Extracellular Vesicles of COVID-19 Patients Reflect Inflammation, Thrombogenicity, and Disease Severity

Abstract

Severe COVID-19 infections present with cytokine storms, hypercoagulation, and acute respiratory distress syndrome, with extracellular vesicles (EVs) being involved in coagulation and inflammation. This study aimed to determine whether coagulation profiles and EVs reflect COVID-19 disease severity. Thirty-six patients with symptomatic COVID-19 infection with mild/moderate/severe disease (12 in each group) were analyzed. Sixteen healthy individuals served as controls. Coagulation profiles and EV characteristics were tested by nanoparticle tracking analysis (NTA), flow cytometry, and Western blot. While coagulation factors VII, V, VIII, and vWF were comparable, significant differences were found in patients’ D-Dimer/fibrinogen/free protein S levels compared to controls. Severe patients’ EVs displayed higher percentages of small EVs (<150 nm) with increased expression of exosome marker CD63. Severe patients’ EVs displayed high levels of platelet markers (CD41) and coagulation factors (tissue factor activity, endothelial protein C receptor). EVs of patients with moderate/severe disease expressed significantly higher levels of immune cell markers (CD4/CD8/CD14) and contained higher levels of IL-6. We demonstrated that EVs, but not the coagulation profile, may serve as biomarkers for COVID-19 severity. EVs demonstrated elevated levels of immune- and vascular-related markers in patients with moderate/severe disease, and may play a role in disease pathogenesis.

Venous thromboembolism and severe COVID-19: a Mendelian randomization trial and transcriptomic analysis

“…Prior investigations revealed that EPCR interacting with coagulation proteases (namely, thrombin or tissue factor), or anticoagulant proteins (namely, activated protein C) to specific cell receptors on mononuclear or endothelial cells may influence cytokine synthesis (e.g., TNF-a, IL-1, IL-6, and IL-8, etc.) or inflammatory cell apoptosis ( 27 , 29 – 31 ). Furthermore, EPCR itself possesses anti-inflammatory activities.…”

Integrated analysis of RNA-seq datasets reveals novel targets and regulators of COVID-19 severity

“…Our analysis identified target genes that encode proteins located in exosomes that were crucial to vesicle transport, such as CD63 , ATP6V1D , and CHMP1A . CD63, commonly used as an exosome marker, increased protein expression, and correlated to higher exosome levels in severely ill COVID-19 patients ( Aharon et al, 2023 ). In addition, CD63 expression was increased in plasma cell-free RNA sequences of severe COVID-19 patients ( Wang et al, 2022 ).…”

Intrinsic factors behind long‐COVID: II. SARS‐CoV‐2, extracellular vesicles, and neurological disorders

“…124 The percentage of expression of CD4 and CD8 are higher in mild and severe COVID-19 infections, respectively, than in healthy people. 125 CD8 T cells can persist for up to 6 months after COVID-19 infection with continuous cytotoxic effect. The expression of CD14 was found to be higher in severe COVID-19 cases than in mild and nondiseased people.…”

“…In addition to the previous immune response after COVID-19 infection, cell-mediated immunity is highly stimulated after its recognition of viral antigens, resulting in the increase of secreted ECVs from T-cells and the promotion of inflammation. 125 Furthermore, the depletion of B cells after the administration of anti-CD20 monoclonal antibody could facilitate the long-COVID effect. 126 In severe COVID-19 infection, the exosome cargo was found to contain C1R, which has a role in activation of complement 1 complex, inflammation, and endothelial dysfunction.…”