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

Abstract

BackgroundIncreased hypercoagulability has been reported with low doses of direct thrombin inhibitors but not with direct factor Xa inhibitors.ObjectivesTo 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.MethodsIn 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 (F1+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.ResultsRivaroxaban 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 F1+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.ConclusionLow 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.

Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

“…The normalization of TG parameter values with those of reference plasmas did not affect results (not shown) . Our ex vivo findings reinforce those obtained in vitro using normal plasma spiked with rivaroxaban and 1‐picomolar to 20‐picomolar TF concentrations . Interestingly, we obtained PD mirror‐inverted time profiles to PK time profiles for both temporal parameters (lag time and time to peak), markedly for peak height and to a lesser extent for ETP, with peak height consistently more affected than ETP in agreement with previous findings .…”

From laboratory to clinical practice: Dabigatran effects on thrombin generation and coagulation in patient samples

“…This has been speculated to erroneously elevate ETP and peak values in the CAT® assay at thrombin inhibitor concentrations up to 200 nM (94 ng/ml) [35]. Yet, in a recent study using spiked plasma samples, prothrombin fragments F1 + 2 were also elevated [25]. In our study, ETP and peak values were elevated with increasing Dabi concentration ( Fig.…”

“…Previous reports on this have been inconsistent. Dabi has been shown to exert hypercoagulable effects at therapeutic concentrations [25][26][27], but some contradictory reports exist [19,23,24,28]. DTIs have been reported to inhibit thrombomodulin-mediated activation of protein C, and fibrinolysis at high concentrations of thrombomodulin [25,29,30].…”

Acenocoumarol vs. low-dose dabigatran in real-world patients discharged after ischemic stroke

“…Several explanations have been proposed for the potential association between dabigatran and MI risk. Preclinical and clinical studies suggest that direct thrombin inhibitors might paradoxically enhance thrombin generation and might promote platelet activation [31,32]. On the contrary, warfarin reduces the risk of MI and it is therefore possible that dabigatran is less protective than warfarin against MI [33][34][35].…”