Sickle cell anemia is caused by a mutation in the p-globin chain of hemoglobin (Hb), replacing glutamic acid with valine at the sixth position of the chain. The association of two wild-type a-globin subunits with two mutant p-globin subunits forms Hb-S, which polymerizes under low oxygen conditions, causing distortion of red blood cells (RBCs) and a tendency for them to lose their elasticity. The gene for sickle cell disease has variable penetration. The sickle cell trait is largely asymptomatic, although patients are at risk of spleen infarction under extreme circumstances, such as exercise-induced exhaustion. Sickle cell disease has various genotypes, including sickle cell SS (homozygous), sickle cell thalassemia (sickle cell ST), and sickle cell C (Sickle SC) disease. In general, the most severe form is homozygous sickle cell (11).
Hb-S RBCs are inherently weak and error prone. The normal globulin molecule helps to protect the RBC membrane from the negative effects of utilizing iron to facilitate its oxygen-carrying capacity. The normal RBC tends to carry iron in the more stable ferrous (Fe2+) state, while the sickle cell globulin molecule promotes iron to rest in the more unstable ferric (Fe3+) state. The ferrous state of heme accelerates the formation of oxygen-free radicals that subsequently damage the erythrocyte's cell membranes. Chronic cell dehydration is critical for sickle deformation. These sickled cells have increased adherence to endothelium, exposing it to shear damage and free radical damage. Additionally, affected individuals have a higher number of immature erythrocytes to compensate for sickled RBCs. These immature cells also tend to adhere to endothelium, leading to further damage. Persistent endothelial damage induces inflammatory change that perpetuates further endothelial damage, leading to a destructive cycle that results in the end-organ damage that affects many patients (12).
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