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Combined effect of a direct oral anticoagulant edoxaban and an inhibitor of activated thrombin-activatable fibrinolysis inhibitor on clot lysis

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Abstract

Fibrinolysis is regulated by the thrombin/thrombin-activatable fibrinolysis inhibitor (TAFI) system. Thus, anticoagulants and inhibitors of TAFI are expected to accelerate fibrinolysis. The combined effects of an anticoagulant and a TAFIa inhibitor on fibrinolysis remain unknown. The aim of this study was to evaluate the combined effect of edoxaban, an oral direct factor Xa (FXa) inhibitor, and a TAFIa inhibitor, potato tuber carboxypeptidase inhibitor (PCI) on tissue-type plasminogen activator (t-PA)-induced clot lysis in human plasma in vitro. Pooled human plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban and/or PCI. Clot formation was induced by 2.5 pM tissue factor and 4 µM phospholipids and clot lysis time was examined. Plasma plasmin-α2 antiplasmin complex (PAP) concentration was measured as a marker of plasmin generation. Edoxaban or PCI alone significantly shortened the t-PA-induced clot lysis time and plasma PAP concentration. The combination of these compounds significantly accelerated the clot lysis compared with the inhibitors alone. Addition of PCI (0.3, 1, and 3 μg/mL) to 75 ng/mL edoxaban increased plasma PAP concentration compared with edoxaban alone; however, compared with PCI alone only the combination of 0.3 μg/mL PCI + 75 ng/mL edoxaban showed the significant increase in PAP concentration. Concomitant use of an oral direct FXa inhibitor, edoxaban, and a TAFIa inhibitor, PCI, significantly accelerate fibrinolysis via enhancement of plasmin generation. These results suggest that the combination of edoxaban and a TAFIa inhibitor might be beneficial for the treatment of thromboembolic diseases.

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Funding

This study was financially 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. Rare Disease Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan

    Chikako Kamisato

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

    Yuko Honda

Authors
  1. Yoshiyuki Morishima
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  2. Chikako Kamisato
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  3. Yuko Honda
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Correspondence to Yoshiyuki Morishima.

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All 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., Kamisato, C. & Honda, Y. Combined effect of a direct oral anticoagulant edoxaban and an inhibitor of activated thrombin-activatable fibrinolysis inhibitor on clot lysis. J Thromb Thrombolysis 49, 94–99 (2020). https://doi.org/10.1007/s11239-019-01929-3

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