Rivaroxaban attenuates leukocyte adhesion in the microvasculature and thrombus formation in an experimental mouse model of type 2 diabetes mellitus

Abstract

Thrombosis is a major complication in diabetes mellitus. Since Factor Xa inhibitors are not only inhibit the coagulation system but also attenuate the leukocyte-endothelial interaction in acute inflammation models, the purpose of this study is to confirm the similar effects of rivaroxaban in a mouse model of type 2 diabetes mellitus. In the treatment groups, either 5 or 10mg/kg of rivaroxaban dissolved in DMSO was orally given to KK-A(y) mice for 7 weeks (n=6 in each group). KK-A(y) mice fed by chow containing DMSO without rivaroxaban for 7 weeks were served for the control group (n=6). Following clamping of the mesenteric vein for 20 minutes, intravital microscopic observation of the intestinal microcirculation and the measurement of bleeding time after the needle puncture were carried-out. In another series, the calculation for blood cell counts and the measurement of blood fluidity using micro channel array flow analyzer (MC-FAN) were performed. The initial event in the microvasculature is the leukocyte adhesion on endothelium. Then, the leukocytes make clusters and the platelets are involved in. These leukocyte-platelet conjugates aggregate and form thrombus. The leukocyte adherence and the microthrombus formation was significantly suppressed with the treatment of 10 mg/kg of rivaroxaban compared to the control group (P<0.05). While, the bleeding time was significantly extended with the treatment with 10mg/kg of rivaroxaban (P<0.01). The blood fluidity was maintained best with the treatment of 10 mg/kg rivaroxaban. Rivaroxaban attenuates the leukocyte-platelet-endothelial interaction, which leads to the attenuation of microthrombus formation in a mouse model of diabetes mellitus.