Effect of P2Y₁₂ inhibitors on thrombus stability and endogenous fibrinolysis

Although used routinely to reduce thrombotic events in patients with coronary disease, the effects of P2Y₁₂ inhibitors on thrombus stability and endogenous fibrinolysis are largely unknown. Blood taken from patients pre- and post-aspirin (n = 20) and on aspirin alone and on dual antiplatelet therapy comprising aspirin plus clopidogrel (n = 20), ticagrelor (n = 20) or cangrelor (n = 20), was tested using the Global Thrombosis Test. The number of "rebleeds" or drops (D) after early platelet-rich thrombus formation (occlusion time, OT), and before final lasting occlusion, was used as an inverse measure of thrombus stability. Whilst clopidogrel had no effect, ticagrelor and cangrelor both increased D significantly, reflecting increased thrombus instability [D pre- and post-clopidogrel 4.3 ± 1.6 vs. 4.5 ± 1.4, p = 0.833; pre- and post-ticagrelor 4.1 ± 2.4 vs. 6.8 ± 5.1, p = 0.048; pre- and post-cangrelor 3.6 ± 2.0 vs. 7.9 ± 8.9, p = 0.046]. Platelet reactivity was reduced by all P2Y₁₂ inhibitors, demonstrated by OT prolongation (clopidogrel 378 ± 87 s vs. 491 ± 93 s, p < 0.001; ticagrelor 416 ± 122 s vs. 549 ± 121 s, p < 0.001; cangrelor 381 ± 146 s vs. 613 ± 210 s, p < 0.001). The magnitude of OT prolongation compared to baseline (ΔOT) was significantly greater for cangrelor compared to clopidogrel and ticagrelor. Cangrelor was the only agent to enhance fibrinolysis (lysis time pre- and post-cangrelor 1622[1240-2048]s vs. 1388[960-1634]s, p = 0.005). We demonstrate the ability to assess the effect of pharmacotherapy on thrombus stability in vitro and show that P2Y₁₂ inhibitors potentiate thrombus instability at high shear. Cangrelor, and to a lesser extent ticagrelor, de-stabilised thrombus formation and cangrelor also enhanced fibrinolysis. Potentiation of thrombus instability could become a new pharmacological target, that may be particularly important in acute coronary syndromes.