Faculty Collaboration Database

Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity. J Thromb Haemost 2018 Nov;16(11):2276-2288

Date

09/04/2018

Pubmed ID

30176116

DOI

10.1111/jth.14281

Scopus ID

2-s2.0-85054559930 (requires institutional sign-in at Scopus site)   38 Citations

Abstract

UNLABELLED: 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 (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.

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.

Author List

Carter RLR, Talbot K, Hur WS, Meixner SC, Van Der Gugten JG, Holmes DT, Côté HCF, Kastrup CJ, Smith TW, Lee AYY, Pryzdial ELG

Author

Christian Kastrup PhD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Administration, Oral
Anticoagulants
Blood Coagulation
Catalytic Domain
Cross-Linking Reagents
Factor Xa
Factor Xa Inhibitors
Fibrin
Fibrinolysin
Fibrinolysis
Humans
Phospholipids
Pyrazoles
Pyridones
Rivaroxaban
Thrombin
Thrombolytic Therapy
Thrombosis
Tissue Plasminogen Activator