Delayed thrombin-induced platelet-fibrin clot generation by clopidogrel: A new dose-related effect demonstrated by thrombelastography in patients undergoing coronary artery stenting

Background: We have previously demonstrated that clopidogrel reduces platelet activation and aggregation in patients undergoing stenting. However, the effect of the clopidogrel loading dose on the rate of thrombin-induced platelet-fibrin clot formation is unknown in this patient population. Methods and results: Using thrombelastography (TEG®) we measured the time to platelet-fibrin clot formation (R), a marker of the speed of thrombin generation, in 120 patients undergoing elective coronary artery stenting treated with standard and high loading doses of clopidogrel. Platelet reactivity to adenosine diphosphate (ADP) by light transmittance aggregometry (LTA) was determined simultaneously. Measurements were made immediately before and at 24 h after clopidogrel treatment. Clopidogrel produced a prolongation in R (4.4 ± 1.4 min pre vs. 5.4 ± 1.7 min post, p < 0.001) that directly correlated with the change in platelet aggregation (r = 0.65, p < 0.0001). Prolongation in R was greatest in patients treated with a high loading dose (p = 0.004). Conclusions: Delayed thrombin-induced platelet-fibrin clot formation as measured by TEG is a newly reported dose-related effect of clopidogrel that may contribute to the overall antithrombotic properties of the drug in patients undergoing stenting. This effect was more marked in patients loaded with 600 mg, lending further mechanistic support for this dose of clopidogrel as a more effective antithrombotic regimen than the standard 300 mg dose. Measurement of R may serve as a new indicator of clopidogrel responsiveness.