Abstract 15792: Effect of Dabigatran and Rivaroxiban on Thrombomodulin Mediated Activation of Protein C and Thrombin Activated Fibrinolysis Inhibitor (TAFI)
Introduction: The new oral anticoagulant agents Dabigatran and Rivaroxiban target thrombin and factor Xa to mediate their anticoagulant effects perspectively. This study was designed to investigate the effects of active form Dabigatran and Rivaroxiban on the activation process of protein C and TAFI by thrombin-thrombomodulin complex. Materials and
Methods: The active form of Dabigatran was synthesized. While Rivaroxiban was extracted from commercially available tablets. Both agents were dissolved in appropriate solution matrices at a stock concentration of 100ug/ml. Thrombin-thrombomodulin mediated activation of protein C and TAFI were measured using specific chromogenic substrate based methods at a concentration of 0-10ug/ml in different matrices. The activation of Protein C and TAFI was laso measured using mass spectrometric and immunoblotting methods.
Results: Dabigatran produced a strong inhibition of the generation of both the activated protein C and TAFI (IC50<1.0ug/ml) whereas Rivaroxiban did not produce any inhibition of the activation of either of these proteases. Dabigatran also inhibited the amidolytic actions of thrombin-thrombomodulin complex whereas Rivaroxiban did not produce any effect. Neither Dabigatran nor Rivaroxiban produced a direct inhibition of activated protein C or TAFI at concentrations of up to 10ug/ml. Mass spectrometric and immunoblotting methods showed that Dabigatran blocked the activation of both TAFI and Activation C by thrombin-thrombomodulin complex.
Conclusions: The persistant inhibition of thrombin and its regulatory effects by Dabigatran may differentiate its pharmacologic profile from Rivaroxiban. Since thrombin plays several regulatory functions, its persistent inhibition may compromise hemostatic regulation. The observed adverse events such as the reported myocardial infarction signal may be related to the indiscriminate inhibition of thrombin.
- © 2012 by American Heart Association, Inc.