Red blood cells and the vaso-occlusive process

Abstract

While the defi nitive genetic defect in sickle cell disease (SCD) is sickle hemoglobin (HbS), the relationship between the HbS mutation and the pathogenesis of vaso-occlusion in SCD remains incompletely understood and likely involves multiple complex and heterogeneous steps. Since chronic transfusion can prevent stroke and reduce the frequency of acute vaso-occlusive events, it is clear that the sickle red blood cell (RBC) plays a critical role in this process. Numerous sickle RBC factors contribute to the vaso-occlusive process, including: HbS polymerization; RBC cation loss and resultant cellular dehydration; oxidative injury of RBC membrane proteins and lipids; band 3 clustering; loss of phospholipid asymmetry and phosphatidylserine exposure; reduced RBC deformability; irreversibly sickled RBCs; increased adhesion of sickle RBCs to the endothelium and other circulating blood cells; intravascular hemolysis with the release of cell-free hemoglobin, arginase, and adenosine deaminase; and RBC microvesiculation. These sickle RBC properties initiate and propagate endothelial injury, vascular stasis, and activation of the coagulation and infl ammatory pathways, precipitating acute vaso-occlusion.