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

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.