The influence of variation in the P2Y12 receptor gene on in vitro platelet inhibition with the direct P2Y12 antagonist cangrelor

Heleen J. Bouman; Jochem W. van Werkum; Goran Rude; Frank W. G. Leebeek; Adrian Kruit; Christian M. Hackeng; Jurriën M. ten Berg; Moniek P. M. de Maat; Henk J. T. Ruven

doi:10.1160/TH09-06-0367

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2010; 103(02): 379-386
DOI: 10.1160/TH09-06-0367

Platelets and Blood Cells

Schattauer GmbH

The influence of variation in the P2Y12 receptor gene on in vitro platelet inhibition with the direct P2Y12 antagonist cangrelor

Autoren

Heleen J. Bouman

¹Department of Cardiology, St. Antonius Hospital Nieuwegein, the Netherlands
Jochem W. van Werkum

¹Department of Cardiology, St. Antonius Hospital Nieuwegein, the Netherlands
Goran Rude

²Department of Hematology, Erasmus University Medical Center Rotterdam, the Netherlands
Frank W. G. Leebeek

²Department of Hematology, Erasmus University Medical Center Rotterdam, the Netherlands
Adrian Kruit

³Department of Clinical Chemistry, St. Antonius Hospital Nieuwegein, the Netherlands
Christian M. Hackeng

³Department of Clinical Chemistry, St. Antonius Hospital Nieuwegein, the Netherlands
Jurriën M. ten Berg

¹Department of Cardiology, St. Antonius Hospital Nieuwegein, the Netherlands
Moniek P. M. de Maat

²Department of Hematology, Erasmus University Medical Center Rotterdam, the Netherlands
Henk J. T. Ruven

³Department of Clinical Chemistry, St. Antonius Hospital Nieuwegein, the Netherlands

Abstract

Summary

Novel P2Y12 inhibitors are in development to overcome the occurrence of atherothrombotic events associated with poor responsiveness to the widely used P2Y12 inhibitor clopidogrel. Cangrelor is an intravenously administered P2Y12 inhibitor that does not need metabolic conversion to an active metabolite for its antiplatelet action, and as a consequence exhibits a more potent and consistent antiplatelet profile as compared to clopidogrel. It was the objective of this study to determine the contribution of variation in the P2Y12 receptor gene to platelet aggregation after in vitro partial P2Y12 receptor blockade with the direct antagonist cangrelor. Optical aggregometry was performed at baseline and after in vitro addition of 0.05 and 0.25 μM cangrelor to the platelet-rich plasma of 254 healthy subjects. Five haplotype-tagging (ht)-SNPs covering the entire P2Y12 receptor gene were genotyped (rs6798347C>t, rs6787801T>c, rs9859552C>a, rs6801273A>g and rs2046934T>c [T744C]) and haplotypes were inferred. The minor c allele of SNP rs6787801 was associated with a 5% lower 20 μM ADP-induced peak platelet aggregation (0.05 μM cangrelor, p<0.05). Aa homozygotes for SNP rs9859552 showed 20% and 17% less inhibition of platelet aggregation with cangrelor when compared to CC homozygotes (0.05 and 0.25 μM cangrelor respectively; p<0.05). Results of the haplotype analyses were consistent with those of the single SNPs. Polymorphisms of the P2Y12 receptor gene contribute significantly to the interindividual variability in platelet inhibition after partial in vitro blockade with the P2Y12 antagonist cangrelor.

Keywords

Cangrelor - P2Y12 receptor - single nucleotide polymorphism - haplotypes - platelet aggregation

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Referenzen

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