Clopidogrel affects leukocyte dependent platelet aggregation by P2Y12 expressing leukocytes.
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). P2Y(12) 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 P2Y(12) 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 P2Y(12) receptor. This interaction is abolished by clopidogrel. Therefore, clopidogrel may act directly on leukocytes via the P2Y(12) receptor. (2) Clopidogrel may be under dosed in obese patients.
Diehl
Philipp
P
Department of Cardiology and Angiology, University-Hospital Freiburg, 79106 Freiburg, Germany.
Olivier
Christoph
C
Halscheid
Christoph
C
Helbing
Thomas
T
Bode
Christoph
C
Moser
Martin
M
D000368:Aged; D015906:Angioplasty, Balloon, Coronary; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000628:therapy; D003328:Coronary Thrombosis / Q000517:prevention & control; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000097:blood / Q000503:physiopathology; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12; D015607:Stents; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin