Heart attack and stroke remain a major cause of death and morbidity in the United States. In most cases, these are caused by the formation of an occlusive thrombus overlying an atherosclerotic lesion. Lysis of these occlusive clots by the infusion of lytic agents is now an approved treatment for heart attack patients. However, lytic therapy is not always successful. The reasons for the failures are not clear. Resistance to thrombolysis is multifaceted and involves the key elements of the clot; fibrin, platelets, and endothelial cells. In previous studies we have shown that, in vitro, secretion of plasminogen activator inhibitor-1 (PAI-1) by platelets and endothelial cells is a factor influencing resistance. However, PAI-1 secretion could not account for all of the lysis delay.