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Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity
Author(s) -
Carter R. L. R.,
Talbot K.,
Hur W. S.,
Meixner S. C.,
Van Der Gugten J. G.,
Holmes D. T.,
Côté H. C. F.,
Kastrup C. J.,
Smith T. W.,
Lee A. Y. Y.,
Pryzdial E. L. G.
Publication year - 2018
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14281
Subject(s) - plasmin , fibrinolysis , rivaroxaban , chemistry , apixaban , tissue plasminogen activator , plasminogen activator , fibrinolytic agent , biochemistry , pharmacology , medicine , enzyme , warfarin , atrial fibrillation
Essentials Activated clotting factor X (FXa) acquires fibrinolytic cofactor function after cleavage by plasmin. FXa‐mediated plasma fibrinolysis is enabled by active site modification blocking a second cleavage. FXa‐directed oral anticoagulants (DOACs) alter FXa cleavage by plasmin. DOACs enhance FX‐dependent fibrinolysis and plasmin generation by tissue plasminogen activator.Background When bound to an anionic phospholipid‐containing membrane, activated clotting factor X ( FX a) is sequentially cleaved by plasmin from the intact form, FX aα, to FX aβ and then to Xa33/13. Tissue‐type plasminogen activator (t‐ PA ) produces plasmin and is the initiator of fibrinolysis. Both FX aβ 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 FX aα active site prevents Xa33/13 formation by plasmin, and the persistent FX aβ enhances plasma fibrinolysis. As the direct oral anticoagulants ( DOAC s) rivaroxaban and apixaban bind to the FX a active site, we hypothesized that they similarly modulate FX a fibrinolytic function. Methods DOAC effects on fibrinolysis and the t‐ PA cofactor function of FX a 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 FX aβ. In normal pooled plasma, the addition of rivaroxaban or apixaban also shortened fibrinolysis times. This was related to the cleavage product, FX aβ, which increased plasmin production by t‐ PA . It was confirmed that these results were not caused by DOAC s 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 DOAC s on FX a in addition to their well‐documented anticoagulant role. By enabling the t‐ PA cofactor function of FX aβ in plasma, DOAC s also enhance fibrinolysis. This effect may broaden their therapeutic indications.