Vascular Endothelial Damage in the Pathogenesis of Organ Injury in Severe COVID-19
Top Cited Papers
- 5 May 2021
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 41 (5), 1760-1773
- https://doi.org/10.1161/ATVBAHA.120.315595
Abstract
Objective: Whether endotheliopathy only mirrors coronavirus disease 2019 (COVID-19) severity or plays an intrinsic role in microvascular thrombosis and organ failure remains unanswered. We assessed whether markers of endothelial damage and immune dysregulation were associated with organ failure, thrombus formation, and death. Approach and Results: Markers of endothelial damage (VWF:Ag [von Willebrand factor antigen], PAI-1 [plasminogen activator inhibitor-1], syndecan-1, TFPI [tissue factor pathway inhibitor], and soluble thrombomodulin), complement activation (C5a and C5b-9), cytokines (IL [interleukin]-6, TNF [tumor necrosis factor]-alpha, and IL-2R), and neutrophil extracellular traps (cell-free DNA, nucleosomes, and myeloperoxidase-DNA) were measured at intensive care unit admission in 82 patients with COVID-19. We also analyzed the histological composition of thrombi collected in critically ill living patients successfully weaned from extracorporeal membrane oxygenation. Beside respiratory failure, VWF:Ag, PAI-1, TFPI, and syndecan-1 were independently associated with liver injury and multiorgan failure development, underlining the direct role of endotheliopathy in organ failure. Nucleosomes were also associated with liver injury, multiorgan failure, and death which occurred in 38%, 60%, and 27% of patients, respectively. Moreover, dysregulated immune response including cytokines, complement, and neutrophil extracellular traps was associated with markers of endothelial damage, respiratory failure, and liver injury. COVID-19 thrombi retrieved from extracorporeal membrane oxygenation circuitry contained accumulation of neutrophils, VWF, and significantly higher amount of neutrophil extracellular traps when compared with non-COVID-19 thrombi. Conclusions: We provide new associative data supporting that endotheliopathy and dysregulated immune responses are involved in respiratory and liver failure through microvascular damage in patients with severe COVID-19.This publication has 61 references indexed in Scilit:
- Human neutrophil peptides inhibit cleavage of von Willebrand factor by ADAMTS13: a potential link of inflammation to TTPBlood, 2016
- Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculatureNature Communications, 2015
- von Willebrand Factor Directly Interacts With DNA From Neutrophil Extracellular TrapsArteriosclerosis, Thrombosis, and Vascular Biology, 2014
- Active von Willebrand factor predicts 28-day mortality in patients with systemic inflammatory response syndromeBlood, 2014
- Ratio of von Willebrand Factor Propeptide to ADAMTS13 Is Associated With Severity of SepsisShock, 2013
- Sepsis: the dark side of histonesNature Medicine, 2009
- Binding of SARS coronavirus to its receptor damages islets and causes acute diabetesActa Diabetologica, 2009
- Thrombospondin-1 controls vascular platelet recruitment and thrombus adherence in mice by protecting (sub)endothelial VWF from cleavage by ADAMTS13Blood, 2006
- Regulation of Functions of Vascular Wall Cells by Tissue Factor Pathway InhibitorArteriosclerosis, Thrombosis, and Vascular Biology, 2002
- Plasma thrombomodulin levels are dependent on renal functionThrombosis Research, 1993