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A direct oral anticoagulant edoxaban accelerated fibrinolysis via enhancement of plasmin generation in human plasma: dependent on thrombin-activatable fibrinolysis inhibitor

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Abstract

A direct oral anticoagulant, edoxaban, is as effective as vitamin K antagonists for the treatment of venous thromboembolism (VTE). However, the mechanism underlying the treatment effect on VTE remains to be determined. The aims of this study were to evaluate the effect of edoxaban on tissue plasminogen activator (t-PA)-induced clot lysis in human plasma and to determine the roles of plasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) in the profibrinolytic effect by edoxaban. Pooled human normal plasma or TAFI-deficient plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban or an activated TAFI inhibitor, potato tuber carboxypeptidase inhibitor (PCI). Clot was induced by adding tissue factor and phospholipids. Clot lysis time and plasma plasmin-α2 antiplasmin complex (PAP) concentration were determined. Clot structure was imaged with a scanning electron microscope. In normal plasma, edoxaban at clinically relevant concentrations (75, 150, and 300 ng/mL) and PCI significantly shortened clot lysis time. PCI increased PAP concentration and a correlation between PAP concentration and percent of clot lysis was observed. Edoxaban also dose-dependently elevated PAP concentration. In TAFI-deficient plasma, the effects of edoxaban and PCI on clot lysis and PAP concentration were markedly diminished as compared with normal plasma. Fibrin fibers were thinner in clots formed in the presence of edoxaban. In conclusion, edoxaban at clinically relevant concentrations accelerates t-PA-induced fibrinolysis via increasing plasmin generation in human plasma. The effects of edoxaban is mainly dependent on TAFI. The profibrinolytic effect of edoxaban might contribute to the efficacy for the treatment of VTE.

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Acknowledgements

The authors would like to acknowledge the technical support from Ms. Toshie Yoshino.

Funding

This study was supported by Daiichi Sankyo Co., Ltd.

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Authors and Affiliations

  1. Medical Science Department, Daiichi Sankyo Co., Ltd., 3-5-1 Nihonbashi Honcho, Chuo-ku, Tokyo, 103-8426, Japan

    Yoshiyuki Morishima

  2. End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan

    Yuko Honda

Authors
  1. Yoshiyuki Morishima
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  2. Yuko Honda
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Correspondence to Yoshiyuki Morishima.

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The authors are the employees of Daiichi Sankyo Co., Ltd.

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This was an in vitro investigation and did not involve any living subjects.

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Morishima, Y., Honda, Y. A direct oral anticoagulant edoxaban accelerated fibrinolysis via enhancement of plasmin generation in human plasma: dependent on thrombin-activatable fibrinolysis inhibitor. J Thromb Thrombolysis 48, 103–110 (2019). https://doi.org/10.1007/s11239-019-01851-8

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  • DOI: https://doi.org/10.1007/s11239-019-01851-8

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