Future directions in plasminogen activator therapy

Abstract

Thrombotic disorders such as myocardial infarction and stroke are the leading causes of death and disability in industrialized nations. Timely institution of thrombolytic therapy can achieve a reduction of infarct size, a preservation of left ventricular function, and a reduction in mortality. The administration of streptokinase, urokinase, and acylated plasminogen-streptokinase activator complex (APSAC) can be associated with a complete breakdown of the hemostatic system. Tissue-type plasminogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA, prourokinase) are more fibrin specific; however, at the large dosages of activator needed for therapeutic efficacy, bleeding complications are still a problem. New approaches to optimizing the risk/benefit ratio for the patient by improving efficacy without sacrificing specificity include the use of synergistic combinations of plasminogen activators, mutants of t-PA and scu-PA, chimeric molecules, and antibody-targeted thrombolytic agents. The last approach opens the possibility of targeting several different components of the clot with either fibrinolytic or antiplatelet effector functions in one optimized molecule.