High levels of TSP1+/CD142+ platelet-derived microparticles characterise young patients with high cardiovascular risk and subclinical atherosclerosis

Abstract

Circulating microparticles (cMPs) play important roles in cellular crosstalk and are messengers of cell activation. We have previously reported that platelet-released microparticles (pMPs) stimulate thrombosis and that lipid-lowering treatment as per guidelines in patients with familial hypercholesterolaemia (FH) is not sufficiently effective in reducing pro-inflammatory cell activation and, consequently, CD45+/CD3+-lymphocyte-derived cMP shedding. FH patients, due to life-long vascular exposure to high LDL-cholesterol levels, are at high cardiovascular risk (HCVR) and develop premature coronary artery disease. Our objectives were to investigate a) whether patients with HCVR have cMPs with a prothrombotic phenotype, and b) whether patients with magnetic resonance imaging (MRI) evidence of lipid-rich atherosclerotic lesions have a specific cMP profile regarding prothrombotic protein cargos. cMPs were isolated from HCVR-patients and from age/gender/treatment-matched control patients. cMP phenotype was characterised by triple-labelling flow cytometry. HCVR--patients have higher numbers of pMPs derived from activated platelets as well as of tissue factor-rich microparticles (TF+-cMPs) than controls (P< 0.0001). TF+-cMPs showed procoagulant activity, which associate with atherosclerotic plaque burden, indicating that TF in the cMPs is functional. In HCVR-patients, overall TF+-cMPs (monocyte-derived [CD142+/CD14+] and platelet-derived [CD142+/TSP1+]) and activated pMPs directly correlate with MRI-detected lipid-rich atherosclerotic plaques while inversely correlate with MRI-detected calcified plaques. C-statistics analysis showed that prothrombotic cMPs add significant prognostic value to a risk factor model for the prediction of lipid-rich plaques. In conclusion, the activation status of blood cells in HCVR-patients differed markedly from controls as shown by higher circulating levels of prothrombotic and TF+-cMPs. Prothrombotic cMP numbers identify subclinical atherosclerotic plaque burden.

Application of Extracellular Vesicles Proteomics to Cardiovascular Disease: Guidelines, Data Analysis, and Future Perspectives

“…Along with numerous studies, it has been proved that the number and content of EVs could differ depending on the state of the disease making them potential candidates for non‐invasive biomarkers. Indeed, increased levels of circulating EVs have been reported in CVDs …”

Role of Platelet-Derived Microvesicles As Crosstalk Mediators in Atherothrombosis and Future Pharmacology Targets: A Link between Inflammation, Atherosclerosis, and Thrombosis

“…Erosion, fissure, or rupture of the atherosclerotic plaques are triggering events in ACS, being platelets a key player in these atherothrombotic processes (Fuster et al, 1990). We have found that HCVR patients have significantly high shedding of cMVs carrying epitopes of platelet activation and directly associate to lipid-rich subclinical atherosclerotic burden (Suades et al, 2015a). Besides, these prothrombotic pMVs have demonstrated an incremental prognostic value beyond the classical risk factor model for the prediction of cardiovascular risk, indicating that the state of activation of platelets in the blood-vascular interface may increase the release of pMVs that become markers of the high atherothrombotic risk (Suades et al, 2015a).…”

“…We have found that HCVR patients have significantly high shedding of cMVs carrying epitopes of platelet activation and directly associate to lipid-rich subclinical atherosclerotic burden (Suades et al, 2015a). Besides, these prothrombotic pMVs have demonstrated an incremental prognostic value beyond the classical risk factor model for the prediction of cardiovascular risk, indicating that the state of activation of platelets in the blood-vascular interface may increase the release of pMVs that become markers of the high atherothrombotic risk (Suades et al, 2015a). Blood thrombogenicity can be partially explained by the fact that TF is not only present in the subendothelium, but also in the circulation (Sambola et al, 2003).…”

The Clinical Utility of Circulating Microparticles’ Measurement in Heart Failure Patients

“…Therefore, increased level of circulating platelet-derived MPs was found in older age individuals without CV disease, as well as in the younger individuals with high CV risk due to subclinical atherosclerosis [96] and patients with known CV diseases [97]. However, the fractions of platelet-derived MPs expressed P-selectin or CD63 were higher in the patients with peripheral arterial disease and ST-segment elevation myocardial infarction [97] that confirmed the role of activated platelets-derived MPs in the pathogenesis of thrombus formation and platelet aggregations [98].…”

“…Although the importance of platelet-derived MPs in the pathogenesis of CV diseases is still debated [93][94][95][96], there are data regarding directly effect of platelet-derived MPs on formation of foam cells in atherosclerotic plaque [97]. Therefore, increased level of circulating platelet-derived MPs was found in older age individuals without CV disease, as well as in the younger individuals with high CV risk due to subclinical atherosclerosis [96] and patients with known CV diseases [97].…”