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A direct oral factor Xa inhibitor edoxaban ameliorates neointimal hyperplasia following vascular injury and thrombosis in apolipoprotein E-deficient mice

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Abstract

Vascular injury activates the coagulation cascade. Some studies report that coagulation factor Xa and thrombin are implicated in proliferation of vascular smooth muscle cells and neointimal hyperplasia after vascular injury. The aim of this study was to determine the effect of an oral direct factor Xa inhibitor, edoxaban, on neointimal hyperplasia following the carotid artery injury in apolipoprotein E (ApoE)-deficient mice. Vascular injury was induced by the application of 10% ferric chloride to the carotid artery for 3 min in ApoE-deficient mice. After vascular injury, all animals were fed with high-cholesterol chow for 6 weeks. Edoxaban at 15 mg/kg was orally administered to the mice 1 h before (n = 10) or 1 h after (n = 9) ferric chloride injury, and thereafter 10 mg/kg edoxaban was orally administered b.i.d. for 6 weeks. Thrombus formation and neointimal hyperplasia were evaluated. Treatment with 15 mg/kg edoxaban before vascular injury almost completely inhibited thrombus formation, and following chronic administration of edoxaban significantly suppressed neointimal hyperplasia. In the mice treated with edoxaban after vascular injury, there was wide interindividual variability. In some mice (four out of nine) the neointimal hyperplasia was inhibited like in edoxaban-pretreated mice, but there was no statistical difference compared with control. This study demonstrated that inhibition of the coagulation and thrombosis by edoxaban ameliorated neointimal hyperplasia caused by vascular injury and high-cholesterol diets in ApoE-deficient mice. This suggests that factor Xa has a crucial role in the formation of neointima following vascular injury.The abstract should be followed by 3-4 bullet points that highlight major findings. The final bullet point should emphasize future directions for research.

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Acknowledgements

We acknowledge Dr. Tomoko Shibutani for discussion about the histopathological evaluation and the members of Nissei Bilis Co., Ltd. for their technical expertise.

Funding

This work was solely 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 and LCM Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan

    Yuko Honda

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

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

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Morishima, Y., Honda, Y. A direct oral factor Xa inhibitor edoxaban ameliorates neointimal hyperplasia following vascular injury and thrombosis in apolipoprotein E-deficient mice. J Thromb Thrombolysis 46, 95–101 (2018). https://doi.org/10.1007/s11239-018-1673-7

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