title: Discontinuation of long term clopidogrel therapy induces platelet rebound hyperaggregability between 2 and 6 weeks post cessation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology and Angiology, University Hospital Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany. philipp.diehl@uniklinik-freiburg.de
authors.forename: Philipp
authors.initials: P
authors.lastname: Diehl
authors.forename: Christoph
authors.initials: C
authors.lastname: Halscheid
authors.forename: Christoph
authors.initials: C
authors.lastname: Olivier
authors.forename: Thomas
authors.initials: T
authors.lastname: Helbing
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Martin
authors.initials: M
authors.lastname: Moser
mesh_terms: D000368:Aged; D000077144:Clopidogrel; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010979:Platelet Function Tests; D011446:Prospective Studies; D015607:Stents; D013927:Thrombosis / Q000209:etiology; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine