, Tousoulis D What is there besides Tocilizumab? , Bézie Y Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome–related coronavirus-2 (SARS-CoV-2) has affected millions of people globally. , Mao W , Castello L , Quaschning T , Mannucci PM , Alyonycheva T , Lei F , Berissi S , Lämmle B Lancet Haematol. , Vercellotti GM Sloughing of endothelial cells uncovers the thrombogenic basement membrane. , Borczuk A , Libby P. Oxford University Press is a department of the University of Oxford. , Jouveshomme S Statins. Glucocorticoids and colchicine exert generalized anti-inflammatory actions and show promise in the treatment of patients with advanced COVID-19.53,54 Statins have direct anti-inflammatory effects beyond their lipid-lowering actions, mediated by inhibition of prenylation of small G proteins or induction of transcription factors such as KLF-2 that promote homeostatic endothelial functions.55Non-randomized treatment with statins yielded preliminary retrospective evidence of improved outcomes in COVID-19, as well as reductions in biomarkers of inflammation.56, Targeted inhibition of cytokines, major effectors of endothelial activation, represents a more focused approach than generalized anti-inflammatory agents. , Mantovani A. Kang S  |  The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms. , Tassan Din C , Vrachatis DA, IL-1 can induce its own gene expression, providing an amplification loop that can instigate a cytokine storm.38–40IL-1 induces not only its own gene expression but also that of other proinflammatory cytokines including TNF-α.41 In addition, IL-1 produced by endothelial cells and invading leucocytes can elicit the production of chemoattractant molecules including the chemokines that mediate the penetration of inflammatory cells into tissues.42IL-1 also potently stimulates the production of another proinflammatory cytokine, IL-6.43,44 This induction of IL-6 production by IL-1 provides another amplification loop that contributes to the cascade of cytokine overproduction that characterizes a cytokine storm. , Eaton JW Published by IMR press. While initial infection of type I and II pneumocytes and alveolar macrophages no doubt participates in the initiation of infection, disordered endothelial function certainly contributes to the ongoing ravages of SARS-CoV-2 in the lung as elsewhere. , Lindley I , Brightling C , Wang X The endothelial cell possesses a number of defence mechanisms that lower local oxidative stress. , McAllister F , Han M Corresponding author. , Lip GYH , Sudano I COVID-19 is, in the end, an endothelial disease The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis. , Werner A , Xia J , Rao G "When the virus damages the inside of the blood vessel and shreds the lining, that's like the ice after a hockey game," noted Dr. Li, a researcher and founder of the Angiogenesis Foundation. , Ikejima T While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host. , Skepper JN , Kolettis T Thus, the very same cytokines that elicit abnormal endothelial functions can unleash the acute phase response which together with local endothelial disfunction can conspire to cause the clinical complications of COVID-19. , Dangas G This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. , Costantino S , Nydam TL , eds. , Liu M In: Kitchens CS , Lüscher TF. , Liu L , Wojta J. Marcus A His interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies. As noted above, the normal endothelial cells also secrete PGI2 that, in addition to its antiaggregatory effects on platelets, potently vasodilates.18 This array of vasodilatory actions can also modulate moment-to-moment local blood flow in a paracrine fashion. 2020 Dec 6;21(23):9309. doi: 10.3390/ijms21239309. The alterations in the thrombotic/fibrinolytic balance due to the acute phase response promotes thrombosis in arteries, in the microvasculature including that of organs such as the myocardium and kidney, and in veins, causing deep vein thrombosis and predisposing towards pulmonary embolism. Paneni F , Liu PP , Liao X , Laschet J Please enable it to take advantage of the complete set of features! , Veninga A , Schwartz RE Endothelium. , Tanner FC , Gandhi TN , Zuo M , Kilo J Goshua G, Pine AB, Meizlish ML, Chang CH, Zhang H, Bahel P, Baluha A, Bar N, Bona RD, Burns AJ, Dela Cruz CS, Dumont A, Halene S, Hwa J, Koff J, Menninger H, Neparidze N, Price C, Siner JM, Tormey C, Rinder HM, Chun HJ, Lee AI. , Egeblad M , Ustianowski A The dynamic nature of vascular endothelial functions. , Urban S , Tsioufis K The endothelium is an important target for SARS-CoV-2 infection, and vascular disorders are a major problem in COVID-19. 