Abstract 111: Effects of the Novel Factor Xa Inhibitor, Apixaban, on Elevated Levels of Thrombotic Biomarkers in Genetically Obese, Diabetic Mice

Abstract

Obesity and related sequelae such as insulin resistance and diabetes present a growing health care burden throughout the world. One of the hallmarks of the disease process in these patients is the presence of a prothrombotic state that manifests itself as heightened levels of circulating thrombotic/platelet biomarkers such as thrombin-antithrombin complex (T-AT), soluble CD40 ligand (sCD40L) and inflammatory cytokines such as interleukin 6 (IL6). We have found that levels of these biomarkers are also elevated in genetic models of obesity and diabetes (db/db mice). Apixaban is a potent, highly selective, direct Factor Xa inhibitor that shows great promise as a safer and more efficacious therapy then the existing standard of care (ARISTOTLE trial). For this reason, we sought to study the differences in the ability of apixaban and current clinical therapies to lower plasma markers of thrombosis (T-AT and sCD40L) in diabetic mice. We administered either apixaban, warfarin or aspirin and clopidogrel to 12 week old, male db/db mice p.o. for 48 h prior to collection of blood. T-AT and sCD40L were measured in plasma by ELISA. db/db mice had 3-fold greater levels of T-AT (P<0.05) and 2-fold (P<0.05) greater levels of sCD40L in plasma as compared to C57Bl6 mice. Warfarin (0.3 mg/kg) dose-dependently decreased T-AT (P<0.05) to levels similar to normoglycemic C57/Bl6 controls. Apixaban (5 and 50 mg/kg) significantly reduced (P<0.05) elevated levels of these biomarkers when administered b.i.d. When administered q.d., apixaban (10 and 100 mg/kg) lowered T-AT levels but did not robustly affect sCD40L. The platelet therapies, aspirin (30 mg/kg) and clopidogrel (3 mg/kg) robustly decreased sCD40L (P<0.05) but did not affect T-AT levels in obese, diabetic mice. Overall, these data suggest that administration of apixaban is equally efficacious as warfarin in lowering elevated thrombotic biomarkers in diabetic mice. Anti-platelet therapies were efficacious on platelet biomarkers but did not affect markers associated with elevated thrombin activation. This study was funded by Bristol-Myers Squibb and Pfizer.