Discontinuation of long term clopidogrel therapy induces platelet rebound hyperaggregability between 2 and 6 weeks post cessation

Background Stent thrombosis occurs frequently within the first weeks after cessation of longterm clopidogrel therapy. We investigated if rebound platelet hyperreactivity occurs to provide a mechanism for this clinical observation. Methods ADP- and TRAP-induced platelet aggregation was measured by impedance aggregometry in 28 patients with coronary stent implantation (observational group, OG) before and 1, 2, 6 and 17 weeks after clopidogrel cessation. Data were compared intraindividually as well as to 67 controls (control group, CG). Results On-clopidogrel platelet activity was significantly reduced (ADP-stimulation, OG vs. CG, 30 ± 3 U vs. 67 ± 3 U, p\0.001) and reached control levels 1 week after clopidogrel cessation (ADP-stimulation, OG vs. CG, 70 ± 4 U vs. 67 ± 3 U, p = n.s.). Most patients (57%) showed a significant platelet hyperaggregation after 2 weeks (ADP, OG vs. CG, 83 ± 6 U vs. 67 ± 3 U, p = 0.02) to 6 weeks (ADP, OG vs. CG, 85 ± 5 U vs. 67 ± 3 U, p = 0.01) post-cessation. This temporary hyperaggregability was also observed in intra-individual time courses (ADP, 2 vs. 17 weeks, 83 ± 6 U vs. 73 ± 4 U, p = 0.007; 6 vs. 17 weeks, 85 ± 5 U vs. 73 ± 4 U, p = 0.0002). After 17 weeks post-cessation, ADP-induced platelet aggregation returned towards physiological levels. The total capacity of platelet aggregability as reflected by stimulation with thrombin receptor activating peptide (TRAP) was not different between time points confirming a clopidogrel-specific rebound effect. Conclusion Abrupt clopidogrel cessation after 1 year of clopidogrel treatment results in ADP specific platelet hyperreactivity between 2 and 6 weeks post withdrawal. This mechanism may contribute to explain increased rates of stent thrombosis at this time as it was observed in clinical studies.