Protease activated receptor-1 (PAR-1) mediated platelet aggregation is dependent on clopidogrel response

Thromb Res. 2012 Aug;130(2):198-202. doi: 10.1016/j.thromres.2012.02.049. Epub 2012 Mar 28.


Introduction: 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.

Material and 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Blood Platelets / cytology
  • Blood Platelets / drug effects*
  • Clopidogrel
  • Cytochrome P-450 CYP2C19
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Percutaneous Coronary Intervention* / adverse effects
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / pharmacology
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Receptor, PAR-1 / metabolism*
  • Receptors, Thrombin / metabolism
  • Thrombosis / prevention & control
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / pharmacology
  • Ticlopidine / therapeutic use


  • Platelet Aggregation Inhibitors
  • Receptor, PAR-1
  • Receptors, Thrombin
  • Clopidogrel
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Ticlopidine