title: Zucker Diabetic Fatty rats exhibit hypercoagulability and accelerated thrombus formation in the Arterio-Venous shunt model of thrombosis.
abstract: BACKGROUND
  Diabetes is a significant risk factor for thrombosis. The present study aimed at assessing coagulability, platelet reactivity, and thrombogenicity of the diabetic female Zucker Diabetic Fatty (ZDF) rat model and its relevance in studying antithrombotic mechanisms.
  
  
  METHODS
  The basal coagulant state in ZDF rats was evaluated by clotting times, thromboelastography, and thrombin generation assay. A 14-day treatment with dapagliflozin in ZDF rats was pursued to investigate if glycemic control can improve coagulability. Thrombus formation in the Arterio-Venous (A-V) shunt model and the FeCl3-induced arterial thrombosis model was studied, with the antithrombotic effect of apixaban in the former model further investigated.
  
  
  RESULTS
  ZDF rats exhibited significantly shortened clotting times, enhanced thrombin generation, and decreased fibrinolysis at baseline. Effective glycemic control achieved with dapagliflozin did not improve any of these parameters. ZDF rats displayed accelerated thrombus formation and were amenable to apixaban treatment in the A-V shunt model albeit with less sensitivity than normal rats. ZDF rats exhibited less platelet aggregation in response to ADP, collagen and PAR-4, and attenuated thrombotic response in the FeCl3 model.
  
  
  CONCLUSIONS
  ZDF rats are at a chronic hypercoagulable and hypofibrinolytic state yet with compromised platelet reactivity. They display accelerated and attenuated thrombosis in the A-V shunt and FeCl3 model of thrombosis, respectively. Results shed new light on the pathophysiology of the ZDF rat model and illustrate its potential value in translational research on anticoagulant agents in diabetics. Caution needs to be exerted in utilizing this model in assessing antiplatelet mechanisms in diabetes-associated atherothrombosis.
authors.affiliation: Department of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, New Jersey. Electronic address: jin_shang@merck.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Shang
authors.affiliation: Department of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, New Jersey. Electronic address: zhu_chen@merck.com.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Wen
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Yangsong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Graziano
authors.affiliation: Department of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001559:Benzhydryl Compounds / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects; D048909:Diabetes Complications / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D004195:Disease Models, Animal; D065427:Factor Xa Inhibitors / Q000627:therapeutic use; D005260:Female; D005960:Glucosides / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D011720:Pyrazoles / Q000627:therapeutic use; D011728:Pyridones / Q000627:therapeutic use; D051381:Rats; D011924:Rats, Zucker; D019851:Thrombophilia / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D013927:Thrombosis / Q000097:blood / Q000150:complications* / Q000188:drug therapy
chemical_list: D001559:Benzhydryl Compounds; D065427:Factor Xa Inhibitors; D005960:Glucosides; D007004:Hypoglycemic Agents; D011720:Pyrazoles; D011728:Pyridones; C529054:dapagliflozin; C522181:apixaban
keywords: Coagulation; Platelet reactivity; Rat; Thrombin generation; Thrombus formation; Type 2 Diabetes