title: Rivaroxaban attenuates leukocyte adhesion in the microvasculature and thrombus formation in an experimental mouse model of type 2 diabetes mellitus.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Rivaroxaban attenuates the leukocyte-platelet-endothelial interaction, which leads to the attenuation of microthrombus formation in a mouse model of diabetes mellitus.
authors.affiliation: Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine. Electronic address: toshiiba@cf6.so-net.ne.jp.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Iba
authors.affiliation: Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Aihara
authors.affiliation: Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine.
authors.forename: Atushi
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine.
authors.forename: Masataka
authors.initials: M
authors.lastname: Nagayama
authors.affiliation: Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tabe
authors.affiliation: Department of Transfusion Medicine and Stem Cell Regulation, Juntendo University Graduate School of Medicine.
authors.forename: Akimichi
authors.initials: A
authors.lastname: Ohsaka
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D065427:Factor Xa Inhibitors; D005260:Female; D007962:Leukocytes / Q000187:drug effects*; D051379:Mice; D055806:Microvessels / Q000187:drug effects*; D009025:Morpholines / Q000008:administration & dosage / Q000627:therapeutic use*; D000069552:Rivaroxaban; D013876:Thiophenes / Q000008:administration & dosage / Q000627:therapeutic use*; D020246:Venous Thrombosis / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban
keywords: Factor Xa inhibitor; leukocyte-endothelial interaction; rivaroxaban; type 2 diabetes mellitus; venous thrombosis