key: cord-0933390-j8oaan97 authors: O'Sullivan, Jamie M; Gonagle, Dennis Mc; Ward, Soracha E; Preston, Roger J S; O'Donnell, James S title: Endothelial cells orchestrate COVID-19 coagulopathy date: 2020-06-30 journal: Lancet Haematol DOI: 10.1016/s2352-3026(20)30215-5 sha: 377aea8bb42bc8e51852b0e732966bb06d5dfdb3 doc_id: 933390 cord_uid: j8oaan97 nan Recent data have shown that coagulation activation is common in patients with severe COVID-19. 1,2 Moreover, autopsy studies have reported widespread microthrombi disseminated throughout the pulmonary vasculature, suggesting that vasculopathy is important in COVID-19 pathogenesis. 3 These post-mortem studies have also highlighted substantial endothelial cell damage, with evidence of apoptosis and loss of tight junctions. Collectively, these data suggest that endothelial cells play a key role in orchestrating the unusual pulmonary intravascular coagulopathy associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. 4 In The Lancet Haematology, George Goshua and colleauges provide novel mechanistic insights into COVID-19-associated endotheliopathy (figure). 5 In keeping with previous studies, they show that coagulation activation is common in hospitalised patients with COVID-19. Additionally, they report elevated plasma von Willebrand factor (VWF) concentrations in these patients, increasing with disease severity (mean VWF antigen of 565% [SD 199] in 48 patients admitted to the intensive care unit [ICU] vs 278% [133] in 20 non-ICU patients; p<0·0001). This observation is interesting because invivo biosynthesis of VWF is restricted to endothelial cells and megakaryocytes only. 6 Following biosynthesis within endothelial cells, VWF is either secreted into the plasma or is stored within intracellular organelles known as Weibel-Palade bodies. Following endothelial cell activation, this stored VWF is secreted and can tether platelets and leucocytes to the vessel wall (figure). 6 The high plasma VWF concentrations associated with severe COVID-19 are thus suggestive of fulminant endothelial cell activation. Consistent with this concept, Goshua and colleagues also report that plasma concentrations of P-selectin (which can be derived from activated platelets or following secretion from Weibel-Palade bodies) are also significantly elevated in patients with COVID-19 who are admitted to the ICU (15·9 ng/mL [4·8] in 40 ICU patients vs 11·2 ng/mL [3·1] in 10 non-ICU patients; p=0·0014). 5 Several lines of evidence suggest that the high VWF concentrations observed by Goshua and colleagues play a role in the pathogenesis underpinning COVID-19 vasculopathy (figure). First, VWF is able to bind to platelet receptors and thus modulate platelet adhesion and aggregation. 6 Second, pathological ultra-large VWF multimers are responsible for thrombotic microangiopathy, which constitutes the hallmark of thrombotic thrombocytopenic purpura. Third, ultralarge VWF multimers also play a role in the pathogenesis of microvasculature occlusion in children with cerebral malaria. 7 Importantly, the thrombotic microangiopathies associated with thrombotic thrombocytopenic purpura and cerebral malaria share several similar features to that observed with severe COVID-19. Finally, VWF has been shown to play a role in regulating angiogenesis. 8 Moreover, angiopoitein-2, another protein stored within Weibel-Palade bodies, is also important in this context. 8 These observations are interesting since vigorous pulmonary intussusceptive angiogenesis has been reported in patients with fatal COVID-19. 3 Normal blood vessels are lined by an endothelial cell monolayer that plays a crucial role in preventing formation of pathological thrombosis. In particular, a number of receptors expressed on endothelial cells function to promote anticoagulant pathways. Thrombomodulin is a transmembrane receptor constitutively expressed on The healthy alveolus and pulmonary vasculature exist in close anatomical juxtaposition, and thrombosis is prevented by the endothelial cell monolayer that expresses surface thrombomodulin. Endothelial cell activation and damage are triggered though multiple pathways, including pro-inflammatory cytokines, hypoxia, complement activation, and NETosis. As a result of this activation, Weibel-Palade body exocytosis from endothelial cells is triggered resulting in the release of ultra-large VWF multimers and P-selectin; released VWF binds to platelets, neutrophils, and monocytes to initiate microvascular thrombosis. Concurrently, thrombomodulin is shed from endothelial cell surfaces, which further promotes a procoagulant and pro-inflammatory local milieu within the pulmonary vasculature. Finally, endothelial cell damage results in separation from the basement membrane and loss of tight junctions, enhancing vascular permeability. NETosis=neutrophil extracellular trap activation and release. PAI-1= plasminogen activator inhibitor-1. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. VWF=von Willebrand factor. . Thrombomodulin binding switches the specificity of thrombin to favor activation of anticoagulant protein C and antifibrinolytic thrombin-activatable fibrinolysis inhibitor (TAFI). 9 Goshua and colleagues report plasma concentrations of soluble thrombomodulin; these were not significantly different between the ICU and non-ICU groups, but did correlate with clinical outcome, with in-hospital mortality significantly lower among patients with low soluble thrombomodulin (<3·26 ng/mL) compared with patients with high soluble thrombomodulin (>3·26 ng/mL) in the entire cohort (p=0·0087) and among ICU patients (p=0·031). Previous studies have shown that proinflammatory cytokines, extracellular histones, and neutrophil proteases can all promote thrombomodulin shedding from endothelial cells (figure). 9 Reduced thrombomodulin expression on endothelial cell surfaces would be anticipated to impair activated protein C generation, further promoting a procoagulant and pro-inflammatory local milieu within the pulmonary vasculature. Of note, the majority of ICU patients described by Goshua and colleauges had been treated with tocilizumab before undertaking the serum biomarker assessments of endothelial function, which might have blunted the magnitude of endothelial cell serum marker differences between the ICU and non-ICU group. 5 Nevertheless, these data highlight that endotheliopathy constitutes a key factor in the pathogenesis underpinning COVID-19 vasculopathy. Further studies will be required to define the different mechanisms through which SARS-CoV-2 infection causes such marked endothelial cell effects, particularly within the pulmonary microvasculature. Given the diffuse nature of COVID-19 pneumonia, the large volume of alveolar cavity and proximity with the pulmonary microvasculature, local inflammation, and dysregulated pro-inflammatory cytokine generation are undoubtedly important in this context (figure). 4 However, other mechanisms might include complement activation, neutrophil extracellular trap activation and release, and significant hypoxia. In addition, endothelial cells express the ACE2 receptor that facilitates viral entry into cells, and electron microscopy studies have reported SARS-CoV-2 viral particles within the endothelium. 10 Irrespective of the mechanisms of endothelial cell activation and associated pulmonary intravascular coagulopathy in COVID-19, it will be interesting to see whether immunosuppressive therapy including corticosteroids and tocilizumab actually improve endothelial cell function towards reversal of in-situ immunothrombosis and survival improvement. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia COVID19 coagulopathy in Caucasian patients Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19 Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends Emerging roles for hemostatic dysfunction in malaria pathogenesis Endothelial von Willebrand factor regulates angiogenesis Exploring traditional and nontraditional roles for thrombomodulin Endothelial cell infection and endotheliitis in COVID-19 We declare no competing interests.