NOVEL ANTITHROMBOTIC AGENT

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This SBIR application is a request for funding of a Phase II study to develop a therapeutically effective antithrombotic agent. The antithrombotic agent to be developed in the present study functions by inhibiting the formation of thrombin. Thrombin is a potent thrombogenic agonist and is derived from prothrombin by the catalytic activity of the prothrombinase complex. The complex consists of factor Xa (a serine protease), factor Va (a co-factor) and Ca2+ assembled on phospholipid surfaces. Complex associated factor Xa is the physiologic enzyme responsible for the activation of thrombin. In the Phase I study we expressed and characterized a proteolytically inactive form of human factor Xa (rXai). Factor rXai inhibits the formation of thrombin by replacing plasma factor Xa in the prothrombinase complex. Factor rXai represents a new class of anticoagulants which function by direct interference with coagulation complex formation. Phase II of this study will be directed to scaling up production of this recombinant protein and testing the antithrombotic activity of factor rXai in rabbit and baboon animal thrombosis models. Phase III of this study will be applied to obtaining Federal Drug and Administration investigatory new drug (IND) approval status, and proceeding to test the human clinical efficacy of factor rXai. It is anticipated that this research will develop a potent and highly selective antithrombotic agent suitable for the treatment of thrombosis in several life-threatening cardiovascular diseases.