There is convincing evidence to show activation of both blood coagulation and platelets in patients with SCD. For example, plasma samples obtained at both steady state and during painful crisis exhibit high levels of thrombin generation, depletion of anticoagulant proteins, and abnormal activation of the fibrinolytic system. Similarly, exposure of such surface markers as CD62P and CD40L, along with increased circulating levels of thrombospondin represents strong evidence of platelet activation. Over and above its effects on the cleavage of fibrinogen and its ability to activate platelets, the increase in thrombin generation, with its wide-ranging effects on endothelial cells and blood vessels, could play an important role in the pathophysiology of SCD. The overall hypothesis that the investigators seek to test in this proposal is that activation of the coagulation system, along with the adhesive and/or inflammatory responses that are initiated by platelet activation, are important contributors to the pathophysiology of vasoocclusion, the hallmark of SCD. The model on which they have chosen to test this hypothesis is the sickle cell leg ulcer, a chronic, painful, and often disabling complication for which there is to date, no effective therapy.
In Specific Aim 1, they will conduct a randomized, single-blind trial of low intensity anticoagulation. They hope that by normalizing thrombin generation and subsequently decreasing platelet activation, they will promote the healing of these leg ulcers.
In Specific Aim 2, they will employ eptifibatide (EPF), a known inhibitor of the glycoprotein Ilb/Illa receptor, to evaluate the adhesive and inflammatory contributions of platelets to the pathophysiology of SCD. Throughout all aspects of this proposal, they will collect extensive data that they hope will enable them to answer the primary question inferred by their overall hypothesis - i.e., is the """"""""hypercoagulability"""""""" observed in patients with SCD a primary cause of the vasoocclusion or is it simply a secondary event that is observed in this clinical setting.
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