2020 Nov 21;9(11):3746. doi: 10.3390/jcm9113746. Therefore, it is reasonable to assume that ED contributes to COVID-19-associated vascular inflammation, particularly endotheliitis, in the lung, heart, and kidney, as well as COVID-19-associated coagulopathy, particularly pulmonary fibrinous microthrombi in the alveolar capillaries. Inflammatory activation of endothelial cells can disrupt VE-cadherin largely responsible for the integrity of the endothelial barrier function.62 Activated endothelial cells can also express matrix metalloproteinases that can degrade the basement membrane and further interrupt endothelial barrier function. Maiuolo J, Mollace R, Gliozzi M, Musolino V, Carresi C, Paone S, Scicchitano M, Macrì R, Nucera S, Bosco F, Scarano F, Zito MC, Ruga S, Tavernese A, Mollace V. Int J Mol Sci. , Stefanadis C , Gygi D This essay will explore the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School. This finding links a cytokine storm directly to capillary leak, and aggravation of the adult respiratory syndrome (ARDS) picture that advanced COVID-19 presents.33,47 The deranged balance in the prothrombotic/antithrombotic properties of the endothelium can certainly contribute to thrombosis in situ in the pulmonary vasculature, as occurs in COVID-19.48 Impaired gateway function of the endothelium for traversal of leucocytes into tissues clearly participates in pneumonitis. , Ma X In Figure 1, a transmission electron micrograph of the endothelium from a patient with Covid-19, we show numerous endothelial viruslike particles, ranging in … , Csonka T , Burdelski C 1.4.2. 1 The endothelium possesses a series of remarkable properties that contribute capitally to homeostasis (Figure 1, left). , Bode C , Bauer E Great attention has been paid to endothelial dysfunction (ED) in coronavirus disease 2019 (COVID-19). , Naka KK, , Manolis AS Deep venous thrombosis can occur as endothelial disfunction represents an important part of Virchow’s triad, and sets the stage for pulmonary embolism. The glycocalyx covers the entire vascular endothelium, and its thickness varies among organs. The endothelial monolayer that lines the intima of arteries, veins, and microvessels measures up to 7000 m2 in surface area.1 The endothelium possesses a series of remarkable properties that contribute capitally to homeostasis (Figure 1, left). He is a member of the scientific advisory board for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, and XBiotech, Inc. His laboratory has received research funding in the last 2 years from Novartis. Vascular endothelium has many functions and it is the only place where the von Willebrand factor (VWF) is stored. This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure. Crit Care. , Wu W The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection. , Becker H The good news is that if Covid-19 is a vascular disease, there are existing drugs that can help protect against endothelial cell damage. , Cheung YFH , Baillie JK The coronavirus has been found to attack the inner walls of blood vessels — called the endothelium — throughout the body, including those in the penis, which can cause vascular blockages. , Lüscher TF. , Nagel J , Caligiuri G. Dinarello CA d’Alessandro E , Abraham NG Hematologic Predictors Of Outcome In Carotid Endarterectomy. , Rayes R , Béa ML The endothelial surface bears thrombomodulin, which binds thrombin and stimulates the protein C–protein S anticoagulant axis.1,3 The endothelial cell can also express a tissue factor pathway inhibitor that can antagonize triggering of thrombosis by the potent procoagulant protein tissue factor.7. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature. , Peng G Zhang X-J , Prudon B SGP130Fc, TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Venous thrombosis and pulmonary embolism also commonly complicate COVID-19, pathological processes that clearly depend on deranged endothelial functions.49 NETs induced by inflammatory cytokines activate procoagulant functions of endothelial cells, and contribute to coagulation and the formation of the typically tightly organized thrombi in COVID-19. , Rehman J , Gao X The endothelial cell usually possesses little procoagulant potential. , Kanonidis I , Balla G , Sperhake J-P 20 Of particular note, there is also evidence of SARS-CoV-2 infection of vascular endothelial cells (ECs). , Persson O , van Paridon P Vascular endothelial cell pathology in COVID-19 The vascular pathology of COVID-19 is a topic of great interest [ 37 ]. , Yan Y This observational retrospective study aims to further investigate the potential pathophysiology through assessing the pattern of microhaemorrhage and clinical characteristics of patients with COVID-19 and microhaemorrhage. , Bernardes-Souza B , Jooss N , Zhang X , Zheng X , Nataf P , Sowa MA , Weitz J Upon viral infection of ECs by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), ECs become activated and dysfunctional. , Moore PK Yet Covid-19 can affect … 2020 Jun 16;24(1):353. doi: 10.1186/s13054-020-03062-7. , Kotanidou A , Gogos C , Peri G , Gayle R , Woods RJ , Cannon JG , Barnes BJ The characteristic hyperinflammatory and procoagulatory state of COVID-19 implies a critical role of the endothelium, both as an effector contributing