Determinants of subacute response to clopidogrel: relative impact of CYP2C19 genotype and PGE1/adenylate cyclase signalling. Issue 2 (August 2015)

• Record Type: Journal Article
• Authors: Hurst, Nicola L.; Nooney, Vivek B.; Chirkov, Yuliy Y.; De Caterina, Raffaele; Horowitz, John D.
• Is Part Of: Thrombosis research. Volume 136:Issue 2(2015)
• Page Start: 308
• Page End: 314
• Publication Date: 2015-08
• Subjects: Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2015.03.011
• Languages: English
• ISSNs: 0049-3848

Abstract

<abstract abstract-type="author" id="ab0005"> <title id="st0005">Abstract</title> <sec> <title id="st0010">Background</title> <p id="sp0005">and Hypotheses: The signal transduction pathway modulated by activation or blockade of platelet P2Y<sub>12</sub> receptors is linked to PGE<sub>1</sub>-stimulated adenylate cyclase effects, but this link's impact on P2Y<sub>12</sub> receptor antagonist response is uncertain. We therefore tested the hypothesis that pre-treatment platelet responsiveness to PGE<sub>1</sub> predicts subsequent responsiveness to clopidogrel.</p> </sec> <sec> <title id="st0015">Methods</title> <p id="sp0010">In order to maximise heterogeneity of platelet responsiveness to PGE<sub>1</sub> we investigated both healthy subjects (n = 30) and patients with CHD undergoing elective coronary stenting (n = 22), all genotyped for common CYP2C19 variants associated with clopidogrel sensitivity (CS). We determined baseline pre-clopidogrel platelet sensitivity to the inhibitory effects of PGE<sub>1</sub> by ADP-induced whole blood aggregation. Clopidogrel was administered for 7 days utilising a weight-based regimen. CS was expressed as change (Δ) in ADP-induced aggregation and in VASP-phosphorylation (VASP-P). We used univariate and multivariate analysis to correlate such parameters with PGE<sub>1</sub> sensitivity, BMI and presence/absence of CHD.</p> </sec> <sec> <title id="st0020">Results</title> <p id="sp0015">In the study cohort, pre-treatment responsiveness to PGE<sub>1</sub> varied widely (70 ± 28 [standard deviation (SD)]% inhibition of aggregation: range 10 to 100%). In the entire study cohort, pre-treatment PGE<sub>1</sub> sensitivity correlated with CS irrespective of genotype. On univariate analysis, CS was not significantly greater for patients without than those with loss-of-function mutations. Moreover, at multivariate analysis, PGE<sub>1</sub> sensitivity, but not genotype, was a strong correlate of ΔADP and ΔVASP-P (P < 0.0001 for both).</p> </sec> <sec> <title id="st0025">Conclusions</title> <p id="sp0020">The integrity of the cAMP pathway is a major determinant of subacute CS.</p> </sec> </abstract>