Yuko Honda1, Chikako Kamisato1, Yoshiyuki Morishima2. 1. Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan. 2. Biological Research Laboratories, R & D Division, Daiichi Sankyo Co., Ltd, Tokyo, Japan. Electronic address: morishima.yoshiyuki.t4@daiichisankyo.co.jp.
Abstract
INTRODUCTION: 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. MATERIAL AND 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.
INTRODUCTION: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. MATERIAL AND METHODS:Humanplatelet aggregation was induced by humantissue 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 humanFXa 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: Francesco Franchi; Fabiana Rollini; Gabriel Faz; Jose Ramon Rivas; Andrea Rivas; Malhar Agarwal; Maryuri Briceno; Mustafa Wali; Ahmed Nawaz; Gabriel Silva; Zubair Shaikh; Naji Maaliki; Kerolos Fahmi; Latonya Been; Andres M Pineda; Siva Suryadevara; Daniel Soffer; Martin M Zenni; Usman Baber; Roxana Mehran; Lisa K Jennings; Theodore A Bass; Dominick J Angiolillo Journal: J Am Heart Assoc Date: 2020-04-20 Impact factor: 5.501
Authors: Christina Christersson; Lars Wallentin; Ulrika Andersson; John H Alexander; Marco Alings; Raffaele De Caterina; Bernard J Gersh; Christopher B Granger; Sigrun Halvorsen; Michael Hanna; Kurt Huber; Elaine M Hylek; Renato D Lopes; Byung-Hee Oh; Agneta Siegbahn Journal: Heart Date: 2018-09-12 Impact factor: 5.994