Variable extent of clopidogrel responsiveness in patients after coronary stenting

Ralf Grossmann; Olga Sokolova; Axel Schnurr; Andreas Bonz; Christian Porsche; Achim Obergfell; Björn Lengenfelder; Ulrich Walter; Martin Eigenthaler

doi:10.1160/TH04-01-0049

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2004; 92(06): 1201-1206
DOI: 10.1160/TH04-01-0049

Theme Issue Article

Schattauer GmbH

Variable extent of clopidogrel responsiveness in patients after coronary stenting

Authors

Ralf Grossmann^*

¹Department of Laboratory Medicine, Blood Coagulation Unit, Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Germany
Olga Sokolova^*

¹Department of Laboratory Medicine, Blood Coagulation Unit, Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Germany
Axel Schnurr

¹Department of Laboratory Medicine, Blood Coagulation Unit, Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Germany
Andreas Bonz

²Division of Cardiology, Department of Internal Medicine, University of Würzburg, Germany
Christian Porsche

²Division of Cardiology, Department of Internal Medicine, University of Würzburg, Germany
Achim Obergfell

¹Department of Laboratory Medicine, Blood Coagulation Unit, Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Germany
Björn Lengenfelder

²Division of Cardiology, Department of Internal Medicine, University of Würzburg, Germany
Ulrich Walter

¹Department of Laboratory Medicine, Blood Coagulation Unit, Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Germany
Martin Eigenthaler

¹Department of Laboratory Medicine, Blood Coagulation Unit, Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Germany

Abstract

Summary

Clopidogrel is an effective and specific inhibitor of ADP-induced platelet aggregation. After metabolic activation, the active clopidogrel metabolite irreversibly impairs the human platelet P2Y12 ADP receptor. Gialpha-protein activation and inhibition of vasodilator-stimulated phosphoprotein (VASP) phosphorylation are two key elements of the P2Y12 receptor pathway suitable for quantitation of clopidogrel effects. So far, only limited data exist about a diminished responsiveness to clopidogrel and underlying possible mechanisms. We investigated clopidogrel effects in 57 patients after percutaneous coronary intervention and stent implantation by flow cytometry for the analysis of intracellular VASP phosphorylation. Patients were treated with a 300 mg clopidogrel loading dose, followed by 75 mg/day clopidogrel in combination with 100 mg/day aspirin. Samples were drawn after a median of 5 days of clopidogrel treatment. Considerable differences in the responsiveness to clopidogrel could be observed and it was shown that 17.5% (10/57) of the patients revealed an inadequate responsiveness to clopidogrel despite continuation of clopidogrel intake. Comparable amounts of Gialpha and VASP were found in two clopidogrel low-responding patients as well as in two responding patients. To exclude a molecular defect of P2Y12 ADP receptor, the P2Y12 receptor gene of eight clopidogrel treated patients (seven patients with inadequate responsiveness, one responder) was sequenced. We only found a single silent mutation in exon 2 at position 1828 (GA). We suggest that individual differences in clopidogrel metabolization could cause relevant variations in clopidogrel responsiveness despite the use of a 300 mg clopidogrel loading dose.

Keywords

Clopidogrel - clopidogrel responsiveness - antiplatelet therapy

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Referenzen

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