Abstract

Cerebral microembolic signal (MES) is an independent predictor of stroke risk and prognosis. The objective of this study is to assess the effects of apixaban, as a representative of the novel oral anticoagulant class, on a rabbit model of cerebral MES. A clinical transcranial Doppler ultrasound instrument was used to assess MES in the middle cerebral artery in a 30% FeCl3-induced carotid arterial thrombosis model in male New Zealand White rabbits. Ascending doses of apixaban were evaluated as monotherapy and in combination with aspirin on both arterial thrombosis and MES. Pharmacokinetic and pharmacodynamic responses were also evaluated. The effective dose for 50% inhibition (ED₅₀) of thrombus formation for monotherapy was 0.04 mg/kg/h apixaban, i.v. (0.03 μM plasma exposure) for the integrated blood flow, 0.13 mg/kg/h apixaban (0.10 μM plasma exposure) for thrombus weight, and 0.03 mg/kg/h apixaban (0.02 μM plasma exposure) for MES. Dual treatment with aspirin (5 mg/kg, p.o.) and apixaban (0.015 mg/kg/h, i.v.) resulted in a significant reduction in cerebral MES (p<0.05) compared to monotherapy with either agent. Pharmacokinetic analysis of apixaban and pharmacodynamic assays using activated partial thromboplastin time (aPTT) and prothrombin time (PT) for apixaban and arachidonic acid induced platelet aggregation for aspirin were used to confirm the exposure - response relationships. In summary, our study demonstrates that apixaban in a concentration-dependent manner inhibits both arterial thrombosis and MES, suggesting a potential association between FXa blockade and the reduction in MES in patients at risk of ischemic stroke.