Prolonging Annexin Antithrombotic Activity

DESCRIPTION (provided by applicant): There is need to develop an agent that can be used to prevent or treat arterial or venous thrombosis without increasing hemorrhage. The human placental anticoagulant protein annexin V inhibits coagulation by binding to phosphatidylserine on the outer surface of activated platelets in which phospholipid asymmetry is lost. Recombinant human annexin V decreases arterial and venous thrombosis in experimental animal models without increasing hemorrhage. However, annexin V (32 kDa) rapidly passes from the circulation into the urine limiting its usefulness as an anti-thromobic agent. The investigators propose to increase the molecular weight of annexin V by conjugation with polyethylene glycol. It is predicted that this modification will prolong the half-life of annexin V in the circulation and its anticoagulant activity, thereby producing a clinically useful anti-thrombotic agent. Pegylated annexin V may also attenuate reperfusion injury. The investigators' milestone for Phase I is development of a pegylated annexin with significantly prolonged serum half-life and which retains its intrinsic anticoagulant activity; clinical efficacy in thrombosis will be tested in a subsequent SBIR-Phase II proposal.