Thrombosis and hemorrhage are two of the dominant problems associated with cardiovascular surgery, and platelets are central to both. The actions of heparin contribute to bleeding, including heparin's effects which lay beyond the inhibition of the classic plasma coagulation pathways. Paradoxically, while heparin may cause pathologic bleeding by impairment of critical platelet hemostatic function, heparin also has limited efficacy in preventing thrombosis in the arterial circulation, a process mediated in part by the interactions between platelets and von Willebrand Factor (vWF) at sites of vessel wall injury. Thus, there is a clear need for the development of antithrombotic agents with more specific and selective platelet effects, suited to the unique requirements of cardiovascular surgery, arterial injury, and blood contact with artificial surfaces. Data from our laboratories suggest that certain heparins bind more avidly to platelets, and we have identified platelet glycoproteins IIb and IIIa as binding sites (among others). Platelet-bound heparin may directly modulate platelet function via its effects on calcium. In contrast, heparin indirectly inhibits platelet hemostatic function, by interfering with vWF- platelet binding. Heparin's inhibition of vWF function is independent of its conventional anticoagulant activity. We have identified and characterized a 23 amino acid domain of vWF which binds heparin, and with this have isolated a heparin fraction with enhanced ability to inhibit vWF- dependent platelet function. We now propose to identify the mechanism(s) by which heparin directly alters platelet function by biochemical analysis of platelet binding sites and heparin structure, and physiologic studies of heparin-mediated platelet activation. We will map the heparin-binding domain(s) of vWF, determine the conformational changes induced by heparin binding, and isolate and characterize the structure of heparins with potent anti-vWF activity. These lines of investigation lead directly to our long term goals: the development of new antithrombotic glycosaminoglycans with unique, focussed biologic activity suited to the specific thrombotic and hemorrhage problems associated with cardiovascular surgery and extracorporeal circulation.
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