Chapter 12. Plasminogen Activators

Abstract

Three thrombolytic agents, streptokinase, urokinase, and alteplase (tissue plasminogen activator, recombinant) are approved in the U.S., and in addition a fourth (APSAC) in Europe. Many new thrombolytic agents are currently in preclinical and clinical development. The agents are large proteins and all work by activating the plasma zymogen plasminogen to plasmin that cleaves fibrin. This chapter describes the clinical and preclinical results that include discussion on first and second generations of plasminogen activators and use of plasminogen activators in indications other than MI: preclinical. Treatment of patients with intravenous streptokinase following acute myocardial infarction has been shown to reduce mortality, reduce infarct size, and improve left ventricular function even though intravenous streptokinase has been shown to be relatively ineffective in inducing prompt coronary artery thrombolysis. Preclinical data have shown tissue plasminogen activator (alteplase) and anisoylated plasminogen streptokinase activator complex (APSAC) to be effective thrombolytic agents in vitro and in animal models of myocardial infarction. Single chain urokinase (scu-PA, prourokinase) synthesized in mammalian cells has been shown to be an effective thrombolytic in a rabbit model. Studies in several models of cerebral thromboembolic occlusion have demonstrated a potential role for thrombolytic agents for this indication. Models of retinal vein thrombosis in cat and posterior penetrating eye injuries in rabbit have also been used to test the efficacy of thrombolysis with urokinase. A placebo-controlled pilot study of alteplase in unstable angina showed a favorable angiographic and clinical effect; whereas, a second placebo-controlled study showed a beneficial effect on pacing threshold.