Aprotinin: Antithrombotic and Vasoactive Mechanisms of Action

Abstract

Aprotinin is a serine protease inhibitor that has been in clinical use since the late 1980s to reduce blood loss in patients undergoing cardiopulmonary bypass surgery. Its hemostatic mechanism of action is mediated predominantly through inhibition of plasmin, thus exerting a net antifibrinolytic effect. Compared to other antifibrinolytics, however, aprotinin provides an additional patient benefit at the level of improved platelet function and diminished inflammatory response to bypass. Recent work on platelets has identified a cell-associated target for aprotinin: the thrombin-receptor, protease-activated receptor 1. Selective blockade of the protease-activated receptor 1 limits thrombin-induced activation and consequent “exhaustion” of platelets in the bypass circuit, while maintaining the hemostatic activity of platelets in the pericardial cavity in response to nonproteolytic agonists, such as collagen, adenosine diphosphate and epinephrine. While no specific cellular receptors have as yet been identified to explain the antiinflammatory and vasoactive properties of aprotinin, awareness is growing that serine protease-sensitive receptors belonging to the protease-activated receptor family (1-4) may represent important aprotinin targets, since these receptors are expressed by all major cells of the vasculature and act as sensors of the coagulation, inflammatory and vasoactive pathways activated by major surgery or trauma. The possibility is discussed that endothelial protease-activated receptor 2, whose natural ligands are trypsin, tryptase and the ternary tissue factor-Vlla-Xa complex, may be targeted by aprotinin.