Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

Toshio Fukuda; Yuko Honda; Chikako Kamisato; Yoshiyuki Morishima; Toshiro Shibano

doi:10.1160/TH11-09-0668

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2012; 107(02): 253-259
DOI: 10.1160/TH11-09-0668

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

Toshio Fukuda

¹Daiichi Sankyo Co., Ltd. – Biological Research Laboratories, Tokyo, Japan

,

Yuko Honda

¹Daiichi Sankyo Co., Ltd. – Biological Research Laboratories, Tokyo, Japan

,

Chikako Kamisato

¹Daiichi Sankyo Co., Ltd. – Biological Research Laboratories, Tokyo, Japan

,

Yoshiyuki Morishima

¹Daiichi Sankyo Co., Ltd. – Biological Research Laboratories, Tokyo, Japan

,

Toshiro Shibano

¹Daiichi Sankyo Co., Ltd. – Biological Research Laboratories, Tokyo, Japan

› Institutsangaben

Abstract

Summary

Edoxaban, an oral, direct factor Xa inhibitor, has a similar or low incidence of bleeding events compared with other anticoagulants in clinical trials. Therefore, agents to reverse the anticoagulant effects of edoxaban could be desirable in emergency situations. In this study, the reversal effects of haemostatic agents were determined on prothrombin time (PT) prolongation in vitro and bleeding time prolongation in vivo by edoxaban. PT using human plasma was measured in the presence of edoxaban at therapeutic and excess concentrations with the haemostatic agents, prothrombin complex concentrate (PPSB-HT), activated prothrombin complex concentrate (Feiba), and recombinant factor VIIa (rFVIIa). In rats, rFVIIa and Feiba was given during intensive anticoagulation with edoxaban. The haemostatic effect was evaluated in a model of planta template bleeding and a potential prothrombotic effect was evaluated in a venous thrombosis model. PPSB-HT, Feiba, and rFVIIa concentration-dependently shortened PT prolonged by edoxaban. Among these, rFVIIa and Feiba showed potent activities in reversing the PT prolongation by edoxaban. rFVIIa (1 and 3 mg/kg, i.v.) and Feiba (100 U/kg, i.v.) significantly reversed edoxaban (1 mg/kg/h)-induced prolongation of bleeding time in rats. In a rat venous thrombosis model, no potentiation of thrombus formation was observed when the highest dose (3 mg/kg) of rFVIIa was added to edoxaban (0.3 and 1 mg/kg/h) compared with the control. The present study indicated that rFVIIa, Feiba, and PPSB-HT have the potential to be reversal agents for edoxaban.

Keywords

Edoxaban - factor Xa inhibitor - anticoagulation - haemostatic agent - reversal

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