Download 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
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
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
» 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 leucopoenia 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
– 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.
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.
– Hgs S/  thalassemia – symptomless to moderate anemia
– 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.
– 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
» Homozygous individuals have a mild to severe
hypochromic, microcytic anemia
» Heterozygous individuals are asymptomatic.