Determinants of subacute response to clopidogrel: relative impact of CYP2C19 genotype and PGE1/adenylate cyclase signalling

• Published in: Thrombosis research Vol. 136; no. 2; pp. 308 - 314
• Main Authors: Hurst, Nicola L., Nooney, Vivek B., Chirkov, Yuliy Y., De Caterina, Raffaele, Horowitz, John D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.08.2015
• Subjects: adenylate cyclase; Adenylyl Cyclases - metabolism; Adult; Aged; Aged, 80 and over; Alprostadil - metabolism; blood platelets; clopidogrel; cyclic AMP; Cytochrome P-450 CYP2C19 - genetics; Female; Genotype; Hematology, Oncology and Palliative Medicine; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors - pharmacology; purinergic P2Y12 receptor antagonists; Signal Transduction; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacology; clopidogrel; cyclic AMP; blood platelets; purinergic P2Y12 receptor antagonists; adenylate cyclase; purinergic P2Y 12 receptor antagonists; purinergic P2Y receptor antagonists
• ISSN: 0049-3848; 1879-2472; 1879-2472
• DOI: 10.1016/j.thromres.2015.03.011

and Hypotheses: The signal transduction pathway modulated by activation or blockade of platelet P2Y12 receptors is linked to PGE1-stimulated adenylate cyclase effects, but this link’s impact on P2Y12 receptor antagonist response is uncertain. We therefore tested the hypothesis that pre-treatment platelet responsiveness to PGE1 predicts subsequent responsiveness to clopidogrel. In order to maximise heterogeneity of platelet responsiveness to PGE1 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 PGE1 by ADP-induced whole blood aggregation. Clopidogrel was administered for 7days 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 PGE1 sensitivity, BMI and presence/absence of CHD. In the study cohort, pre-treatment responsiveness to PGE1 varied widely (70±28 [standard deviation (SD)]% inhibition of aggregation: range 10 to 100%). In the entire study cohort, pre-treatment PGE1 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, PGE1 sensitivity, but not genotype, was a strong correlate of ΔADP and ΔVASP-P (P<0.0001 for both). The integrity of the cAMP pathway is a major determinant of subacute CS. •A potential basis for clopidogrel resistance extends beyond impaired bioactivation.•Impaired “downstream” PGE1/adenylate cyclase signalling is a potential modulator.•Pre-clopidogrel PGE1 platelet response predicted clopidogrel response at 7days.•This was a stronger multivariate associate of response than bio-activator genotype.