Download PDF
CC BY 4.0 · TH Open 2021; 05(03): e363-e375
DOI: 10.1055/s-0041-1735154
Original Article

Aprotinin Inhibits Thrombin Generation by Inhibition of the Intrinsic Pathway, but is not a Direct Thrombin Inhibitor

Ton Lisman
1   Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
,
Jelle Adelmeijer
1   Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
,
Dana Huskens
2   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Synapse Research Institute, Maastricht, The Netherlands
,
Joost C. M. Meijers
3   Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands
4   Department of Experimental Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
› Author Affiliations Funding This study was sponsored in part by an unrestricted educational grant of Nordic Pharma to TL. In addition, this collaboration project is co-financed by the Ministry of Economic Affairs and Climate Policy of the Netherlands by means of the PPP-allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Background 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.

Aim 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.

Methods 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.

Results 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.

Conclusion 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.

Keywords

fibrinolysis - aprotinin - tranexamic acid - thrombin - platelets

Author Contributions

TL: Designed the study, supervised experimental work, analyzed and interpreted data, wrote the manuscript; JA: Performed, analyzed and interpreted experiments, revised the manuscript; DH: Performed, analyzed and interpreted experiments, revised the manuscript; JCMM: Designed the study, interpreted data, revised the manuscript. All authors approved the final version of the manuscript.




Publication History

Received: 16 April 2021

Accepted: 29 June 2021

Article published online:
31 August 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany