Clopidogrel resistance: Role of body mass and concomitant medications
Introduction
Platelets have a central role in the development of arterial thrombosis and subsequent cardiovascular events. An appreciation of this complex process has made antiplatelet therapy the cornerstone of cardiovascular disease management [1]. Clopidogrel is frequently administered in patients with ischaemic heart disease or other atherothrombotic manifestations and proved to be effective in the prevention of cardiovascular diseases. The thienopyridine clopidogrel is a pro-drug metabolised in the liver via the cytochrome P450 (CYP) 3A4 system to the active compound which inhibits the P2Y12 ADP platelet receptor [2]. Studies have shown interindividual variations in response to clopidogrel, where a cohort of patients seems to be resistant to the antithrombotic effects of clopidogrel. Furthermore, there is an apparent link between clopidogrel resistance and clinical outcomes. The variability in response may be due to a number of mechanisms which may be classified into two categories: extrinsic and intrinsic. Extrinsic mechanisms include poor or inadequate compliance with treatment, and drug–drug interactions. Intrinsic mechanisms include genetic polymorphisms of the P2Y12 receptor gene and polymorphisms of the CYP3As which are the hepatic enzymes responsible for conversion of clopidogrel into the active metabolite. Increased release of ADP and up-regulation of other platelet activation pathways may also be involved [2]. Currently, there is neither a universally accepted definition of clopidogrel resistance nor an agreement on the phenomenon's mechanism [3], [4]. The aim of our present study was to compare some parameters of patients with effective platelet inhibition by clopidogrel (risk profile, previous diseases, medication, hemorheological parameters, plasma von Willebrand factor and soluble P-selectin levels) to patients with ineffective clopidogrel treatment.
Section snippets
Assessment of platelet aggregation
Epinephrine (adrenaline)-, adenosine diphosphate (ADP)- and collagen-induced aggregation of platelets was analysed. This involved measuring aggregation in 450 μL of platelet-rich plasma and 450 μL of platelet-poor plasma. Induced platelet aggregation was then measured following addition of 50 μL of the following agonists: ADP (5 and 10 μmol/L), epinephrine (10 μmol/L) or collagen (2 μg/mL) to platelet-rich plasma. Platelet aggregation was measured using a Carat TX4 aggregometer (Carat
Platelet aggregation
Among 157 involved in our study ineffective platelet aggregation was identified in 35 patients (22%). There were no significant differences in mean age, male/female ratio and mean dosage of clopidogrel between the two groups. There was also no difference in the mean ages of patients of each sex in the two groups (Table 1).
Risk profile and previous diseases
Patients with effective inhibition had lower BMI (28.8 kg/m2 vs. 26.1 kg/m2, p < 0.05). There were no other differences in cardiovascular risk profile or previous disease
Discussion
Platelet aggregation is a key event in arterial thrombosis. It is also involved in the initiation and development of atherosclerotic lesions, through platelet adhesion to dysfunctional endothelium and release of growth factors and cytokines [11]. Adenosine diphosphate (ADP) belongs to the key mediators of platelet stimulation and mediates its effect through two 7 transmembrane receptors, P2Y1 and P2Y12 [12]. P2Y12 plays a particularly important role in platelet aggregation, since its coupling
Conclusion
In summary, our study is among the first studies which examined the potential background(s) of clopidogrel resistance. We showed that BMI is associated with low response to clopidogrel and psychotropic agents (benzodiazepines and SSRIS) but not statins may inhibit the metabolism of clopidogrel possibly by the way of CYP3A4 and CYP1A2. Finally, our study had some limitations. The baseline aggregation values of our patients were unknown because at the moment of the examination they already were
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