Increased platelet reactivity is associated with circulating platelet-monocyte complexes and macrophages in human atherosclerotic plaques

Objective: Platelet 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. Methods: Platelet 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). Results: We 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 pl

Amplified endogenous plasmin activity resolves acute thrombotic thrombocytopenic purpura in mice

Essentials Plasmin is able to proteolyse von Willebrand factor. It was unclear if plasmin influences acute thrombotic thrombocytopenic purpura (TTP). Plasmin levels are increased during acute TTP though suppressed via plasmin(ogen) inhibitors. Allowing amplified endogenous plasmin activity in mice results in resolution of TTP signs.status: publishe

Age and coumarin-type anticoagulation are associated with the occurrence of intraplaque hemorrhage, while statins are associated less with intraplaque hemorrhage: A large histopathological study in carotid and femoral plaques

INTRODUCTION: Intraplaque hemorrhage (IPH) is an important determinant of progression and destabilization of atherosclerotic plaque. We recently demonstrated that IPH is an independent predictor of future cardiovascular events after carotid endarterectomy. Thus far, it is unknown whether clinical patient characteristics, such as medication use, are associated with the occurrence of IPH. The purpose of this study was to examine the association of IPH with clinical patient characteristics. METHODS AND RESULTS: 1070 consecutive patients who underwent a carotid (n=794) or femoral (n=276) endarterectomy were included. Endarterectomy specimens were subjected to histopathological examination. IPH was observed in 644/794 (81%) carotid and 175/276 (63%) femoral plaques. Carotid IPH was positively correlated with advanced age (69 years [IQR: 62-75] vs. 65 years [IQR: 57-73]; P=0.002) and coumarin-type anticoagulation use prior to operation (104/116 [90%] with coumarin derivatives vs. 540/678 [80%] without coumarin derivatives; P=0.01). Carotid IPH was less frequently observed in patients that used statins prior to endarterectomy (468/595 [79%] with statin vs. 176/199 [88%] without statin; P=0.002). In multivariate analysis, age, coumarin-type anticoagulation use and statin use were independently correlated with carotid IPH. No association was observed between femoral IPH and clinical patient characteristics. CONCLUSION: Advanced age and coumarin-type anticoagulation use are associated with the occurrence of IPH, while statin use is associated with less IPH.status: publishe

Different stages of intraplaque hemorrhage are associated with different plaque phenotypes: A large histopathological study in 794 carotid and 276 femoral endarterectomy specimens

BACKGROUND AND PURPOSE: Intraplaque hemorrhage (IPH) is an important determinant of progression and destabilization of atherosclerotic plaque. We recently demonstrated that IPH is an independent predictor of cardiovascular events. IPH has become more clinically relevant since magnetic resonance imaging (MRI) technique is able to visualize IPH in vivo. Different stages of IPH have been described. However, etiology of the different stages is not known and it is unclear if these detected different stages are all associated with the vulnerable plaque phenotype. METHODS AND RESULTS: 1070 patients who underwent a carotid (n=794) or femoral (n=276) endarterectomy were included. Histopathological presence of IPH was determined and divided into 3 types: recent, organized and amorphous IPH. Carotid IPH was observed in 644/794 (81%) plaques, divided into 14 (2%) recent, 70 (11%) organized and 560 (87%) amorphous. Femoral IPH was observed in 175/276 (63%) plaques, divided into 2 (1%) recent, 89 (51%) organized and 84 amorphous (48%). Overall presence of carotid IPH was associated with a large lipid core, no or minor staining of smooth muscle cells, no or minor calcification and high microvessel density. Overall presence of femoral IPH was associated with moderate to heavy staining of macrophages. Plaques with organized IPHs revealed more macrophages, a larger lipid core, less smooth muscle cells, less calcification and higher microvessel density than plaques with amorphous IPHs. CONCLUSIONS: IPH is a significant characteristic of carotid and femoral atherosclerotic plaque and can be classified into different types. Organized IPH is associated with unstable and amorphous IPH with stable plaque characteristics.status: publishe

Platelet reactivity related to macrophage levels.

<p>Comparison of the AUC after ADP stimulation between low (n = 67) versus high macrophage levels in atherosclerotic carotid plaques (n = 24). Grey bars represent means with standard deviations. MFI = mean fluorescence intensity, AUC = area under curve, ADP = adenosine diphosphate.</p

Histology of macrophage levels in atherosclerotic carotid plaques.

<p>Macrophage staining (brown), nucleus staining with haematoxylin (blue). (<b>a</b>) Low macrophage levels (40× magnification). (<b>b</b>) Higher magnification of the indicated area in (a) (100× magnification). (<b>c</b>) High macrophage levels (40× magnification). (<b>d</b>) Higher magnification of the indicated area in (c) (100× magnification).</p

Conversion of dose-response curve into area under the curve.

<p>In order to compare total platelet reactivity between patients, we derived the area under the curve from each dose response curve. MFI = mean fluorescence intensity, AUC = area under curve, ADP = adenosine diphosphate.</p

Baseline characteristics.

<p>Continuous values are expressed as mean ± standard deviation (unless specified otherwise). Categorical values are expressed as number of total (percentage).</p><p>CG = Cockroft-Gault, CEA = carotid endarterectomy, IQR = interquartile range.</p