Investigations into hemostatic abnormalities associated with Sickle Cell Disease (SCD) have been numerous. The data suggests that thrombin generation and fibrin formation are increased during steady state, with conflicting data whether further activation occurs in vasocclusive crisis (VOC). Platelet activation during VOC occurs, with variable findings during steady state. A selective, concomitant evaluation of the hemostatic pathways i.e. intrinsic, tissue factor (TF) or extrinsic activation, fibrinolysis, and platelet-endothelial activation has not been reported. Neither has a longitudinal evaluation been performed in infants during the unique transition period when HbF levels fall from 70- 80% to <10%. Studies in older children and adults will assess whether intrinsic activation (relevant to the origin of pain and acute inflammation) occurs only during VOC. Studies will use appropriate """"""""negative"""""""" and """"""""positive"""""""" control groups. Studies will include intrinsic markers [kininogen profiling, high molecular weight kininogen (HK) and low molecular weight kininogen (LK) cleavages, western blotting of HK and LK, and kallikrein-alpha2 macroglobulin; extrinsic markers [TF and factor V11a]; other activation and fibrinolytic markers [prothrombin F1.2, FPA, TAT, tPA, PAI-I, D-dimer and plasma alpha2 antiplasmin]; platelet- endothelial markers [evaluation of activation dependent epiptopes]. Unequivocal demonstration of contact pathway activation during VOC would provide a crucial link between VOC and its accompanying phenomenon including pain, and inflammation. Finally our studies should provide a unique perspective on the continuum of hemostatic changes that unfold during the course of SCD, and those that develop as vascular insufficiencies supervene in the adult.
