Abstract 475: Overexpression of Platelet and Monocyte Cyclooxygenase-2 in Coronary Thrombi from Diabetic Patients: A Potential Mechanism of Aspirin Treatment Failure
Antiplatelet therapy may not always be efficient enough in diabetics. Although the concept of aspirin resistance is extensively studied, its precise mechanisms are still unknown. We tested the hypothesis that cyclooxygenase (COX)-2 expression in newly formed platelets (PLTs) and monocytes might represent a mechanism of aspirin-insensitive PLT activation in diabetic patients. We studied 25 type II diabetic patients (T2D) and 25 matched non diabetic patients developing acute myocardial infarction (AMI). Ten type I diabetic (T1D) patients with AMI were also studied to assess the role of insulin in PLT function. All patients underwent immediate thrombectomy before PTCA, and coronary thrombi were collected and analyzed by immunohistochemistry. We also measured mean PLT volume (MPV), and COX-2 expression in circulating PLTs and monocytes. COX-2 expression in coronary thrombi was markedly higher in the diabetic patients vs controls (18±4% vs 3±1.2%, P<0.001), with similar rates in T1D (17±6%), and T2D (16±4%). COX-2 staining indicated its localization in PLTs and monocytes. COX-2 co-localized with thromboxane-synthase, type 1 inducible prostaglandin E-synthase, and EP3 receptor. Higher COX-2 expression in thrombi from diabetic patients was associated with a comparably higher COX-2 expression in circulating PLTs and monocytes (12±1% vs 2.5±0.3%, and 16±2.1% vs 3±1.3%, respectively P<0.001), mainly when present as PLT-monocyte microaggregates (80±6% vs 20±3% for PLTs, and 74±4% vs 14±3% for monocytes, respectively; P<0.001). Enhanced COX-2 in PLTs likely reflected an accelerated PLT turnover in diabetic patients, as it was associated with higher serum level of thrombopoietin (68.2±26 vs 22.3±14 pg/mL, P<0.001) and higher MPV (12.4±2.3 vs 8.4±1.5 fl, P<0.001). Notably, a strong correlation among HbA1c, MPV and COX-2 expression was found in diabetics, suggesting that PLT turnover may be regulated by glycemic control. This study shows that newly formed, COX-2 expressing PLTs as well as PLT-primed monocytes characterize coronary thrombi of diabetic patients developing AMI. Aspirin-resistant thromboxane biosynthesis is likely to contribute to coronary occlusion and could account, at least in part, for treatment failure in diabetes.