Inhibited and Uninhibited Platelet Deposition Within a Thrombus

Platelet-rich thrombus generation at the vascular injury site is a primary underlying mechanism of ischemic event occurrence in patients with coronary artery disease. Thromboxane (Tx) A2 and ADP act synergistically during platelet aggregation, and the ADP–P2Y12 receptor interaction plays a central role in sustaining the activation of glycoprotein (GP) IIb/IIIa receptors by amplifying the response to agonists. On the basis of large-scale clinical trial data, therapy with clopidogrel (a P2Y12 receptor blocker) plus aspirin (a cyclooxygenase [COX]-1 inhibitor)—dual antiplatelet therapy—has revolutionized the treatment of patients with high-risk coronary artery disease.1 However, multiple pharmacodynamic studies primarily based on light transmittance aggregometry in patients undergoing stenting, uniformly revealed wide response variability and high platelet reactivity to ADP during clopidogrel therapy.2 The latter observation subsequently was linked to single nucleotide polymorphisms in a major gene involved in the generation of clopidogrel active metabolite. Additional studies demonstrated an independent relation among high platelet reactivity, single nucleotide polymorphism carriage, and poststenting ischemic event occurrence.3 Persistent treatment failure in large-scale clinical trials despite the ability of more potent and pharmacodynamically predictable P2Y12 inhibitors, such as prasugrel and ticagrelor, to overcome high platelet reactivity has fueled the controversy surrounding mechanisms of clinical and laboratory resistance.4See accompanying article on page 2122 In the accompanying article, Hoefer …