Pathophysiology

The genetic abnormality responsible for the sickling process is caused by a single amino acid substitution of valine for glutamic acid in the beta subunit of the hemoglobin molecule. The resultant hemolytic anemia is caused by the abnormal properties of HgbS. Affected red blood cells undergo repeated cycles of sickling and unsickling, with the HgbS strands polymerizing abnormally in response to deoxygenation. Without an attached O 2 molecule, they tend to coalesce and stretch into long monofilaments, thereby resulting in the distorted sickle shape of the red cell membrane. These irreversibly sickled cells diminish blood viscosity, causing hemolysis and obstructing the microcirculation (vasoocclusive phenomenon) of end-organ tissues. Capillary obstruction deprives tissues of oxygen and metabolic nutrition. It has long been presumed that the resultant hypoxia and ischemia cause the pathologic and clinical features of the disease. This entire process is felt to be self-perpetuating and sustains continued sickling. Others have recently proposed that plasma proteins, endothelial cells, and other genetically driven mechanisms play a major role in this complex process. A few investigators have even questioned whether vaso-occlusion exists at all, theorizing that tissue ischemia and infarction result from shunting of blood away from end-organ vascular beds rather than occlusion by deformed, sickled cells.

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