• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • During the activation of the coagulation cascade


    During the activation of the coagulation cascade, factor Xa (FXa) forms a complex with activated factor V and calcium Ellagic acid on the surface of platelet membrane (so called prothrombinase complex) and converts prothrombin to thrombin [5], [6]. Selective FXa inhibitors do not directly inhibit platelet aggregation mediated by thrombin [7], [8], but by inhibiting FXa, FXa inhibitors are expected to suppress thrombin generation and has the potential to decrease indirectly thrombin-mediated platelet aggregation. Actually direct FXa inhibitors, apixaban and rivaroxaban, inhibit tissue factor-induced platelet aggregation in vitro [9], [10]. In contrast, it is reported that FXa incorporated into the prothrombinase complex is highly protected from inhibition by fondaparinux, an antithrombin-dependent FXa inhibitor [11], [12]. This raised a possibility that the inhibitory effect of fondaparinux on tissue factor-induced platelet aggregation would be limited. FXa binds to clots during clot formation and contributes to the procoagulant activity of thrombi to grow thrombus [13], [14], [15], [16], [17]. When associated with thrombi, FXa is resistant to inhibition by antithrombin-dependent anticoagulants [13]. Therefore, the inhibition of clot-associated FXa by direct (antithrombin-independent) FXa inhibitors seems more effective than by indirect (antithrombin-dependent) FXa inhibitors for the prevention of thrombosis. In our previous studies, the antithrombotic effects of a direct FXa inhibitor, edoxaban, and an antithrombin-dependent FXa inhibitor, fondaparinux, were compared in rat arterial thrombosis models [18]. Edoxaban inhibits arterial thrombosis at similar doses as in venous models. However, fondaparinux exerts an only partial antithrombotic effect at more than 60-times higher doses in arterial thrombosis models compared with venous models [18].
    Materials and methods
    Discussion Tissue factor-induced platelet aggregation and FXa bound to clot contribute to the formation and growth of thrombus [9], [10], [13], [14], [15], [16], [17]. In the present study, we determined the effects of edoxaban, a direct FXa inhibitor, on human platelet aggregation induced by tissue factor and prothrombinase activity of clot-bound FXa in vitro and compared the effects with that of fondaparinux, an antithrombin- dependent FXa inhibitor. Our study demonstrated that edoxaban inhibited tissue factor (Dade Innovin and RecombiPlasTin)-induced platelet aggregation in a concentration-dependent manner (IC50=0.15 and 0.11μM, respectively) and complete inhibition was observed at 1μM, as well as apixaban and rivaroxaban [9], [10]. Since the peak plasma concentration of edoxaban after oral administration of the approved dose 60mg is approximately 0.5μM [19], the inhibition of tissue factor-induced platelet aggregation would be expected to occur in clinical settings. In contrast, fondaparinux had no effect on Dade Innovin-induced platelet aggregation up to 30μM and only partially inhibited RecombiPlasTin- induced platelet aggregation with IC50 of 9.3μM. However, the effect of fondaparinux would not be expected in patients because the peak plasma concentration at a therapeutic dose (2.5mg, s.c.) is approximately 0.2μM [20], 47-times lower than the IC50. The reason of the different effects of fondaparinux on Dade Innovin- and RecombiPlasTin -induced platelet aggregation is unclear. It is reported that the responses of prothrombin time prolongation by factor Xa inhibitors varies depending on tissue factor reagents used [21], [22]. Similar variation of response is likely to be observed particularly for fondaparinux in this study. The potent antiplatelet effect of edoxaban is likely to be indirect and via the reduction of thrombin generation by inhibiting FXa. This is evidenced by the following findings. First, edoxaban does not affect thrombin-induced platelet aggregation up to 1μM [7], indicating the lack of the direct inhibitory effect on thrombin activity at the concentration. Second, edoxaban suppresses tissue factor-induced thrombin generation in human PRP at the same concentrations as the present study [22]. Third, edoxaban has no effects on platelet aggregation induced by common platelet agonists, like ADP, collagen, or a thromboxane A2 receptor agonist up to 100μM [7].