Welcome to Touch Briefings

Paul A Gurbel and Udaya S Tantry
American Heart Journal Volume 7 No.1

Platelet activation and aggregation are central to the development of thrombotic complications during acute coronary syndromes (ACS) and following percutaneous coronary interventions (PCIs). Adenosine diphosphate (ADP) and thromboxane (TX) A2 are major secondary agonists released by platelets following activation.¹ These secondary agonists play an important role in the amplification of platelet activation and aggregation and stable thrombus generation at the site of plaque rupture.

Simultaneous inhibition of the P2Y12 receptor by thienopyridines and TxA2 generation by aspirin is an effective antiplatelet treatment strategy to inhibit platelet function. Landmark clinical trials have demonstrated the central role of dual antiplatelet therapy in the treatment of ACS and in the prevention of complications during and after PCI.^2-4 In recent years, despite the well-documented clinical efficacy of clopidogrel and aspirin treatment, the phenomenon of antiplatelet resistance or non-responsiveness has been repeatedly reported by various investigators and has been correlated in small studies with the occurrence of ischemic events.^5-8

Definition of Antiplatelet Resistance
Platelet activation and aggregation are processes mediated by various receptor signaling pathways. A single treatment strategy directed against a specific receptor cannot overcome all thrombotic complications, and treatment failure following a single antiplatelet agent is not synonymous with drug resistance. It is our position that the optimal definition of resistance or nonresponsiveness to an antiplatelet agent is the failure of the antiplatelet agent to inhibit the target of its action. he identification of resistance would therefore utilize a laboratory technique that detects residual activity of the target. In the case of clopidogrel resistance, there would be significant evidence of residual post-treatment P2Y12 activity and in the case of aspirin there would be residual post-treatment cyclo-oxygenase (COX)-1 activity.⁹

Clopidogrel-Mechanism of Action
Clopidogrel is rapidly absorbed from the intestine and converted by the hepatic cytochrome P450 isoenzymes to an active thiol metabolite.^10,11 This short-lived active metabolite binds to the P2Y12 receptor specifically and irreversibly via a disulfide bridge between the reactive thiol group and two cysteine residues (cys17 and cys270) present in the extracellular domains of the P2Y12 receptor.¹² Clopidogrel has also been reported to attenuate platelet-leukocyte aggregate formation, the level of C-reactive protein (CRP), P-selectin, and CD40L, and the rate of thrombin formation.⁹

Laboratory Evaluation of Clopidogrel Responsiveness
Since clopidogrel specifically inhibits the ADP receptor on platelets, ex vivo measurement of ADP-induced maximum platelet aggregation by light transmittance aggregometry (LTA) has been the most commonly used laboratory method to evaluate clopidogrel responsiveness and is considered the gold standard.¹³ Recently, it was suggested that the response to clopidogrel would be better demonstrated by measuring late platelet aggregation at six minutes after stimulation with ADP rather than maximum aggregation.¹⁴

View Article here