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Endothelial Injury in COVID-19 and Acute Infections

Putting the Pieces of the Puzzle Together
Originally published, Thrombosis, and Vascular Biology. 2021;41:1774–1776

Beyond respiratory and renal failure in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), also known as coronavirus disease 2019 (COVID-19), COVID-19–associated coagulopathy is a major challenge with a high incidence of thromboembolic complications.1 Endothelial vascular injury and thromboinflammation associated with SARS-CoV2 viral infections are emerging as likely culprits mediating the pathology and some of the clinical manifestations of COVID-19.2,3 In this issue of ATVB, Dupont et al4 from the Lille COVID Research Network Group quantify vascular endothelial damage as part of the pathogenesis of organ injury in severe COVID-19. They investigated the contribution of endotheliopathy to microvascular thrombosis and multiorgan failure by examining biomarkers of endothelial damage from 82 COVID-19 patients on admission to an intensive care unit. Interestingly, the investigators also performed histological examination of thrombi retrieved from the extracorporeal membrane oxygenation circuitry supporting 8 COVID-19 and 3 control patients following weaning from extracorporeal membrane oxygenation support. Understanding how different biomarkers of vascular injury and thromboinflammation behave across the course of the disease could help in identifying severe disease earlier, aid in clinical decisions around therapeutics and management, and subsequently improve prognosis.

See accompanying article on page 1760

The endothelium has major functions in the vasculature to control vascular permeability and tone, which are largely controlled by NO release from the endothelium.5 Maintenance of platelet passivity and control of coagulation are also achieved, in part, by expression of endothelial proteins and secretion of factors aimed at controlling thrombin generation and platelet activation (Figure). During COVID-19 infection, critically ill patients can have disrupted coagulation function, predisposing them to consumptive coagulopathies, with both venous and thromboembolic complications, often with unique characteristics.6,7 Elevated fibrinogen, D-dimer, and other biomarkers released from damaged endothelium have all been associated with increased disease severity. Further, pulmonary embolism, deep vein thrombosis, ischemic stroke, myocardial infarction, and systemic arterial embolism have all been noted, implying a dramatic dysregulation of hemostasis, despite hospitalized patients receiving standard thromboprophylaxis.8 In the current study,4 the investigators measured an extensive panel of biomarkers that included endothelial damage markers in plasma such as VWF (von Willebrand factor), PAI-1 (plasminogen activator inhibitor-1), syndecan-1, and soluble thrombomodulin and could demonstrate an association of elevated levels at intensive care unit admission, with respiratory and multiorgan failure, liver injury, and death in COVID-19 patients. Plasma-based proinflammatory cytokines including IL (interleukin)-6, TNFα (tumor necrosis factor alpha), IL-2R (IL-2 receptor), and components of neutrophil extracellular traps including cell-free DNA, nucleosomes, MPO (myeloperoxidase)-DNA, as well as TFPI (tissue factor pathway inhibitor), C5a (complement 5a), and membrane attack component (MAC; C5b-9; Figure) were also elevated. As the field of biomarker data from critically ill COVID-19 patients accumulates, what is important is to ascertain what can be done with the bank of information regarding thromboinflammatory responses in patients vis-à-vis management strategies. Nonetheless, this study suggests that thromboinflammation contributes significantly to the primary pathophysiology of COVID-19.


Figure. Damage to the endothelium could underpin the thrombosis and inflammation induced by coronavirus disease 2019 (COVID-19) viremia. The healthy endothelium provides a passive, nonadhesive protective barrier with broad anticoagulant properties. Upon damage, the surface becomes adhesive for both platelets and leukocytes and is highly procoagulant. As part of the thromboinflammatory process to limit the spread of an invading pathogen, the onset of NETosis ensues. Signaling the endothelium damage, markers such as VWF (von Willebrand factor), PAI-1 (plasminogen activator inhibitor 1), syndecan-1, and soluble thrombomodulin increase in plasma. Further, proinflammatory cytokines such as IL (interleukin)-6, TNFα (tumor necrosis factor alpha), IL-2R (IL-2 receptor), and neutrophil extracellular traps (NETs) components including cell-free DNA, nucleosomes, and MPO (myeloperoxidase)-DNA were also elevated. TFPI (tissue factor pathway inhibitor), C5a (complement 5a), and membrane attack component (MAC; C5b-9) are also potential biomarkers in COVID-19.