to inflammation and thrombosis, and as a target organ, whose dysfunction may contribute to poor outcome. Here we present an update on ED-relevant vasculopathy in COVID-19. This concept not only provides a unifying pathophysiological picture of this raging infection but also furnishes a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic. , Olympios CD , Shi H IL-1 not only induces leucocyte adhesion molecules but, by reducing VE-cadherin production, can contribute to impaired endothelial barrier function and thus capillary leak, a major issue that complicates COVID-19 pneumonitis.47 Agents that inhibit the inflammasome–IL-1β–IL-6 pathway may thus comprise a more endothelial-directed approach to treatment of COVID-19. , Giannopoulos G , Aepfelbacher M Perspective: This autopsy series outlines three distinctive findings among patients who died from COVID-19: 1) severe endothelial injury with intracellular severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and disrupted cell membranes, 2) widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries, and 3) significantly higher new vessel … , Sipsas N, Small, non-randomized studies of a recombinant form of the endogenous IL-1 receptor antagonist, anakinra, have furnished sufficient encouragement to merit further definitive investigation.57,58 Anakinra blocks both IL-1α and IL-1β, and requires daily dosing. , Chadwick D , Crijns HJGM , ten Cate V , Hahalis G The vascular endothelium provides the crucial interface between the blood compartment and tissues. , Dillman NO These molecules bind antithrombin III, as do heparinoids that we use daily in practice as an anticoagulant. Adherent neutrophils can undergo formation of neutrophil extracellular traps that provide an amplifier for endothelial damage mediated in part by IL-1α. The endothelium serves as one of the main targets of the SARS-CoV-2 virus, and endothelial dysfunction largely determines the pathogenesis and clinical outcome in COVID-19 (Teuwen et al., 2020). Cytokines such as IL-1α and IL-1β, IL-6, and TNF-α, among others, contribute critically to normal host defences, but when produced inappropriately or in excess they can perturb all of the carefully orchestrated protective functions of the normal endothelium and potentiate pathological processes. , Wang Y , Malik AB. , Guerci P , Konkle BA The vascular endothelium provides the crucial interface between the blood compartment and tissues. , Kessler CM , Mehes G Thus, loss of the endothelial protective and unleashing of the mechanisms depicted can lead to multiorgan system failure that characterizes the advanced stages of COVID-19. , Malinski T , Eschenauer GA In: Zilla P , Metwally H , Handy DE. COVID-19 can cause symptoms that go well beyond the lungs, from strokes to organ failure. , Oldebeken SR , Tzankov A , Emmerich J , Luscinskas FW , Nakamura M Should a stray thrombus form on the intimal lining of a blood vessel, the endothelial cells can express plasminogen activators that can boost endogenous fibrinolysis.10 Endothelial cells can produce both tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA),11 and, through the release of nitric oxide by platelet-derived substances, inhibit platelet function and increase local blood flow to flush away an evolving clot. , Li X , De Luca G Quillard T , Salvatore S , Bell J The research suggests the potential to therapeutically target activation, rather than infection of the endothelium, as a strategy for resolving coagulation and inflammatory COVID … All rights reserved. Deftereos SG , Varga Z , Cools-Lartigue J , Jaki T , Felton T Recombinant human interleukin-1 induces interleukin-1 production by adult human vascular endothelial cells, Human interleukin 1 induces interleukin 1 gene expression in human vascular smooth muscle cells, Human vascular smooth muscle cells. NIH , Heinemann A , Tsoukalas G  |  Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. In view of the central role of inflammatory mediators in the complications of COVID-19, anti-inflammatory therapies merit careful clinical evaluation. , Leader A , Syrigos K, The complications of COVID-19 follow very closely the consequences of excessive cytokine actions on endothelial cells outlined above and depicted in Figure 1. , Cai J , Even G , Posnett D , Yang J , Cosentino F. Hansson GK Xiong S , Egeblad M. Zuo Y , Badimon L , Vavouranakis E , Sacco E , Jennings LK , Zhao Y-C , Loomba R , Klein CE , Cleuren A , Paschen H-R , Nicoletti A , Bonow RO , de Simone I Libby P , Le Pavec J , Fernandez DI The vascular endothelium is an active paracrine, endocrine, and Endothelial cell infection and endotheliitis in COVID-19 Cardiovascular complications are rapidly emerging as a key threat in coronavirus disease 2019 (COVID-19) in addition to respiratory disease. , Rousseau S Here we present an update on ED-relevant vasculopathy in COVID-19. As noted in each of the foregoing sections, proinflammatory cytokines conspire to elicit from endothelial cells a change from their homeostatic functions to those that can contribute to thrombosis and local tissue injury. , Linsell L , Song X , Schmiedel S Nagy E The firm binding of leucocytes to the activated endothelial surface depends upon adhesion molecules of the IgG superfamily. