The purpose of this proposal is to evaluate the in vivo efficacy of a new class of thrombin inhibitors, designated as thrombostatins. Thrombostatins are a group of agents that prevent a and g -thrombins from activating platelets. Thrombostatins prevent thrombin from activating platelets by interacting with the platelet receptor for thrombin (PARI). Thrombostatins represent a new generation of thrombin inhibitors. Such an agent is needed because potent and specific agents which are directed to thrombin itself have been associated with too much hemorrhage in clinical trials. In this proposal, using several different experimental approaches, the in vivo efficacy of thrombostatin will be evaluated. One experimental approach involves the use of the well-established Folt's model of coronary artery thrombosis. This model of thrombosis was selected because of the extensive work demonstrating that the type of lesion that develops in this model is a platelet-rich thrombus. In the first part of this proposal the preventive-effects of thrombostatin alone on thrombus formation and then in the presence of aspirin will be evaluated. Other ex vivo techniques will be used to directly examine the effects of thrombostatin on platelet activity. These studies will lead to the generation of a new class of selective thrombin inhibitors which alone or in combination with other platelet inhibiting agents potentiate inhibition of thrombosis in the coronary artery. Such an agent is needed since all present anticoagulant regiments only achieve an 18-35% reduction in adverse events in acute coronary artery syndromes.
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