title: Protease activated receptor-1 (PAR-1) mediated platelet aggregation is dependent on clopidogrel response.
abstract: BACKGROUND
  Clopidogrel inhibits ADP mediated platelet aggregation through inhibition of the P2Y12 receptor by its active metabolite. Thrombin induces platelet aggregation by binding to protease activated receptor-1 (PAR-1), and inhibition of PAR-1 has been evaluated in patients treated with clopidogrel to reduce ischemic events after acute coronary syndromes. Residual PAR-1 mediated platelet aggregation may be dependent on extent of clopidogrel response.
  
  
  METHODS
  Platelet aggregation was measured in 55 patients undergoing elective PCI at 16-24 hours after 600 mg clopidogrel loading dose by light transmittance aggregometry using ADP 20 μM and thrombin receptor agonist peptide (TRAP) at 15 μM and 25 μM as agonists. Genomic DNA was genotyped for common CYP2C19 variants.
  
  
  RESULTS
  Increasing quartiles of 20 μM ADP induced platelet aggregation after clopidogrel loading were associated with increasing levels of TRAP mediated platelet aggregation. Patients in the highest quartile (clopidogrel non-responders) of post treatment ADP aggregation had significantly higher TRAP mediated aggregation than the patients in the lowest quartile (clopidogrel responders) [TRAP 15 μM: 79.6 ± 5% vs. 69.5 ± 8%, p<0.001].
  
  
  CONCLUSIONS
  Non-responders to clopidogrel show increased residual platelet aggregation induced by TRAP, whereas clopidogrel responders exhibit attenuated response to TRAP. Addition of PAR-1 antiplatelet drugs may be most effective in patients with reduced clopidogrel response and high residual TRAP mediated platelet aggregation.
authors.affiliation: Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. rkreutz@iupui.edu
authors.forename: Rolf P
authors.initials: RP
authors.lastname: Kreutz
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Breall
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kreutz
authors.forename: Janelle
authors.initials: J
authors.lastname: Owens
authors.forename: Deshun
authors.initials: D
authors.lastname: Lu
authors.forename: Islam
authors.initials: I
authors.lastname: Bolad
authors.forename: Elisabeth
authors.initials: E
authors.lastname: von der Lohe
authors.forename: Anjan
authors.initials: A
authors.lastname: Sinha
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D044463:Receptor, PAR-1 / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000517:prevention & control; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine