Compositions and methods for antiplatelet/anti-thrombotic therapy in a mammalian subject are provided. The method involves administering a therapeutically effective amount of SERP-1 admixed with a pharmaceutically acceptable carrier to a subject in need of such therapy. Methods of administering SERP-1 with at least one other antiplatelet agent are also provided. The compositions and methods of the present invention are useful for treating and preventing recurrence of numerous cardiovascular diseases and injuries.