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Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity.
- Source :
-
Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2018 Nov; Vol. 16 (11), pp. 2276-2288. Date of Electronic Publication: 2018 Oct 09. - Publication Year :
- 2018
-
Abstract
- 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.<br />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 FXaα 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.<br />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.<br />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.<br />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.<br /> (© 2018 International Society on Thrombosis and Haemostasis.)
- Subjects :
- Administration, Oral
Anticoagulants chemistry
Blood Coagulation drug effects
Catalytic Domain
Cross-Linking Reagents chemistry
Factor Xa Inhibitors pharmacology
Fibrin chemistry
Fibrinolysin chemistry
Fibrinolysis
Humans
Phospholipids chemistry
Thrombin chemistry
Thrombolytic Therapy
Thrombosis
Tissue Plasminogen Activator chemistry
Factor Xa chemistry
Pyrazoles pharmacology
Pyridones pharmacology
Rivaroxaban pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7836
- Volume :
- 16
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of thrombosis and haemostasis : JTH
- Publication Type :
- Academic Journal
- Accession number :
- 30176116
- Full Text :
- https://doi.org/10.1111/jth.14281