Lisman Ton, Adelmeijer Jelle, Huskens Dana, Meijers Joost C M
Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Synapse Research Institute, Maastricht, The Netherlands.
TH Open. 2021 Aug 31;5(3):e363-e375. doi: 10.1055/s-0041-1735154. eCollection 2021 Jul.
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 prohemostatic properties of aprotinin likely are related to its antifibrinolytic effects, but other mechanisms including preservation of platelet function have been proposed. 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. However, in the presence of thrombomodulin, aprotinin enhanced thrombin generation in reactions started by tissue factor. 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. 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.
抑肽酶是一种具有广泛作用的丝氨酸蛋白酶抑制剂，临床上已用于预防包括心脏手术和肝移植在内的重大外科手术中的失血。抑肽酶的促止血特性可能与其抗纤维蛋白溶解作用有关，但也有人提出了其他机制，包括维持血小板功能。 在这里，我们评估了抑肽酶在体外对各种止血途径的影响，并将其与氨甲环酸（TXA）的作用进行了比较，氨甲环酸是一种抗纤维蛋白溶解剂，但不是丝氨酸蛋白酶抑制剂。 我们使用了基于血浆的凝块溶解试验、全血、血浆中的凝血试验以及使用纯化蛋白的试验，以及添加了药理浓度的抑肽酶或氨甲环酸的血小板活化试验。 抑肽酶和氨甲环酸剂量依赖性地抑制血浆中的纤维蛋白溶解。抑肽酶抑制通过内源性途径启动的凝块形成和凝血酶生成，但对由组织因子启动的反应没有影响。然而，在存在血栓调节蛋白的情况下，抑肽酶增强了由组织因子启动的反应中的凝血酶生成。氨甲环酸对凝血没有影响。抑肽酶不抑制凝血酶，仅微弱抑制TF-VIIa复合物，对包括凝血酶在内的各种激动剂引起的血小板活化和聚集没有影响。抑肽酶和氨甲环酸抑制纤溶酶诱导的血小板活化。 药理相关浓度的抑肽酶抑制通过内源性途径启动的凝血。抑肽酶的抗纤维蛋白溶解活性可能解释了其在外科手术期间的促止血作用。在例如体外循环等内源性途径发生病理激活的外科手术中，其抗凝特性可能是有益的。