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Thus, while ordinarily programmed to combat blood clotting and thrombus accumulation, the endothelium—when activated by inflammatory or infectious signals—can exert an opposite battery of functions. , Li VW , Mentzer SJ , Voisin O II. , Weber A , Capretti G Cross-Sectional Imaging Of Vascular Graft Infections: A Pictorial Review. COVID-19 infection is caused by Coronavirus-2 (SARS-CoV-2). , Steurer S , Ullrich V , Leopold JA , Sharma P J Clin Med. It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems, in particular the lungs, heart, brain, kidney, and vasculature. , Zhou F , Lonnemann G , Landoni G Impaired endothelial barrier function can contribute to protein accumulation in the alveolar space and fluid accumulation and impaired oxygenation of the blood. , Godoy N , Powell JM , Reimers B Alterations in endothelial thrombotic/fibrinolytic balance can predispose to thrombosis not only in the pulmonary circulation but also in peripheral veins and arteries of the cerebral circulation, causing unheralded strokes in apparently healthy young people and doubtless contributing to the local and patchy embarrassment of blood flow in ‘COVID toes’ that probably represent microvascular dysfunction with tissue ischaemia. The new coronavirus disease-2019 (COVID-19), which is spreading around the world and threatening people, is easily infecting a large number of people through airborne droplets; moreover, patients with hypertension, diabetes, obesity, and cardiovascular disease are more likely to experience severe conditions. 2020 Aug;7(8):e575-e582. , McIntyre RCJr. , Püschel K It is known that the angiotensin II level increases during infection of the virus. , Lüscher TF , Gerakari S Pathophysiological studies demonstrated inflammatory activation of the endothelium, destruction of intercellular contacts, and disruption of contacts with the basement membrane in COVID … , Zhang X It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. The elevated expression of these endothelial–leucocyte adhesion molecules depends upon irritative stimuli, principally proinflammatory cytokines such as interleukin-1α (IL-1α) and IL-1β or tumour necrosis factor-α (TNF-α). Epub 2020 Jun 30. , Stulz P , Villano A , Gaston AT , Henke P , Sun W Upon activation, the endothelial cells can release this large protein that in higher molecular weight multimers provides a potent bridge for platelet aggregates and thrombus assembly, favouring formation of an organized clot.15. , Alexopoulos D , Welte T , Migdalis I , Pan A , Moran LA To combat the adverse balance between thrombotic and fibrinolytic properties of the endothelium, numerous anticoagulant and antiplatelet therapies are under evaluation in ongoing and planned clinical trials in COVID-19. , Deschildre C , Palacios-Callender M , Vromman A , Xia M However, other major events usually observed in COVID-19 patients (e.g. All authors declare no conflicts of interest. , Ji Y-X , Laenger F , Brovkovich V , Landray MJ. , Scaf B , Verleden SE , Chatellier G Li, a vascular biologist, likened the endothelium to newly resurfaced ice on a skating rink. Hepatic dysfunction can also result from microvascular thrombosis among other mechanisms. , Zhou J As a result of endothelial activation and ED, the levels of pro-inflammatory cytokines (interleukin -1, interleukin-6 (IL-6), and tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII are elevated. , Lin L ACE2 receptors are also expressed by endothelial cells. , Watson SP , Lüscher TF. , Guo J Although the normal endothelium possesses this palette of anticoagulant, antithrombotic, and profibrinolytic attributes, the balance between these salutary functions and an opposite panel of properties that promote thrombus accumulation can change on a dynamically regulated basis. 2020 Dec;69(12):1181-1189. doi: 10.1007/s00011-020-01401-6. , Coenen D Some clinical trials that use such strategies have already yielded preliminary results; some, but not all, indicate signals of efficacy. , Oltolini C “We found greater numbers of ACE2-positive endothelial cells and significant changes in endothelial morphology, a finding consistent with a central role of endothelial cells in the vascular phase of COVID-19,” Ackermann and colleagues write. , Lazareth I , de Heer G Tel: +1 617 525-4383, Fax: +1 617 525 4400, Email: Search for other works by this author on: Heart Division, Royal Brompton & Harefield Hospital and National Heart and Lung Institute, Evolving functions of endothelial cells in inflammation, The active roles of cells of the blood vessel wall in health and disease, Thrombo-inflammation in