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Summary   Background  Increased hypercoagulability has been reported with low doses of direct thrombin inhibitors but not with direct factor Xa inhibitors.    Objectives  To compare the effects of rivaroxaban with those of melagatran and dabigatran on thrombin generation ( TG ) and tissue factor‐induced hypercoagulability and to explore the possible involvement of the thrombin–thrombomodulin/activated protein C system.    Methods  In normal human plasma and in protein C‐deficient plasma,  TG  was investigated  in vitro  in the presence and absence of recombinant human soluble thrombomodulin (rhs‐ TM ).  TG  was determined by calibrated automated thrombography and an  ELISA  for prothrombin fragments 1+2 (F 1+2 ). In an  in vivo  rat model, hypercoagulability was induced by tissue factor; levels of thrombin–antithrombin ( TAT ) and fibrinogen and the platelet count were determined.    Results  Rivaroxaban inhibited TG in a concentration‐dependent manner. In the absence of rhs‐TM, melagatran and dabigatran also inhibited TG concentration dependently. However, in the presence of rhs‐TM, lower concentrations of melagatran (119–474 nmol L –1 ) and dabigatran (68–545 nmol L −1 ) enhanced endogenous thrombin potential, peak TG, and F 1+2  formation in normal plasma but not in protein C‐deficient plasma.  In vivo , rivaroxaban dose‐dependently inhibited TAT generation, whereas melagatran showed a paradoxical effect, with an increase in TAT and a small decrease in fibrinogen and platelet count at lower doses.    Conclusion  Low concentrations of the direct thrombin inhibitors melagatran and dabigatran enhanced  TG  and hypercoagulability, possibly via inhibition of the protein C system. In contrast, rivaroxaban reduced  TG  and hypercoagulability under all conditions studied, suggesting that it does not suppress this negative‐feedback system.

journal of thrombosis and haemostasis

Direct thrombin inhibitors, but not the direct factor Xa inhibitor rivaroxaban, increase tissue factor‐induced hypercoagulability  in vitro  and  in vivo