Transcript Hemolytic anemias - Hemoglobinopathies

HEMOLYTIC ANEMIAS HEMOGLOBINOPATHIES
Part 2
THALASSEMIAS
 Thalassemias
are a heterogenous group of
genetic disorders
Individuals with homozygous forms are
severely affected and die early in childhood
without treatment
 Heterozygous individuals exhibit varying
levels of severity
 The disorders are due to mutations that
decrease the rate of synthesis of one of the two
globin chains ( or ). The genetic defect may
be the result of:

THALASSEMIAS
A mutation in the noncoding introns of the gene
resulting in inefficient RNA splicing to produce
mRNA, and therefore, decreased mRNA production
 The partial or total deletion of a globin gene
 A mutation in the promoter leading to decreased
expression
 A mutation at the termination site leading to
production of longer, unstable mRNA
 A nonsense mutation


Any of these defects lead to:
An excess of the other normal globin chain
 A decrease in the normal amount of physiologic
hemoglobin made
 Development of a hypochromic, microcytic anemia

WORLD DISTRIBUTION OF
THALASSEMIAS
THALASSEMIAS

Beta () thalassemia
The disease manifests itself when the switch from  to
 chain synthesis occurs several months after birth
 There may be a compensatory increase in  and 
chain synthesis resulting in increased levels of hgb F
and A2.
 The genetic background of  thalassemia is
heterogenous and may be roughly divided into two
types:

0 in which there is complete absence of  chain
production. This is common in the Mediterranean.
+
  in which there is a partial block in  chain synthesis.
At least three different mutant genes are involved:
 +1 – 10% of normal  chain synthesis occurs
 +2 – 50% of normal  chain synthesis occurs
 +3 - > 50% of normal  chain synthesis occurs

ALPHA AND BETA THALASSEMIAS
THALASSEMIAS

The clinical expression of the different gene
combinations (1 from mom and 1 from dad) are as
follows:

0/0, +1/ +1, or 0/ +1,+2,or +3 = thalassemia major, the
most severe form of the disease.
 Imbalanced synthesis leads to decreased total RBC
hemoglobin production and a hypochromic, microcytic
anemia.
 Excess  chains precipitate causing hemolysis of RBC
precursors in the bone marrow leading to ineffective
erythropoiesis
 In circulating RBCs,  chains may also precipitate
leading to pitting in the spleen and decreased RBC
survival via a chronic hemolytic process.
 The major cause of the severe anemia is the
ineffective erythropoiesis.
THALASSEMIAS

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
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The severe, chronic anemia early in life leads to
marked expansion of the marrow space and skeletal
changes due to the increased erythropoiesis.
Untreated individuals die early, usually of cardiac
failure (due to overwork and hemochromatosis).
Individuals may have massive splenomegaly leading to
secondary leukopoenia and thrombocytopenia. This
can lead to infections and bleeding problems.
Lab findings include:
- hypochromic, microcytic anemia
- marked anisocytosis and poikilocytosis
- schistocytes, ovalocytes, and target cells
- basophilic stippling from  chain precipitation
- increased reticulocytes and nucleated RBCs
THALASSEMIAS
- serum iron and ferritin are normal to increased
and there is increased saturation
- chronic hemolysis leads to increased bilirubin and
gallstones
- hemoglobin electrophoresis shows increased hgb F, variable
amounts of hgb A2, and no to very little A
THALASSEMIA MAJOR
THALASSEMIAS
Therapy – transfusions plus iron chelators to prevent
hemochromatosis and tissue damage from iron
overload; Gene therapy?
+2, or 3 homozygous = thalassemia intermedia
 
 Heterozygosity of 0, or + = thalassemia minor
 Mild hypochromic, microcytic anemia
 Patients are usually asymptomatic with symptoms
occurring under stressful conditions such as pregnancy
  thalassemia may also be found in combination with any
of the hemoglobinopathies (S, C, or E) leading to a mild
to severe anemia depending upon the particular
combination.

THALASSEMIA MINOR
THALASSEMIAS
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Alpha () thalassemia
The disease is manifested immediately at birth
 There are normally four alpha chains, so there is a great
variety in the severity of the disease.
 At birth there are excess  chains and later there are excess
 chains. These form stable, nonfunctional tetramers that
precipitate as the RBCs age leading to decreased RBC
survival.
 The disease is usually due to deletions of the  gene and
occasionally to a functionally abnormal  gene.

THALASSEMIAS
The normal haploid genotype is / 
 If one gene is deleted, the haploid phenotype is  thal
2
 If both genes are deleted, the haploid phenotype is 
thal 1
 Since one gets two genes from each parent, there are
four types of  thalassemia:

/  thal 2 = silent carrier
 /  thal 1, or  thal 2/  thal 2 =  thal trait with mild
anemia
  thal 1/  thal 2 = hemoglobin H disease (4 = hgb H)
Hgb H has a higher affinity for O2 and precipitates in
older cells. Anemia may be chronic to moderate to
severe.
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THALASSEMIAS
 thal 1/  thal 1 = hydrops fetalis which is fatal with
stillbirth or death within hours of birth. Hemoglobin
Barts (4) forms and has such a high affinity for O2 that
no O2 is delivered to the tissues.
 Hgb S/  thalassemia – symptomless to moderate anemia

ALPHA THALASSEMIAS
THALASSEMIAS
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Delta/beta (/) thalassemia – both  and 
chains are absent with no or little
compensatory increase in  chain synthesis.
This leads to 100% hgb F and mild
hypochromic, microcytic anemia
Hereditary persistence of hgb F – are a group
of heterogenous disorders with the absence of 
and  chain synthesis which is compensated
for by an increase in  chain synthesis leading
to 100% hgb F. Since hgb F has an increased
affinity for O2, this results in polycythemia.
THALASSEMIAS

Hemoglobin Constant Spring – formed by a
combination of two structurally abnormal 
chains (each elongated by 31 amino acids at
the COOH end) and two normal  chains.
The abnormal  chains are inefficiently synthesized
resulting in an  thal 1 like phenotype (excess 
chains)
 Homozygous individuals have mild hypochromic,
microcytic anemia similar to a mild a  thalassemia.

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Hemoglobin Lepore – a normal  chain plus a
- hybrid (N-terminal , and C-terminal ).

There is ineffective synthesis of the hybrid chain leading
to  chain excess and the same problems seen in 
thalassemia.
THALASSEMIAS
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Homozygous individuals have a mild to severe hypochromic,
microcytic anemia
Heterozygous individuals are asymptomatic.