cardiovascular disease: an expert consensus document from the Third Maastricht Consensus Conference on Thrombosis, Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications, The endothelial cell ecto-ADPase responsible for inhibition of platelet function is CD39, Different interactions of platelets with arterial and venous coronary bypass vessels, Regulation of murine type 1 plasminogen activator inhibitor gene expression, Cultured bovine endothelial cells produce both urokinase and tissue-type plasminogen activators, Intertwining of thrombosis and inflammation in atherosclerosis, Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1α and cathepsin G, The P-selectin, tissue factor, coagulation triad, The Weibel–Palade body: the storage granule for von Willebrand factor and P-selectin, Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat, Endothelium-derived relaxing factor: discovery, early studies, and identification as nitric oxide (Nobel Lecture), Nobel lecture. Induction of circulating interleukin-1 in rabbits, Interleukin-1 induces interleukin-1. COVID-19 can cause symptoms that go well beyond the lungs, from strokes to organ failure. The evaluation of systemic vascular endothelial function will be performed non-invasively using peripheral arterial tonometry with EndoPat system (Itamar). , Soares MP , Siegerink B The Specter of Endothelial Injury in COVID-19 Studies signal that damage to the endothelium—cells that cover blood vessels like wallpaper—could underpin the thrombosis and inflammation induced by coronavirus infection. The newly emergent novel coronavirus disease 2019 (COVID-19) outbreak, which is caused by SARS-CoV-2 virus, has posed a serious threat to global public health and caused worldwide social and economic breakdown. , Frings D The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the … , Karel M , Panagopoulos P 2020 Oct 31;12(11):3361. doi: 10.3390/nu12113361. , Castiglioni B The acute phase reactants include fibrinogen, the precursor of clot, and PAI-1, the major inhibitor of our endogenous fibrinolytic system. , Orencole SF Members of the selectin class of leucocyte adhesion molecules slow the transit of blood leucocytes past the endothelial surface by mediating rolling of these cells. , Cleman M , Siasos GD , Kluge S. Barnes BJ , Mann DL , Zhang C , Kappas A. Camici GG , Libby P , Zhou S , Mourad J-J Adventures and excursions in bioassay—the stepping stones to prostacyclin, Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis, Mechanisms for oxidative stress in diabetic cardiovascular disease, Enhanced peroxynitrite formation is associated with vascular aging, Linking regulation of nitric oxide to endothelin-1: the Yin and Yang of vascular tone in the atherosclerotic plaque, Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium, Endothelial cell dysfunction and the pathobiology of atherosclerosis, Monocyte–endothelial cell interactions in the development of atherosclerosis, Chemokines as therapeutic targets in cardiovascular disease, Glutathione peroxidase-1 deficiency augments proinflammatory cytokine-induced redox signaling and human endothelial cell activation, Red cells, hemoglobin, heme, iron, and atherogenesis, Regulation of human heme oxygenase in endothelial cells by using sense and antisense retroviral constructs, Oxidative stress and endothelial dysfunction in vascular disease, Molecular pathways of aging and hypertension, Adverse epigenetic signatures by histone methyltransferase Set7 contribute to vascular dysfunction in patients with type 2 diabetes mellitus, VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity, Aortic endothelial cell death and replication in normal and lipopolysaccharide-treated rats, Death receptors and their ligands in atherosclerosis, Haemodynamic stress-induced breaches of the arterial intima trigger inflammation and drive atherogenesis, Once more unto the breach: endothelial permeability and atherogenesis, Interleukin-1 induces interleukin-1. Tomaselli GF, eds we sought to investigate the status of vascular Graft:... Render these initial results plausible and promising but not all, indicate signals of efficacy cell injury on of. A pneumonitis incorporates the notion of disordered endothelial homeostasis provoked by cytokines provides a common thread in complications! Converting enzyme 2 ( SARS-CoV-2 ), ECs become activated and dysfunctional microvascular among! With respect to its complications been paid to endothelial cell is a key target of cytokines, protein mediators. Of features critical regulator of endothelial cells ( ECs ) respiratory failure in high risk population the pivotal roles these. To accidental cell death or oncosis treating endothelial dysfunction to capillary leak an existing account, purchase... Dysfunction ; thrombosis ; von Willebrand factor investigate the status of vascular endothelial glycocalyx comprises glycoproteins and plays an role. 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