Abstract 5884: Efficacy Assessment of Antiplatelet Therapy in Acute Coronary Syndrome by Time-Volume Analysis of Platelet Thrombus Formation
Platelet thrombus formation contributes to the pathogenesis of acute coronary syndrome (ACS), and patients who exhibit a reduced response to antiplatelet therapy have an increased risk for adverse cardiovascular events. To assess “resistance” to antiplatelet therapy, we have measured platelet thrombus formation by four-dimensional (time-volume) analysis in real time using confocal videomicroscopy of heparinized blood perfused over collagen type I fibrils under controlled flow conditions. We studied 36 patients with the diagnosis of ACS who were treated with aspirin (100 mg daily) and clopidogrel (600 mg loading dose followed by 75 mg daily). Measurements were obtained within 24 h from admission and then at 5 days, 1 and 6 months. In 30 patients, thrombus volume was inhibited >50% relative to control in all samples tested. Notably, the difference between control and patient samples was significant only after 6 min of flow, i.e. initial platelet adhesion and aggregation were normal in spite of antiplatelet treatment. Ex vivo perfusion studies showed that inhibition of the P2Y12 ADP receptor (the target of clopidogrel) has no effect on collagen-induced platelet activation under flow; this may explain the initially normal thrombus formation and suggests that the effect of antiplatelet therapy is limited to the subsequent propagation and stabilization phase of thrombus growth. Six patients (16.7%) exhibited no decrease of thrombus volume in spite of antiplatelet treatment, and 3 of them developed stent thrombosis. These, and 2 other “resistant” patients, were switched to ticlopidine, after which they all showed >50% inhibition of thrombus volume. The platelet VASP phosphorylation index, a direct test of P2Y12 inhibition, showed no correlation with the volume of thrombi formed onto collagen under flow, but its value was >50% in all patients with <50% thrombus volume inhibition. One patient with VASP index decreased to 21% but no inhibition of thrombus volume developed stent thrombosis. Our findings indicate that thrombus volume measurement in flowing blood exposed to collagen may provide a clinically relevant correlate of the effect of antiplatelet therapy, and provide a more reliable prediction of thrombotic risk than the VASP index.