CORRESPONDENCE: LETTER TO THE EDITOR
Multiple Mechanisms Affect the Clopidogrel Response
Gerasimos Siasos, MD, PhD,
Dimitris Tousoulis, MD, PhD, FACC* and
Christodoulos Stefanadis, MD, PhD, FACC
* 1st Cardiology Unit, Hippokration Hospital, Athens University Medical School, 69 South Karagiorga Street, Glifada, Athens 16675, Greece (Email: drtousoulis{at}hotmail.com).
We read with interest the paper by Ang et al. (1) in a previous issue of the Journal. The purpose of the study was to identify factors associated with lower platelet inhibition (PI) with clopidogrel in patients with cardiovascular disease. Their results showed that elevated plasma fibrinogen  375 mg/dl is a unique factor associated with lower PI in diabetic patients, whereas increased body mass index remains independently associated with lower PI after clopidogrel therapy. They also identify the presence of diabetes mellitus as a factor associated with lower PI. However, this finding was only significant in the presence of an elevated serum fibrinogen level. No other statistical association with PI was found in the multiple variable model.
Although these findings are interesting, other factors involving clopidogrel response have not been completely evaluated. For example, the impact of genetic polymorphisms or other genetic factors on clopidogrel response has not been evaluated in the study. It is well known that P2Y12 receptor inhibition is implemented by an active metabolite of clopidogrel. Therefore, genetic variants of enzymes within the metabolic pathways (P450 enzymes) or downstream targets of the active metabolite (P2Y, platelet glycoproteins IIb/IIIa and Ia) might affect clopidogrel response. Moreover, the metabolic activity of the P450 enzymes varies considerably among individuals. Genetic polymorphisms of the cytochrome P450 isoenzymes such as CYP3A4*1B (rs2740574), CYP3A5*3 (rs776746), and CYP2C19*2 (rs4244285) have been implicated to modulated individual response to clopidogrel (2). However, only CYP2C19*2 (SNP rs4244285, AA genotype) polymorphism association with variable clopidogrel response has been validated in both healthy and acute coronary syndrome individuals (3). The association of platelet glycoproteins IIIa and P2Y12 receptor polymorphisms with clopidogrel variable response has not been confirmed in previous studies (4), and it should also be examined in the study by Ang et al. (1).
Finally, other mechanisms, such as cellular factors (accelerated platelet turnover, reduced CYP3A metabolic activity, increased ADP exposure, up-regulation of P2Y pathways), or clinical factors (noncompliance, underdosing, poor absorption) may cause suboptimal clopidogrel response.
This interesting study by Ang et al. (1) sheds some light on mechanisms underlying reduced response of platelets to the antiaggregatory effect of clopidogrel. Although the limited number of patients with lower inhibition of platelet reactivity by clopidogrel makes the findings exploratory, further studies with a larger cohort of patients are needed to elucidate the multiple mechanisms involving clopidogrel response.
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1. Ang L, Palakodeti V, Khalid A, et al. Elevated plasma fibrinogen and diabetes mellitus are associated with lower inhibition of platelet reactivity with clopidogrel J Am Coll Cardiol 2008;52:1052-1059.[Abstract/Free Full Text]2. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel Arterioscler Thromb Vasc Biol 2006;26:1895-1900.[CrossRef][Web of Science][Medline] 3. Frere C, Cuisset T, Moragne PE, et al. Effect of cytochrome P450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome Am J Cardiol 2008;101:1088-1093.[CrossRef][Web of Science][Medline] 4. Lev EI, Patel RT, Guthikonda S, et al. Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel Thromb Res 2007;119:355-360.[CrossRef][Web of Science][Medline]
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