Vascular Endothelial Damage in the Pathogenesis of Organ Injury in Severe COVID-19

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]-α, 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.

Patients with COVID-19: in the dark-NETs of neutrophils

“…Endothelial injury is considered an essential pathogenic process in COVID-19, leading to lung and kidney damage [102][103][104]. Organ-and microenvironment-associated endothelial heterogeneity likely contributes to different COVID-19 outcomes [105].…”

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

“…Taken together, these data suggest that VWF elevation is an accurate mirror of the intensity of endothelial damage, most likely resulting from a dysregulated immune-inflammatory response, as shown by the strong association between VWF levels and circulatory inflammatory cytokines in COVID-19 patients in the ICU [ 116 ]. On its own, such a significant increase of VWF could explain its prothrombotic effect but additional qualitative anomalies of VWF have been described in COVID-19.…”

Insights into the Functional Role of ADTRP (Androgen-Dependent TFPI-Regulating Protein) in Health and Disease

“…Low plasma levels of TFPIα (full-length TFPI) correlate with prothrombotic diseases, including DVT/VTE [ 1 ], coronary artery disease (CAD), ischemic stroke, peripheral artery occlusive disease (reviewed in [ 2 ]), and, lately, COVID-19 [ 3 ]. Excessive and/or ectopic TF-driven coagulation not adequately balanced by TFPI [ 4 , 5 , 6 ] could lead to thrombotic complications in sepsis [ 7 ], atherosclerosis [ 4 , 8 ], lupus [ 9 ] and cancer [ 10 ].…”

“…If lower levels of circulating ADTRP correlate with low ADTRP expression in EC and/or monocytes, this may reflect cellular dysfunction, which would indeed support the development of CAD/MI, but this needs to be experimentally demonstrated. Knowing that plasma TFPI level is significantly higher in CVD and other pathologies, including COVID-19 [ 3 ], where TFPI increase is universally accepted to reflect endotheliopathy, it is crucially important to correlate the plasma levels of ADTRP with those of TFPI in the same sample groups. Because ADTRP is a transmembrane protein with location in lipid rafts/caveolae, it is hard to envision how it could be released from the cells.…”