Abstract
Plasma extracellular vesicles (EVs) are lipid membrane vesicles involved in several biological processes including coagulation. Both coagulation and lipid metabolism are strongly associated with cardiovascular events. Lowering very-low- and low-density lipoprotein ((V)LDL) particles via dextran sulphate LDL apheresis also removes coagulation proteins. It remains unknown, however, how coagulation proteins are removed in apheresis. We hypothesize that plasma EVs that contain high levels of coagulation proteins are concomitantly removed with (V)LDL particles by dextran sulphate apheresis. For this, we precipitated (V)LDL particles from human plasma with dextran sulphate and analyzed the abundance of coagulation proteins and EVs in the precipitate. Coagulation pathway proteins, as demonstrated by proteomics and a bead-based immunoassay, were over-represented in the (V)LDL precipitate. In this precipitate, both bilayer EVs and monolayer (V)LDL particles were observed by electron microscopy. Separation of EVs from (V)LDL particles using density gradient centrifugation revealed that almost all coagulation proteins were present in the EVs and not in the (V)LDL particles. These EVs also showed a strong procoagulant activity. Our study suggests that dextran sulphate used in LDL apheresis may remove procoagulant EVs concomitantly with (V)LDL particles, leading to a loss of coagulation proteins from the blood.
Highlights
Circulating extracellular vesicles (EVs) have been recognized for their emerging roles inphysiology and their potential as biomarkers in cardiovascular disease [1,2]
And colleagues showed that the concentration of plasma EVs in patients with familial hypercholesterolemia was reduced after low-density lipoprotein (LDL) apheresis [8]
Four proteins present in the Ingenuity Pathway Analysis (IPA) coagulation system pathway were selected for verification using a bead-based immunoassay: von Willebrand factor (VWF), SerpinC1, plasminogen (PLG), and SerpinF2
Summary
Circulating extracellular vesicles (EVs) have been recognized for their emerging roles in (patho)physiology and their potential as biomarkers in cardiovascular disease [1,2]. We have shown that cardiovascular events, such as myocardial infarction and stroke, are associated with coagulation-pathway proteins that are carried by the plasma EVs [3,4]. Depletion of coagulation factors by apheresis is assumed to reduce blood viscosity and improve regional myocardial perfusion in patients with severe hypercholesterolemia [20,21]. And colleagues showed that the concentration of plasma EVs in patients with familial hypercholesterolemia was reduced after LDL apheresis [8]. The content of these apheresis-depleted plasma EVs, has not been characterized. We precipitated (V)LDL particles from human plasma using dextran sulphate (as an in vitro model for DSA apheresis) followed by a proteomic analysis of the content and a measurement of the pro-coagulant activity of precipitated EVs
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