PP:20| Volume 35, SUPPLEMENT 1, S36, October 2021



      Aprotinin is a broad-acting serine protease inhibitor that has been clinically used to prevent blood loss during major surgical procedures including cardiac surgery and liver transplantation. The effect of aprotinin in reducing perioperative blood loss is generally assumed to be related to its antifibrinolytic effect. Aprotinin is a direct inhibitor of plasmin, but also inhibits FXIIa-dependent activation of fibrinolysis by inhibiting kallikrein which activates factor XII in the contact pathway. By inhibition of kallikrein, aprotinin also inhibits activation of coagulation via the contact pathway. It has also been shown that aprotinin inhibits platelet activation, although reports in the literature have been conflicting with some reporting that aprotinin inhibits platelet activation by various agonists, whereas others report selective inhibition of platelet activation by thrombin (1-3). Anticoagulant effects of aprotinin, including inhibition of the TF-VIIa complex (4) and of thrombin (3) have been described as have procoagulant effects, notably inhibition of the anticoagulant activated protein C (5).


      Here we assessed effects of aprotinin on various hemostatic pathways in vitro, and compared effects to tranexamic acid (TXA), which is an antifibrinolytic but not a serine protease inhibitor. We used plasma-based clot lysis assays, clotting assays in whole blood, plasma, and using purified proteins, and platelet activation assays to which aprotinin or TXA were added in pharmacological concentrations.


      Aprotinin and TXA dose-dependently inhibited fibrinolysis in plasma. Aprotinin inhibited clot formation and thrombin generation initiated via the intrinsic pathway, but had no effect on reactions initiated by tissue factor or FXIa. However, in the presence of thrombomodulin, which is an activator of the protein C pathway, aprotinin enhanced thrombin generation in reactions started by tissue factor or FXIa. This procoagulant effect of aprotinin relates to its inhibitory activity towards activated protein C. TXA had no effect on coagulation. Aprotinin did not inhibit thrombin, only weakly inhibited the TF-VIIa complex and had no effect on platelet activation and aggregation by various agonists including thrombin. Aprotinin and TXA inhibited plasmin-induced platelet activation.


      Pharmacologically relevant concentrations of aprotinin inhibit coagulation initiated via the intrinsic pathway, which is in line with the observation that aprotinin decreases markers of coagulation activation in vivo (6-7). The antifibrinolytic activity of aprotinin likely explains the prohemostatic effects of aprotinin during surgical procedures. The anticoagulant properties may be beneficial during surgical procedures in which pathological activation of the intrinsic pathway, for example by extracorporeal circuits, occurs. Aprotinin is not a direct thrombin inhibitor or an inhibitor of platelet activation. The clinically reported preservation of platelet count and function by aprotinin (8-9) is likely explained by inhibition of plasmin-induced platelet activation and inhibition of platelet activation by thrombin generated via the intrinsic pathway of coagulation.
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