Pre-clinical studies of plasmin: Superior benefit-to-risk ratio of plasmin compared to tissue plasminogen activator☆

Abstract 

Currently-used thrombolytic agents are plasminogen activators (PA). While effective for treating thrombotic disease, PA use is associated with unavoidable hemorrhagic complications in susceptible individuals. Thus, there is an urgent need for new agents or approaches that provide greater hemostatic safety without sacrificing thrombolytic efficacy. Evidence now strongly indicates that ‘direct-acting’ thrombolytics, which do not require conversion of the precursor plasminogen to the active form plasmin, offer such a potential. The biochemical properties of plasmin provide a theoretical foundation for safe and effective therapy, based on thrombolytic efficacy upon local catheter delivery of agent and neutralization of circulating agent by its inhibitor (α-2 antiplasmin) to prevent bleeding complications.

In vitro and animal studies support these predictions. In comparison with tissue-plasminogen activator (t-PA), plasmin shows a distinct benefit-to-risk advantage. First, plasmin is equally effective as t-PA in thrombolysis and may be superior for treating thrombi in totally-occluded vessels. Second, whereas t-PA causes bleeding from vascular trauma sites in animals when infused at dosages used for thrombolysis (0.5–1 mg/kg), plasmin exhibits safety at therapeutic dosages. In fact, plasmin can be used at several fold higher concentrations than is needed for thrombolysis, thereby providing a significant safety margin that is not attainable for t-PA or other PAs. Phase I trials with plasmin in hemodialysis graft occlusion and peripheral arterial occlusion have thus far confirmed the hemostatic safety of plasmin.