Minimally modified human blood coagulation factor X to bypass direct factor Xa inhibitors.

Autor:	Schreuder M; Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands., Jourdi G; Assistance publique - Hôpitaux de Paris (AH-HP) Centre, Service d'hématologie biologique, Hôpital Cochin, Paris, France; Innovative Therapies in Haemostasis, Institut national de la santé et de la recherche médicale (INSERM) U1140, Université Paris Cité, Paris, France; Assistance publique - Hôpitaux de Paris (AH-HP) Nord, Service d'hématologie biologique, Hôpital Lariboisière, Paris, France., Veizaj D; Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands., Poole DA 3rd; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Division of Molecular and Computational Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Cheung KL; Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands., Poenou G; Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands; Innovative Therapies in Haemostasis, Institut national de la santé et de la recherche médicale (INSERM) U1140, Université Paris Cité, Paris, France., Verhoef D; Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands; VarmX B.V., Leiden, The Netherlands., Thomassen S; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands., Janssen LFH; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Division of Molecular and Computational Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Stepanian A; Assistance publique - Hôpitaux de Paris (AH-HP) Nord, Service d'hématologie biologique, Hôpital Lariboisière, Paris, France; EA3518 Institut Universitaire d'Hématologie, Hôpital Saint Louis, Paris-Diderot, Paris, France., Hackeng TM; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands., Gaussem P; Innovative Therapies in Haemostasis, Institut national de la santé et de la recherche médicale (INSERM) U1140, Université Paris Cité, Paris, France; Assistance publique - Hôpitaux de Paris (AP-HP) Centre, Service d'hématologie biologique, Hôpital Européen Georges Pompidou, Paris, France., Reitsma PH; Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands; VarmX B.V., Leiden, The Netherlands., Geerke DP; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Division of Molecular and Computational Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Siguret V; Innovative Therapies in Haemostasis, Institut national de la santé et de la recherche médicale (INSERM) U1140, Université Paris Cité, Paris, France; Assistance publique - Hôpitaux de Paris (AH-HP) Nord, Service d'hématologie biologique, Hôpital Lariboisière, Paris, France., Bos MHA; Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: M.H.A.Bos@lumc.nl.
Jazyk:	angličtina
Zdroj:	Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2024 Aug; Vol. 22 (8), pp. 2211-2226. Date of Electronic Publication: 2024 May 09.
DOI:	10.1016/j.jtha.2024.04.022
Abstrakt:	Background: Direct oral factor (F)Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity. Objectives: The ability of FXa variants to bypass the direct oral FXa inhibitors was assessed. Methods: Human FXa variants were generated through substitution of phenylalanine 174 (F174) for either alanine, isoleucine, or serine. FXa variants were stably expressed in HEK293 cells and purified to homogeneity using ion-exchange chromatography. Results: F174-substituted human FX variants demonstrated efficacy in restoring thrombin generation in plasma containing direct FXa inhibitors (apixaban, rivaroxaban, edoxaban). Their ability to bypass the anticoagulant effects stems from a significantly reduced sensitivity for the direct FXa inhibitors due to a decrease in binding affinity determined using molecular dynamics simulations and free energy computation. Furthermore, F174 modification resulted in a partial loss of inhibition by tissue factor pathway inhibitor, enhancing the procoagulant effect of F174-substituted FX. Consequently, the F174A- and F174S-substituted FX variants effectively counteracted the effects of 2 widely used anticoagulants, apixaban and rivaroxaban, in plasma of atrial fibrillation and venous thromboembolism patients. Conclusion: These human FX variants have the potential to serve as a rescue reversal strategy to overcome the effect of direct FXa inhibitors in case of life-threatening bleeding events or emergency surgical interventions. Competing Interests: Declaration of competing interests P.H.R. and D. Verhoef own equity in VarmX B.V. T.M.H. and S.T. own equity in Coagulation Profile B.V. M.H.A.B. has received consultancy fees from VarmX B.V. (all fees to the institution) and is inventor on intellectual property related to this work. The remaining authors declare no competing financial interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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