Saturday, November 10, 2012

Hemoglobin S:

It is the most widespread Hb variants and arise from substitution of valine for glutamic acid at position 6 in the A helix of the β-globin chain. The widespread distribution of single point gene mutation responsible for the synthesis of HbS in areas where P. falciparum malaria is endemic is due to protection of HbS heterozygotes from manifestation of malaria. is one of the commonest genetic disorders with estimated 60 million carriers worldwide. It was the first human disorder to be understood at molecular level and is the first hemoglobinopathy to be identified. 

Sickle haemoglobin polymerizes on deoxygenation to produce the classic sickle-shaped erythrocytes that give the disease its name. This leads to microvascular occlusion and shortened red cell survival producing anaemia, endothelial damage, organ damage susceptibility to infection due to hyposplenism. There is single base change (CAG to CTG) in the sixth codon of the β globin gene that leads to the substitution of valine for glutamic acid resulting in HbS.

The primary pathophysiological event is sickling is intracellular polymerization of deoxy HbS. The β6 valine substitution alters the surface charge of Hb, resulting in interaction between Hb tetramers and the formation of 14-stranded polymers. These forms fibre bundles. The formation of polymer fibers is affected by four variables: oxygen tension, HbS concentration, temperature and presence of non-sickling Hb. Small increases in Hb concentration as occur with cellular dehydration, may act as trigger for sickling process.

Polymer formation make RBC less deformable and fragile and less flexible. This compromises oxygen delivery leading to further sickling during deoxy state. Deformed cells adhere or accumulate in intravascular space occluding blood flow. There is loss of potassium due to deformed membrane exceeding sodium gain, resulting in loss of cell water and increased concentration of intracellular Hb. This is accompanied by an up to four fold increase in intracellular calcium.

Homozygous HbSS: 

Here a valine for glutamic acid substitution occurs on both β-globin chains due to inheritance of mutated β-globin chain genes from both parents. This condition is described as sickle cell anemia or sickle cell disease because of sickle shaped RBC. In electrophoresis there is no HbA, but small HbA2. There is single large band in HbS with small bands at HbA2 and HbF (raised HbF) position. HbS forms 85% to 90% of total Hb. The sickle cell screen test is positive.

CBC analysis shows moderate to major decrease in Hb (6-10 g/dL) with normal or raised MCV, MCH. In PBS there are sickle red cells, target cells and howell jolly bodies, boat shaped RBC, etc.
Heterozygous Hemoglobin S (HbS Trait): 
There is increased HbA and HbS. HbF concentration is variable. Electrophoresis at both alkaline and acid pH shows bands in A and S position. CBC analysis shows slightly decreased Hb, typically sickle cells are not seen in PBS.
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