Edoxaban, a direct factor Xa inhibitor, suppresses tissue-factor induced human platelet aggregation and clot-bound factor Xa in vitro: Comparison with an antithrombin-dependent factor Xa inhibitor, fondaparinux

- A direct Xa inhibitor edoxaban inhibited tissue factor-induced platelet aggregation.
- The effect of edoxaban was more potent than an indirect Xa inhibitor fondaparinux.
- Edoxaban inhibited both free and clot-bound Xa with similar IC50 values.
- IC50 of fondaparinux for clot-bound Xa was 40-times greater than that of free Xa.

IntroductionTissue factor-induced platelet aggregation and factor Xa (FXa) activity bound to clot contribute to the formation and growth of thrombus. The effects of edoxaban, a direct FXa inhibitor, on these responses were determined and compared with that of fondaparinux, an antithrombin-dependent (indirect) FXa inhibitor.Material and methodsHuman platelet aggregation was induced by human tissue factor (Dade Innovin or RecombiPlasTin) in platelet-rich plasma spiked with edoxaban or fondaparinux. Clot formed from human whole blood was incubated with 0.9 μM prothrombin in the absence or presence of FXa inhibitors. As the index of FXa activity, the amount of prothrombin fragment F1 + 2 was measured with an ELISA. Free FXa activity was measured using human FXa and its chromogenic substrate S-2222.ResultsEdoxaban inhibited tissue factor-induced platelet aggregation in a concentration-dependent manner with the IC50 values of 150 and 110 nM for Dade Innovin and RecombiPlasTin-induced platelet aggregation, respectively. At 1 μM, edoxaban completely inhibited the aggregation. Fondaparinux inhibited RecombiPlasTin-induced aggregation with the IC50 of 9.3 μM, but did not show complete inhibition up to 30 μM and had no effect on Dade Innovin-induced aggregation. Edoxaban inhibited both free and clot-bound FXa with the IC50 of 2.3 and 8.2 nM, respectively. Fondaparinux inhibited free FXa (IC50 5.4 nM), but 40-times higher concentration were required to inhibit clot-bound FXa (IC50 217 nM).ConclusionsEdoxaban, a direct FXa inhibitor, was a more potent inhibitor of tissue factor-induced platelet aggregation and clot-bound FXa than fondaparinux, an indirect FXa inhibitor.