Influence of high‐density lipoprotein and paraoxonase‐1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy

Abstract

To cite this article: Tselepis AD, Tsoumani ME, Kalantzi KI, Dimitriou AA, Tellis CC, Goudevenos IA. Influence of high-density lipoprotein and paraoxonase-1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy. J Thromb Haemost 2011; 9: 2371-8.Summary. Background: The paraoxonase activity of the enzyme paraoxonase-1 (PON-1) associated with high-density lipoprotein (HDL) may significantly influence clopidogrelÕs antiplatelet and clinical efficacy as a result of its involvement in the clopidogrel biotransformation to the pharmacologically active thiol metabolite. We evaluated the possible relationships of HDL levels as well as PON-1 activities and the Q192R genotype with clopidogrelÕs antiplatelet efficacy in acute coronary syndrome (ACS) patients. Methods and results: The platelet aggregation, P-selectin expression and platelet/leukocyte conjugates as well as the clopidogrel response variability (evaluated by the VASP phosphorylation test and expressed as platelet reactivity index, PRI) were assessed in 74 ACS patients undergoing percutaneous coronary intervention (PCI) in relation to the PON-1 Q192R genotype and to serum HDLcholesterol levels, and PON-1 (paraoxonase and arylesterase) activities. Patients were loaded with 600 mg of clopidogrel followed by 75 mg per day. HDL-cholesterol levels and PON-1 activities at baseline (before clopidogrel loading) were not altered at 5-and 30-day post-clopidogrel loading, whereas baseline platelet activation parameters were significantly attenuated. At 5 days, 17 patients were clopidogrel non-responders (PRI: 64.2 ± 11.1%). HDL-cholesterol was inversely associated with platelet activation parameters independently on platelet response variability to clopidogrel whereas a negative association between platelet activation parameters and paraoxonase activity was observed in patients adequately responding to clopidogrel but not in clopidogrel non-responders. Similarly, the platelet activation markers were significantly higher in PON-1 Q192Q genotype carriers compared with those having one or two R alleles only in patients adequately responding to clopidogrel. Conclusions: PON-1 is an important determinant of clopidogrel antiplatelet efficacy only in patients adequately responding to clopidogrel. These findings may be clinically important in ACS patients receiving clopidogrel therapy, especially the first days after the episode.

Influence of the paraoxonase‐1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta‐analysis

“…[14] and most subsequent studies are unclear. Differences in populations may be an issue; indeed, the frequency of the Q192 allele is somewhat lower in their cohort study (63.9%) than in any of the other studies [12,15–17,25–33,42]. A recent in vitro study by Dansette et al.…”

Paraoxonase-1 Deficiency does not Influence Clopidogrel Antiplatelet Function in Mice

“…They also highlighted that individuals carrying the QQ isoform of PON1 192 gene polymorphism have a higher risk of stent thrombosis. Tselepis et al [5] showed an inverse association between PON-1 activity and platelet activation following clopidogrel administration, and suggested that PON-1 is an important determinant of clopidogrel antiplatelet efficacy in these patients. Dansette et al [6] reported that PON1 catalyzes the formation of a minor thiol metabolite, while the biosynthesis of the major clopidogrel metabolite is CYP P450 dependent.…”

The impact of genetic polymorphisms of drug metabolizing enzymes on the pharmacodynamics of clopidogrel under steady state conditions

“…There were no significantly differences in the three pharmacodynamic parameters, AUEC 0e24h , E max and E min of clopidogrel response observed among subjects with homozygous wild-type and heterozygous CYP2C19*2 genotypes who carried different PON1 genotypes. It should be noted that in the previous studies they did not take into account the different CYP2C19 genotypes among the subjects with different PON1 genotypes and thus these differences may influence the real impact of PON1 genetic polymorphism reported [16,17].…”

“…It has been demonstrated in some studies that individuals with the QQ192 genotype of PON1 have lower PON1 plasma activity, lower plasma concentrations of clopidogrel active metabolites and lower platelet inhibition as well as a higher risk of stent thrombosis compared to the individuals with RR192 genotypes [16,17], however, these results could not be confirmed in several studies [8,9]. The present results revealed that neither platelet inhibition measured by both the whole blood impedance aggregometry and the VerifyNow ® P2Y12 assays of subjects with different PON1 Q192R genotypes were significantly different.…”

“…The common genetic variant of PON1, glutamine (Q)/arginine (R) at position192 (Q192R) which mostly accounts for the wide inter-individual variation in serum paraoxonase activity has been reported to be associated with clopidogrel response. The PON1 QQ192 homozygous individuals showed considerably lower PON1 plasma activity, lower plasma concentrations of clopidogrel active metabolite and lower platelet inhibition as well as at the higher risk of stent thrombosis than RR192 homozygous individuals [16,17]. Some recent studies reported that the PON1 Q192R genetic polymorphism did not influence the platelet response to clopidogrel or the cardiovascular events in clopidogrel-treated patients [8,9].…”