Reduced thrombus cohesion in an ex vivo human model of arterial thrombosis induced by clopidogrel treatment: kinetics of the effect and influence of single and double loading-dose regimens

OBJECTIVE: To compare the effects of clopidogrel on ex vivo thrombogenesis with those on ADP-dependent platelet aggregation, and to compare single and double loading-dose regimens. METHODS AND RESULTS: Step 1: Volunteers (n=12) received clopidogrel 75 mg/day for 8 days. ADP-induced platelet aggregation was measured in platelet-rich plasma (PRP). Thrombogenesis was measured in an ex vivo model. Clopidogrel produced rapid platelet inhibition, increasing up to day 5. Maximal intensity of platelet aggregation correlated with density of platelet thrombus, surface of collagen covered by platelets and thrombus cross-sectional surface (p<0.001). Step 2: On day 1, volunteers (n=60) randomly received clopidogrel 75 mg, a single 300-mg loading dose or two 300-mg loading doses separated by a 12-h interval. On day 2, all volunteers received clopidogrel 75 mg. Both loading dose regimens enhanced platelet inhibition at all time points (p<0.03 vs. clopidogrel 75 mg). After 3 h, the antiplatelet effect of a loading dose was substantial, and the mean decrease in dense thrombus surface was greater in the loading-dose groups than in the 75 mg group (p=0.041 for the single loading dose). Ex vivo, there were no significant differences between loading-dose groups. CONCLUSIONS: Clopidogrel reduces arterial thrombus cohesion by an effect that correlates with inhibition of ADP-induced platelet aggregation. A single 300-mg loading dose provides a rapid onset of such an antithrombotic effect, which was more significant at 24 h with the double loading dose.