Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity

Area of Science:

• Hemostasis and Thrombosis
• Pharmacology
• Biochemistry

Background:

• Activated Factor X (FXa) gains fibrinolytic cofactor activity upon plasmin cleavage, forming FXaβ and Xa33/13, which enhance tissue-type plasminogen activator (t-PA)-mediated plasminogen activation.
• FXa's t-PA cofactor function is limited in plasma due to rapid loss of Xa33/13 activity, but FXa active site modification stabilizes the FXaβ form, enhancing fibrinolysis.
• Direct oral anticoagulants (DOACs) target the FXa active site, prompting investigation into their potential to modulate FXa's fibrinolytic properties.

Purpose of the Study:

• To investigate the impact of direct oral anticoagulants (DOACs) on the fibrinolytic function of activated Factor X (FXa).
• To determine if DOACs alter FXa cleavage by plasmin and influence FXa's cofactor activity in fibrinolysis.
• To explore potential new therapeutic implications of DOACs based on their effects on fibrinolysis.

Main Methods:

• Studied DOAC effects on fibrinolysis and FXa's t-PA cofactor function using patient plasma, normal pooled plasma, and purified protein systems.
• Employed light scattering assays, chromogenic assays, and immunoblots to quantify fibrinolysis times and analyze FXa cleavage products.
• Verified that observed effects were not due to DOAC interference with fibrin crosslinking, clot structure, or thrombin-activatable fibrinolysis inhibitor (TAFI) activation.

Main Results:

• Patients on rivaroxaban exhibited enhanced plasma fibrinolysis, correlating with increased levels of the FXaβ cleavage product.
• In vitro addition of rivaroxaban or apixaban to normal plasma shortened fibrinolysis times by increasing FXaβ and boosting t-PA-mediated plasmin production.
• Confirmed that DOACs do not influence FXIII-mediated fibrin crosslinking, clot ultrastructure, or TAFI activation, isolating the effect to FXa-mediated fibrinolysis.

Conclusions:

• Direct oral anticoagulants (DOACs) possess a previously unrecognized function of enhancing fibrinolysis by stabilizing the FXaβ form, thereby enabling its t-PA cofactor activity in plasma.
• This FXa-modulating effect of DOACs adds to their known anticoagulant properties, suggesting a dual mechanism of action.
• The enhanced fibrinolytic activity induced by DOACs may broaden their therapeutic applications and warrants further investigation.