not to
precipitate CHF from fluid overload
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Anticipatory Guidance and Follow Up

ImmunizationsHepatitis B, Pneumovax
Follow for signs of diabetes, hypothyroid,
gonadotropin deficiency
Follow for signs of cardiomyopathy or CHF
Follow for signs of hepatic dysfunction
Osteoporosis prevention
Diet, exercise
Hormone supplementation
Osteoclast-inhibiting medications

Follow ferritin levels

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On The Horizon
Oral Chelation Agents
Pharmacologically upregulating gamma globin
synthesis, increasing Hgb F
Carries O2 better than Hgb A2
Will help bind globins and decrease precipitate

Bone Marrow transplant

Gene Therapy
Inserting healthy genes into stem cells and
transplanting
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