title: 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.
abstract: BACKGROUND
  Tissue 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.
  
  
  METHODS
  Human 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 0.9μM 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.
  
  
  RESULTS
  Edoxaban inhibited tissue factor-induced platelet aggregation in a concentration-dependent manner with the IC50 values of 150 and 110nM for Dade Innovin and RecombiPlasTin-induced platelet aggregation, respectively. At 1μM, edoxaban completely inhibited the aggregation. Fondaparinux inhibited RecombiPlasTin-induced aggregation with the IC50 of 9.3μM, but did not show complete inhibition up to 30μM and had no effect on Dade Innovin-induced aggregation. Edoxaban inhibited both free and clot-bound FXa with the IC50 of 2.3 and 8.2nM, respectively. Fondaparinux inhibited free FXa (IC50 5.4nM), but 40-times higher concentration were required to inhibit clot-bound FXa (IC50 217nM).
  
  
  CONCLUSIONS
  Edoxaban, 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.
authors.affiliation: Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Honda
authors.affiliation: Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Kamisato
authors.affiliation: Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan. Electronic address: morishima.yoshiyuki.t4@daiichisankyo.co.jp.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morishima
mesh_terms: D000991:Antithrombins / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors / Q000494:pharmacology*; D005260:Female; D000077425:Fondaparinux; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010979:Platelet Function Tests; D011134:Polysaccharides / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: D000991:Antithrombins; D065427:Factor Xa Inhibitors; D010975:Platelet Aggregation Inhibitors; D011134:Polysaccharides; D011725:Pyridines; D013844:Thiazoles; D013925:Thromboplastin; D015951:Factor Xa; D000077425:Fondaparinux; C552171:edoxaban
keywords: Antithrombin-dependent factor Xa inhibitor; Clot-bound factor Xa; Direct factor Xa inhibitor; Tissue factor-induced platelet aggregation