In severe COVID, Antithrombotic Endothelial Dysfunction is prevented by Tie2 Activation

Research suggests that COVID-19 pathophysiology may be affected by microvascular thrombosis. Analysis of histologic specimens and measurement of circulating proteins and metabolites have shown severe vascular inflammation and endothelial injury. Several studies support the theory that severe COVID-19 may be associated with increased circulating levels of these markers, including procoagulant Von Willebrand factor (VWF), vascular cell adhesion markers (VCAM, ICAM, E-selectin), and plasminogen activator inhibitor (PAI-1).

Increased circulating antithrombotic endothelial surface proteins tissue factor pathway inhibitor (TFPI) and thrombomodulin, which are removed from the endothelial surface during inflammation, are also said to be associated with severe COVID-19. Researchers from the US recently assessed if severe COVID-19 is linked to procoagulant dysfunction of the endothelium and changes in the Tie2-angiopoietin axis. They assessed circulating endothelial markers in a study cohort of 98 patients with mild, moderate, or severe COVID-19.

The assessment showed profound endothelial dysfunction, which indicates a prothrombotic state. Angpt-2 concentrations increased with an increase in disease severity, and the highest levels of Angpt-2 were linked to the worst survival outcomes. The researchers found that when treated with plasma taken from severe COVID-19 patients, primary human endothelial cells upregulated the expression of thrombo-inflammatory genes, inhibited the expression of antithrombotic genes, and endorsed coagulation on the endothelial surface. They also noticed that pharmacologic activation of Tie2 with the AKB-9778 reversed the prothrombotic state caused by COVID-19 plasma in endothelial cells.

They examined lung autopsy specimens from severe COVID-19 patients and found a prothrombotic endothelial signature as shown by an increase in von Willebrand Factor and loss of anticoagulant proteins.

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Ref Link: https://www.medrxiv.org/content/10.1101/2021

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