As the pathophysiology of COVID-19–associated coagulopathy is complex and could differ in important ways from the common mechanisms of thrombosis reported in critically ill patients,9 the physical characteristics of blood clots may provide some important clues. In other studies,10 data gathered from thrombi isolated postmortem from COVID-19 patients may be difficult to interpret due to confounding factors indolent to samples from people treated for extended periods in intensive care unit facilities. Dupont et al performed histological examination of thrombi isolated from the extracorporeal membrane oxygenation tubing of COVID-19 or non–COVID-19 patients following successful separation from extracorporeal membrane oxygenation life support. Although thrombi from mechanical support devices do not necessarily reflect the properties of thrombi formed within a patient’s vasculature, these thrombi showed a considerable accumulation of nucleated cells, primarily neutrophils, and citrullinated histones, indicative of active NETosis. Consistent with this, a recent report demonstrated that neutrophil activation precedes the onset of critical COVID-19 illness and predicts mortality.11 Following acute infections, multiple host surveillance and defense pathways have evolved to eradicate or restrain pathogens, and in this regard, the host responses to COVID-19 infection are not likely to differ from responses to other viremias. The acute inflammatory responses have long been known to cause vascular endothelial injury and orchestrate complex cellular and humoral thromboinflammatory and hypercoagulable responses, also called immunothrombosis.12 In this scenario, neutrophils and VWF may act as a scaffold for thrombus formation and the immunothrombotic injury of COVID-19. Based on the current report, a multitude of bioactive cellular components, including procoagulants released from the damaged endothelium and during cell death, are major contributors to the observed multiorgan injury.

A major hallmark of COVID-19 is the acute lung injury from an initial viral load delivered from the respiratory tract to the lung, resulting in alveolar and microvascular injury.13 Reports of pulmonary infection-induced microvascular and macrovascular thrombosis in patients with adult respiratory distress syndrome have existed for >30 years.14 However, in many patients with COVID-19, this localized thromboinflammatory response in the pulmonary microcirculation can progress to a systemic response, as the authors have shown in their report, a finding consistent with the exuberant inflammatory response to viral infection observed in SARS-CoV-2. The extent of systemic transition is likely to explain the variability of multiorgan dysfunction observed as COVID-19 progresses, and is where a panel of biomarkers ideally in combination with other vascular markers,15 may have utility as sentinels of that transition.

Based on the extensive investigation of standard and novel biomarkers,4,11,16,17 can we stratify patients and personalize potential therapeutic approaches to mollify the complex endothelial injury due to thromboinflammation? The extensive endothelial injury associated with SARS-CoV-2, as well as in other acute infectious processes including bacterial induced septic shock and disseminated intravascular coagulopathy, continues to be a major driver of thromboinflammatory injury.3 A major problem with treating the acute inflammatory injury of SARS-CoV-2 is that treatment after the acute inflammatory insult limits the potential benefits of these therapeutic interventions. Of course, it is essential to keep in mind that association does not necessarily mean causality, and prior efforts at antagonizing specific mediators both in COVID-19 and other major infectious processes like septic shock with disseminated intravascular coagulopathy have not been shown to consistently reduce mortality.18 Nonetheless, continuing research on endothelial injury in COVID-19 to enhance understanding of the pathophysiological features will help us to piece together the puzzle of this thromboinflammatory state and refine existing and develop new therapeutic approaches to treat the acute COVID-19 disease state.


J.H. Levy, T. Iba, and E.E. Gardiner contributed to the writing of the manuscript.

Disclosures J.H. Levy serves on research, data safety, or advisory committees for Instrumentation Labs, Merck, and Octapharma. T. Iba receives research grants from Japan Blood Products Organization and JIMRO. The other author reports no conflicts.


The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

For Sources of Funding and Disclosures, see page 1776.

Correspondence to: Jerrold H. Levy, MD, FAHA, Duke University Medical Center, 2301 Erwin Rd, 5691H HAFS Box 3094, Durham, NC 27710. Email


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