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Clopidogrel affects leukocyte dependent platelet aggregation by P2Y12 expressing leukocytes

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Abstract

Up to 30% of all patients who are treated with a coronary stent do not respond sufficiently to antiplatelet therapy. This condition results in an increased risk for thrombotic complications such as stent thrombosis and myocardial infarction. The aim of the study was to determine clinical parameters modulating ASA and clopidogrel responsiveness. Patients were enrolled into three groups: (A) Patients with coronary artery disease without recent PCI treated with 100 mg/day ASA (n = 67). (B) Patients who underwent coronary stent implantation taking 100 mg/day ASA and 75 mg/day clopidogrel (n = 87). (C) Patients in whom CAD was excluded by angiography and who were not treated with anti-platelet medication served as controls (n = 32). Platelet aggregation was determined by impedance aggregometry using the Multiplate® point of care device. Drug response was differentiated by stimulation of whole blood with arachidonic acid (AA, ASA responsiveness) or adenosine diphosphate (ADP, clopidogrel responsiveness). P2Y12 receptor expression was determined by RT-PCR. ADP induced platelet aggregation correlated with the leukocyte count (r = 0.61, p < 0.001) suggesting that platelets and leukocytes interact functionally. Clopidogrel treatment abolished the influence of leukocytes on platelets and caused decreased leukocyte activation. We detected the expression of the clopidogrel target P2Y12 on leukocytes suggesting that clopidogrel may act directly on these cells and not only on platelets. In contrast to ASA responsiveness, clopidogrel response correlated with body mass index (r = 0.34; p = 0.001). In conclusion, (1) leukocytes influence ADP induced platelet aggregation most likely by expression of the P2Y12 receptor. This interaction is abolished by clopidogrel. Therefore, clopidogrel may act directly on leukocytes via the P2Y12 receptor. (2) Clopidogrel may be under dosed in obese patients.

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Acknowledgment

We are grateful to Alf Zerweck (Dept. of Oncology, University of Freiburg) for providing leukapheresis blood samples.

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  1. Department of Cardiology and Angiology, University-Hospital Freiburg, Hugstetterstr. 55, 79106, Freiburg, Germany

    Philipp Diehl, Christoph Olivier, Christoph Halscheid, Thomas Helbing, Christoph Bode & Martin Moser

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  1. Philipp Diehl
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  2. Christoph Olivier
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Correspondence to Martin Moser.

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395_2009_73_MOESM1_ESM.pdf

Similar clopidogrel effects after loading dose or longterm maintenance dose. To prove that longterm clopidogrel maintenance therapy (75 mg/d) results in similar platelet inhibition as a recent loading dose (300 mg followed by 75 mg/d) we compared these conditions. There were no differences between the two groups in our study (p=0.37). (PDF 221 kb)

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Diehl, P., Olivier, C., Halscheid, C. et al. Clopidogrel affects leukocyte dependent platelet aggregation by P2Y12 expressing leukocytes. Basic Res Cardiol 105, 379–387 (2010). https://doi.org/10.1007/s00395-009-0073-8

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