The role of inflammatory and prothrombotic biomarkers in severe COVID-19-associated endothelial dysfunction
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Authors
Hinds, Megan
Date
2024-09-05
Type
thesis
Language
eng
Keyword
COVID-19 , Endothelial cell
Alternative Title
Abstract
Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December of 2019, coronavirus disease 2019 (COVID-19) associated endothelial cell (EC) dysfunction has been well documented in critically ill patients. Studies have identified elevated hemostatic factors as indicators of acute and sustained EC activation, including the large, highly adhesive clotting protein, von Willebrand factor (VWF). Reduced activity of the VWF cleaving protease ADAMTS-13 has also been described and is associated with poor disease outcome. These observations have been coupled with serious clinical effects, including deep vein thrombosis (DVT) and acute pulmonary embolism (PE). This suggests that severe COVID-19-driven EC injury is fulminant and sustained, and presents a major risk for thrombotic complications. However, the role of inflammatory and prothrombotic biomarkers in EC activation and injury requires further investigation.
Plasma samples were collected from 61 severe COVID-19 patients at various timepoints throughout their ICU stay. Clinical outcomes were recorded, and relevant plasma biomarkers were measured. ECs from healthy donors were treated with severe COVID-19 plasma and the effects of these biomarkers on EC activation, VWF secretion, and monolayer disruption were analyzed via flow cytometry, ELISA, and confocal immunofluorescence microscopy.
Clinical outcomes included DVT, PE, stroke, and death. Prothrombotic biomarkers were consistently elevated, with mean values peaking at days 11 to 15 of their ICU stay. Mean ADAMTS13 levels were below normal range, with some patients experiencing a reduction to ≤10% of normal. Cytokine profiles were diverse but represented a significant increase in biomarkers associated with innate immunity coupled with a mean reduction in those associated with adaptive immune system. In addition, ECs exposed to severe COVID-19 plasma displayed significant monolayer disruption, activation, and VWF secretion compared to cells treated with normal plasma.
This study confirms the association of biomarkers with significant clinical outcomes and highlights their use as a predictive tool. Severe COVID-19 induces a prothrombotic and hyperinflammatory state that may sustain EC activation and disrupt monolayer integrity independent of direct viral infection by SARS-CoV-2. Results of this study could provide new insights into disease mechanisms, uncover therapeutic targets, and validate cellular models for future studies on EC dysfunction.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.