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Clopidogrel action solely depends on dose and time. Clopidogrel also decreases the enzymatic activation of coagulation pathway, decreasing thrombin formation. Furthermore, clopidogrel reduces secretions from dense granules in platelets and reduces arachidonic acid, collagen, and thrombin‐induced platelet activation. Hence, inhibiting the activation of receptor complex gp IIb/III.
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Thus, protein kinase level increases, stimulating phosphorylation of vasodilator‐stimulated phosphoprotein (VASP). Thiol will irreversibly bind to P2Y12‐ADP receptor on platelets via a permanent disulfide bond with two cysteine residues (cys 17 and cys 270) on the receptor, thus inhibiting the ADP binding permanently and thereby activating adenylyl cyclase enzyme to increase cyclic adenosine monophosphate (cAMP).
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CLPM, clopidogrel metabolite CTM, converted to thiol metabolite of clopidogrel Metabolic activation of clopidogrel prodrug in patients. CTM consists of four isomers H1‐H4, where H3 (inactive form) and H4 (active circulating form) are mainly considered in monitoring the action of clopidogrel (Figure 1). CTM involves in specific and irreversible blocking of P2Y12 receptors, inhibiting the adenosine diphosphate (ADP)‐induced platelet aggregation. Fifteen percent will be converted to thiol metabolite of clopidogrel (CTM) by the hepatic cytochrome isoenzymes (CYP P450 1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4). This is known as CLPM (clopidogrel metabolite), which is a major inactive metabolic product circulating in the blood and helps to determine the pharmacokinetics of the prodrug. When clopidogrel is ingested, 85% of prodrug is absorbed by liver and converted to its carboxylic acid derivative by carboxylic esterase.
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Major reason for clopidogrel resistance was identified as the cytochrome P450 CYP2C19 polymorphism. Genetic variations between patients and delayed onset of action of clopidogrel result in the increase in resistance to clopidogrel therapy. However, modified assays are required which could overcome the limitations associated with currently available assays.Ībbreviations ADP adenosine diphosphate APTT activated partial thromboplastin time AU aggregation units CAD coronary artery disease CADP collagen‐ADP cAMP cyclic adenosine monophosphate CFT clot formation time CLPM clopidogrel metabolite CTM converted to thiol metabolite of clopidogrel EDTA‐K ethylenediaminetetraacetic potassium salt HPLC high‐performance liquid chromatography HTPR high on‐treatment platelet reactivity INR international normalized ratio LTA light transmission aggregometry MCF maximum clot firmness MFI mean fluorescence intensity ML maximum lysis MPV mean platelet volume MS mass spectrometry NSAID nonsteroidal anti‐inflammatory drug PCI percutaneous coronary intervention PFA platelet function assay PGE1 prostaglandin E1 POCT point of care test PRI platelet reactivity index PRP platelet‐rich plasma PRU platelet reactivity units PT prothrombin time ROTEM rotational thromboelastometry STEMI ST‐elevated myocardial infarction TEG thromboelastography UHPLC ultra‐high‐performance liquid chromatography VASP vasodilator‐stimulated phosphoprotein vWF von Willebrand factorĪntiplatelet therapy is an essential pharmacological therapy given to patients with atherothrombotic disease to inhibit the platelet aggregation by blocking the platelet receptors involved in adhesion. VerifyNow P2Y12 assay can be accepted as the ideal point of care test out of the discussed assays. In this review, the most commonly used PFA used for monitoring the effect of clopidogrel, LTA, vasodilator‐stimulated phosphoprotein assay phosphorylation, rotational thromboelastometry (ROTEM) delta and ROTEM platelet, thromboelastography, PFA‐100, VerifyNow P2Y12 assay, Multiplate analyzer, Plateletworks assay and pharmacogenetic studies, are comparatively discussed including their principles of action, advantages, and disadvantages. Light transmission aggregometry (LTA) is considered as the gold standard test among all PFA. The nonresponsiveness of patients to clopidogrel and the possibility of testing for clopidogrel resistance by platelet function assays (PFA) are contentious issues. Clopidogrel is the most common and widely used antiplatelet agent for patients with coronary artery disease following confirmation by electrocardiographic studies.