Paradoxical enhancement of the intrinsic pathway-induced thrombin generation in human plasma by melagatran, a direct thrombin inhibitor, but not edoxaban, a direct factor Xa inhibitor, or heparin.

Introduction: The blood coagulation cascade consists of two pathways, the tissue factor (TF)-dependent extrinsic pathway and the contact factor-dependent intrinsic pathway. We have previously shown that a direct thrombin inhibitor, melagatran, paradoxically increased TF-induced thrombin generation (TG) in thrombomodulin (TM)-containing human plasma in vitro. However, the effect of melagatran on the intrinsic pathway-induced TG remains to be investigated. We investigated whether melagatran enhances the intrinsic pathway-induced TG.

Methods And Results: TG was induced by kaolin in human plasma and assayed by the calibrated automated thrombography method. Melagatran at 150 and 300 nM significantly increased the peak level (2.40-fold) and endogenous thrombin potential of TG in normal plasma in the presence of 5 nM TM. In the absence of TM or in protein C (PC)-deficient plasma, the paradoxical enhancement of TG by melagatran disappeared. A direct FXa inhibitor, edoxaban, and an antithrombin-dependent anticoagulant, unfractionated heparin (UFH), did not increase, but simply decreased TG under each condition in a concentration dependent manner.

Conclusion: Melagatran enhanced the intrinsic pathway-induced TG as well as the extrinsic pathway-induced TG in human plasma under the condition where PC system is active. In contrast, edoxaban and UFH showed concentration-dependent decrease of TG, but no enhancement. These results indicated that edoxaban and UFH may have a low risk of the paradoxical enhancement of TG by both the extrinsic and intrinsic pathway activation.