STUDIES ON THE MECHANISMS OF ACTION OF APROTININ AND TRANEXAMIC ACID AS PLASMIN INHIBITORS AND ANTIFIBRINOLYTIC AGENTS

Both aprotinin and tranexamic acid are effective inhibitors of fibrino lysis in vitro and in vivo and both agents can act as plasmin inhibito rs in purified systems, although there is some debate on their exact m echanism of action in vivo. The studies reported here using an in vitr o clot lysis system designed to provide precise inhibition constants s how that aprotinin remains a very potent inhibitor of plasmin even in the presence of fibrin with K-i = 2 nM. Plasmin-aprotinin interactions in solution are not affected by a number of kringle binding ligands, aminohexanoic acid, tranexamic acid or CNBr-fibrinogen fragments with K-i = 0.4 nM. The difference between these two K-i values is explained by competition for the plasmin active site between substrate (fibrin) and inhibitor (aprotinin). Inhibition of fibrinolysis by tranexamic a cid is not readily analysed by a simple inhibition model which may be due to multiple overlapping ligand-kringle interactions or tranexamic- fibrin interactions. Experiments using combinations of aprotinin and t ranexamic acid in the clot lysis system confirm the complementary natu re of inhibitory mechanisms and suggest a slight synergism. These resu lts support the idea that aprotinin inhibition of plasmin is a primary mode of action in vivo, and suggest that combination therapy of aprot inin with tranexamic acid might be more effective than either inhibito r alone.