Abstract 34: Impact of Thrombomodulin and Thrombin-activatable Fibrinolysis Inhibitor on the Anti-coagulant and Pro-fibrinolytic Effects of Rivaroxaban

Rivaroxaban is a novel oral anticoagulant that directly inhibits factor Xa and has recently been implemented as a favorable alternative to warfarin in anticoagulation therapy. Rivaroxaban effectively reduces the generation of thrombin, which plays a major role in the activation of thrombin activatable fibrinolysis inhibitor (TAFI) to TAFIa. Activated TAFI functions by downregulating fibrinolysis, and this effect is highly dependent on the availability of thrombomodulin (TM), as the thrombin-TM complex activates TAFI with a 1250-fold greater efficiency than thrombin alone. Additionally, a naturally occurring SNP in the gene encoding TAFI gives rise to a Thr325Ile polymorphism that increases the stability and antifibrinolytic potential of TAFIa. Since inhibition of thrombin generation could lead to decreased TAFIa formation, we hypothesized that these parameters could influence the pharmacodynamics and pharmacogenomics of rivaroxaban. To assess this, effects on coagulation and fibrinolysis were measured using an in vitro plasma clot lysis assay. Rivaroxaban and TM were titrated into TAFI-deficient plasma in the presence or absence of 10 nM wild-type or T325I recombinant TAFI. With increasing concentrations of rivaroxaban, clot formation latency was accordingly increased. TM further delayed clot formation, and this effect was equal in the absence or presence of either TAFI variant. Rivaroxaban was also shown to decrease the rate of coagulation, which was decreased further at higher concentrations of TM. The presence of either TAFI variant also seemed to decrease clot formation rate at higher levels of rivaroxaban and TM. At all concentrations of TM, TAFI-dependent resistance to fibrinolysis was attenuated by rivaroxaban. The effect of rivaroxaban was, however, greater for wild-type TAFI than for the T325I variant. In conclusion, rivaroxaban exhibits TAFI-dependent profibrinolytic effects that are influenced by the levels of TM and the by intrinsic stability of TAFIa. TM also affected the dynamics of coagulation. These findings suggest a role for the anatomical location of a procoagulant stimulus and plasma TM-altering disease phenotypes in the pharmacodynamics and a role for the T325I polymorphism in the pharmacogenomics of rivaroxaban.