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Clopidogrel Withdrawal Is Associated With Proinflammatory and Prothrombotic Effects in Patients With Diabetes and Coronary Artery Disease

¹ Division of Cardiology, University of Florida, Shands Jacksonville, Jacksonville, Florida
² Cardiovascular Institute, San Carlos University Hospital, Madrid, Spain

Address correspondence and reprint requests to Dominick J. Angiolillo, MD, FACC, FESC, Division of Cardiology, University of Florida, Shands Jacksonville, 655 West 8th St., Jacksonville, FL 32209. E-mail: dominick.angiolillo{at}jax.ufl.edu

Abbreviations: CEPI, collagen and epinephrine; CT, closure time; hs-CRP, high-sensitivity C-reactive protein; PCI, percutaneous coronary intervention; PFA, platelet function analyzer; PPP, platelet-poor plasma; PRP, platelet-rich plasma

Inhibition of the P2Y₁₂ pathway by the platelet antagonist clopidogrel is associated with a marked reduction in platelet reactivity. Recent reports have shown that P2Y₁₂ inhibition has anti-inflammatory effects as well. However, whether clopidogrel withdrawal is associated with proaggregatory and proinflammatory effects has not yet been explored. Since diabetic subjects are characterized by a prothrombotic and proinflammatory status, we hypothesize that these patients may be more vulnerable to these effects. A total 54 patients with diabetes on long-term (12 months) dual antiplatelet therapy (aspirin plus clopidogrel) were studied. Platelet aggregation (following 6 and 20 µmol/l ADP stimuli) and inflammatory markers (C-reactive protein and P-selectin expression) were assessed before and 1 month following clopidogrel withdrawal. Following clopidogrel withdrawal, aspirin responsiveness using platelet function analyzer–100 was determined as well. A significant increase in all the assessed platelet (P < 0.0001 for 6 and 20 µmol/l ADP-induced aggregation) and inflammatory (P < 0.05 for C-reactive protein, P < 0.001 for P-selectin expression in resting platelets, and P < 0.0001 for P-selectin expression in ADP-stimulated platelets) biomarkers was observed following clopidogrel withdrawal. Low responders to aspirin had increased platelet aggregation profiles (P < 0.05 for 6 and 20 µmol/l ADP-induced aggregation) but no differences in inflammatory markers. In conclusion, clopidogrel withdrawal is associated with an increase in platelet and inflammatory biomarkers in diabetic patients, supporting pleiotropic effects coupled with P2Y₁₂ receptor antagonism.

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