Antithrombotic and Prohemorrhagic Actions of Different Concentrations of Apixaban in Patients Exposed to Single and Dual Antiplatelet Regimens

BACKGROUND: Treatment with triple antithrombotic therapies increases bleeding risks. AIM: We evaluated the antithrombotic and prohemorrhagic actions of different concentrations of apixaban (APIX) in healthy donors and patients exposed to currently used antiplatelet regimens. METHODS: 25 healthy subjects and 53 patients treated with aspirin (ASA, n=21), ASA and clopidogrel (ASA+CLOPI, n=11), or ASA and ticagrelor (ASA+TICA, n=21) participated in the study. Blood samples from participants were spiked ex vivo with apixaban 0 (APIX0), 40 (APIX40), and 160 ng/mL (APIX160). We assessed the effects of APIX on 1) clot formation, by ROTEM thromboelastometry; 2) thrombin generation primed by platelets; and 3) platelet and fibrin interactions with a thrombogenic surface, in a microfluidic model with circulating blood. RESULTS: APIX caused dose-related prolongations of clotting time with minimal impact on other ROTEM parameters. Thrombin generation was significantly inhibited by APIX160 and moderately affected by the antiplatelets, with ASA+TICA actions being the strongest among them (p<0.01 vs APIX0). Confocal analysis of microfluidic studies showed the additional inhibitory effect of the APIX160 to the antiplatelet therapies. APIX160 was the more potent at suppressing platelet and fibrin interactions (p<0.001 vs. APIX0). APIX40 showed a consistent antithrombotic action but with a favorable protective effect on the structural quality of fibrin. CONCLUSIONS: APIX potentiated the antithrombotic effects of current antiplatelet regimens. APIX at 40 ng/mL, enhanced the antithrombotic action of single or dual antiplatelet regimens but appears more conservative for hemostasis than the concentrations of 160 ng/mL that corresponds to the C max reached after the standard dose for thromboprophylaxis.