Abstract
ObjectivePlatelet reactivity, platelet binding to monocytes and monocyte infiltration play a detrimental role in atherosclerotic plaque progression. We investigated whether platelet reactivity was associated with levels of circulating platelet-monocyte complexes (PMCs) and macrophages in human atherosclerotic carotid plaques.MethodsPlatelet reactivity was determined by measuring platelet P-selectin expression after platelet stimulation with increasing concentrations of adenosine diphosphate (ADP), in two independent cohorts: the Circulating Cells cohort (n = 244) and the Athero-Express cohort (n = 91). Levels of PMCs were assessed by flow cytometry in blood samples of patients who were scheduled for percutaneous coronary intervention (Circulating Cells cohort). Monocyte infiltration was semi-quantitatively determined by histological examination of atherosclerotic carotid plaques collected during carotid endarterectomy (Athero-Express cohort).ResultsWe found increased platelet reactivity in patients with high PMCs as compared to patients with low PMCs (median (interquartile range): 4153 (1585–11267) area under the curve (AUC) vs. 9633 (3580–21565) AUC, P<0.001). Also, we observed increased platelet reactivity in patients with high macrophage levels in atherosclerotic plaques as compared to patients with low macrophage levels in atherosclerotic plaques (mean±SD; 8969±3485 AUC vs. 7020±3442 AUC, P = 0.02). All associations remained significant after adjustment for age, sex and use of drugs against platelet activation.ConclusionPlatelet reactivity towards ADP is associated with levels of PMCs and macrophages in human atherosclerotic carotid plaques.
Highlights
Platelets and monocytes play a crucial role in the initiation and progression of atherosclerosis [1]
The role of platelet binding to inflamed endothelial cells during the development of atherosclerosis was evidenced by a significant reduction in monocyte accumulation and atherosclerotic plaque progression after treatment with Glycoprotein Iba (GPIba) blocking antibodies [4]
Previous work has shown that formation of these circulating platelet-monocyte complexes results in increased infiltration of monocytes into atherosclerotic plaques in mice [8] and elevated levels of circulating PMCs were observed in patients with coronary artery disease [9,10,11]
Summary
Platelets and monocytes play a crucial role in the initiation and progression of atherosclerosis [1]. The role of platelet binding to inflamed endothelial cells during the development of atherosclerosis was evidenced by a significant reduction in monocyte accumulation and atherosclerotic plaque progression after treatment with GPIba blocking antibodies [4]. The interaction of platelets with inflamed endothelial cells facilitates the capturing of monocytes to the vessel wall through interaction between Gp1ba and the constitutively expressed monocyte receptor P-Selectin Glycoprotein Ligand-1 (PSGL1)[5]. This interaction, together with the interaction between GPIba and the integrin macrophage-1 antigen (MAC-1), results in firm cellular arrest of monocytes and their subsequent infiltration into the vascular wall [6,7]. Previous work has shown that formation of these circulating platelet-monocyte complexes results in increased infiltration of monocytes into atherosclerotic plaques in mice [8] and elevated levels of circulating PMCs were observed in patients with coronary artery disease [9,10,11]
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