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Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity Carter, Rolinda Louise Raphaelle; Talbot, Kimberly K.; Hur, Woosuk Steve; Meixner, S. C.; van der Gugten, Jessica G.; Holmes, Daniel T.; Côté, Hélène C. F.; Kast Rup, C. J.; Lee, Agnes Y. Y.; Pryzdial, E. L. G

Abstract

Background: When bound to an anionic phospholipid-containing membrane, activated clotting factor X (FXa) is sequentially cleaved by plasmin from the intact form, FXaα, to FXaβ and then to Xa33/13. Tissue-type plasminogen activator (t-PA) produces plasmin and is the initiator of fibrinolysis. Both FXaβ and Xa33/13 enhance t-PA-mediated plasminogen activation. Although stable in experiments using purified proteins, Xa33/13 rapidly loses t-PA cofactor function in plasma. Bypassing this inhibition, covalent modification of the FXaβ active site prevents Xa33/13 formation by plasmin, and the persistent FXaβ enhances plasma fibrinolysis. As the direct oral anticoagulants (DOACs) rivaroxaban and apixaban bind to the FXa active site, we hypothesized that they similarly modulate FXa fibrinolytic function. Methods: DOAC effects on fibrinolysis and the t-PA cofactor function of FXa were studied in patient plasma, normal pooled plasma and purified protein experiments by the use of light scattering, chromogenic assays, and immunoblots. Results: The plasma of patients taking rivaroxaban showed enhanced fibrinolysis correlating with FXaβ. In normal pooled plasma, the addition of rivaroxaban or apixaban also shortened fibrinolysis times. This was related to the cleavage product, FXaβ, which increased plasmin production by t-PA. It was confirmed that these results were not caused by DOACs affecting activated FXIII-mediated fibrin crosslinking, clot ultrastructure and thrombin-activatable fibrinolysis inhibitor activation in plasma. Conclusion: The current study suggests a previously unknown effect of DOACs on FXa in addition to their well-documented anticoagulant role. By enabling the t-PA cofactor function of FXaβ in plasma, DOACs also enhance fibrinolysis. This effect may broaden their therapeutic indications.

Item Metadata

Title
Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity
Creator
Carter, Rolinda Louise Raphaelle; Talbot, Kimberly K.; Hur, Woosuk Steve; Meixner, S. C.; van der Gugten, Jessica G.; Holmes, Daniel T.; Côté, Hélène C. F.; Kast Rup, C. J.; Lee, Agnes Y. Y.; Pryzdial, E. L. G
Contributor
University of British Columbia. Centre for Blood Research; St. Paul's Hospital (Vancouver, B.C.)
Date Issued
2019-09-03
Description
Background: When bound to an anionic phospholipid-containing membrane, activated clotting factor X (FXa) is sequentially cleaved by plasmin from the intact form, FXaα, to FXaβ and then to Xa33/13. Tissue-type plasminogen activator (t-PA) produces plasmin and is the initiator of fibrinolysis. Both FXaβ and Xa33/13 enhance t-PA-mediated plasminogen activation. Although stable in experiments using purified proteins, Xa33/13 rapidly loses t-PA cofactor function in plasma. Bypassing this inhibition, covalent modification of the FXaβ active site prevents Xa33/13 formation by plasmin, and the persistent FXaβ enhances plasma fibrinolysis. As the direct oral anticoagulants (DOACs) rivaroxaban and apixaban bind to the FXa active site, we hypothesized that they similarly modulate FXa fibrinolytic function. Methods: DOAC effects on fibrinolysis and the t-PA cofactor function of FXa were studied in patient plasma, normal pooled plasma and purified protein experiments by the use of light scattering, chromogenic assays, and immunoblots. Results: The plasma of patients taking rivaroxaban showed enhanced fibrinolysis correlating with FXaβ. In normal pooled plasma, the addition of rivaroxaban or apixaban also shortened fibrinolysis times. This was related to the cleavage product, FXaβ, which increased plasmin production by t-PA. It was confirmed that these results were not caused by DOACs affecting activated FXIII-mediated fibrin crosslinking, clot ultrastructure and thrombin-activatable fibrinolysis inhibitor activation in plasma. Conclusion: The current study suggests a previously unknown effect of DOACs on FXa in addition to their well-documented anticoagulant role. By enabling the t-PA cofactor function of FXaβ in plasma, DOACs also enhance fibrinolysis. This effect may broaden their therapeutic indications.
Subject
Direct oral anticoagulant; Factor Xa; Fibrinolysis; Plasmin; Tissue-type plasminogen activator
Genre
Article; Postprint
Type
Text
Language
eng
Date Available
2019-09-26
Provider
Vancouver : University of British Columbia Library
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
DOI
10.14288/1.0381021
URI
http://hdl.handle.net/2429/71783
Affiliation
Medicine, Faculty of; Other UBC; Non UBC; Biochemistry and Molecular Biology, Department of; Medicine, Department of; Pathology and Laboratory Medicine, Department of
Citation
Carter RLR, Talbot K, Hur WS, Meixner SC, Van Der Gugten JG, Holmes DT, Côté HCF, Kastrup CJ, Smith TW, Lee AYY, Pryzdial ELG. "Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity". J Thromb Haemost 2018; 16: 2276–88.
Publisher DOI
10.1111/jth.14281
Peer Review Status
Unreviewed
Scholarly Level
Faculty; Researcher
Rights URI
http://creativecommons.org/licenses/by-nc-nd/4.0/
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Attribution-NonCommercial-NoDerivatives 4.0 International