Background Platelet surface P-selectin is considered the “gold standard” marker of platelet activation. Degranulated, P-selectin–positive platelets, however, aggregate with leukocytes in vitro and rapidly lose surface P-selectin in vivo. Methods and Results Flow cytometric tracking of autologous, biotinylated platelets in baboons enabled us to directly demonstrate for the first time in vivo that (1) infused degranulated platelets very rapidly form circulating aggregates with monocytes and neutrophils, and (2) 30 minutes after infusion of the degranulated platelets, the percentage of circulating monocytes aggregated with infused platelets persist at high levels, whereas the percentage of circulating neutrophils aggregated with infused platelets and the platelet surface P-selectin of nonaggregated infused platelets return to baseline. We therefore performed 2 clinical studies in patients with acute coronary syndromes. First, after percutaneous coronary intervention (n=10), there was an increased number of circulating monocyte-platelet (and to a lesser extent, neutrophil-platelet) aggregates but not P-selectin–positive platelets. Second, of 93 patients presenting to an Emergency Department with chest pain, patients with acute myocardial infarction (AMI) (n=9) had more circulating monocyte-platelet aggregates (34.2±10.3% [mean±SEM]) than patients with no AMI (n=84, 19.3±1.4%, P <0.05) and normal control subjects (n=10, 11.5±0.8%, P <0.001). Circulating P-selectin–positive platelets, however, were not increased in chest pain patients with or without AMI. Conclusions As demonstrated by 3 independent means (in vivo tracking of activated platelets in baboons, human coronary intervention, and human AMI), circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin.

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To examine the extent of platelet inhibition by prasugrel vs. clopidogrel in a TRITON-TIMI 38 substudy. TRITON-TIMI 38 randomized acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) to prasugrel or standard dose clopidogrel. Selected sites prospectively enrolled TRITON-TIMI 38 patients to evaluate adenosine diphosphate (ADP)-attenuated phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) (n = 125 patients) and, in a subset (n = 31 patients), ADP-stimulated platelet aggregation. VASP platelet reactivity index (PRI) was lower in prasugrel-treated patients than in clopidogrel-treated patients at 1–2 h post-PCI (≥1 h after loading dose) (P < 0.001) and at 30 days (P < 0.001). Maximal platelet aggregation to 20 µM ADP was lower in prasugrel-treated patients than in clopidogrel-treated patients at 1–2 h (P = 0.004) and 30 days (P = 0.03). Results were similar with 5 µM ADP. Thienopyridine hyporesponsiveness, prespecified as VASP PRI >50%, was more frequent in clopidogrel-treated patients than in prasugrel-treated patients at 1–2 h (P < 0.001) and 30 days (P = 0.03). The TRITON-TIMI 38 platelet substudy shows that prasugrel results in greater inhibition of ADP-mediated platelet function in ACS patients than clopidogrel, supporting the hypothesis that greater platelet inhibition leads to a lower incidence of ischaemic events and more bleeding both early and late following PCI.