key: cord-0904515-xesiyw8m authors: Nicosia, Roberto F.; Ligresti, Giovanni; Caporarello, Nunzia; Akilesh, Shreeram; Ribatti, Domenico title: COVID-19 Vasculopathy: Mounting Evidence for an Indirect Mechanism of Endothelial Injury date: 2021-05-23 journal: Am J Pathol DOI: 10.1016/j.ajpath.2021.05.007 sha: 566da2d34667c58e35d4f91feaeb956773ab9154 doc_id: 904515 cord_uid: xesiyw8m COVID-19 patients who are critically ill develop vascular complications characterized by thrombosis of small, medium and large vessels. Dysfunction of the vascular endothelium due to the SARS-CoV-2 infection has been implicated in the pathogenesis of the COVID-19 vasculopathy. Although initial reports suggested that endothelial injury was caused directly by the virus, recent studies indicate that endothelial cells do not express ACE2 – the receptor that SARS-CoV-2 uses to gain entry into cells – or express it at low levels and are resistant to the infection. These new findings, together with the observation that COVID-19 triggers a cytokine storm capable of injuring the endothelium and disrupting its antithrombogenic properties, favor an indirect mechanism of endothelial injury mediated, locally, by an augmented inflammatory reaction to infected nonendothelial cells such as the bronchial and alveolar epithelium and, systemically, by the excessive immune response to infection. Here we review the vascular pathology of COVID-19 and critically discuss the potential mechanisms of endothelial injury in this disease. Histologically, COVID-19 lungs show features of diffuse alveolar damage including injury/necrosis 87 of the alveolar epithelium, intra-alveolar fibrin deposition and hemorrhage, alveolar edema, hyaline 88 membranes, type 2 pneumocyte hyperplasia, interstitial inflammation, and organizing connective 89 tissue in the alveolar septa 8, 12, 13 . 90 The microvasculature of COVID-19 lungs is abnormal and characterized by acute endothelial 92 injury, thrombotic occlusion of alveolar capillaries and neutrophilic capillaritis / endothelialitis 8, 13, 14 . 93 Injured alveolar capillaries become leaky, distorted, and undergo remodeling with formation of 94 intraluminal endothelial pillars indicative of intussusceptive /splitting angiogenesis 12 . COVID-19 95 lungs also show pulmonary thromboembolism, pulmonary infarctions and venous thrombosis [15] [16] [17] . 96 In one study, microvascular thrombosis was found to be more prevalent in COVID-19 lungs 97 compared with lungs of patients who died from influenza (H1N1) 12 . A meta-analysis of twenty-98 seven diagnostic imaging studies showed that the incidence of pulmonary emboli in patients 99 admitted to the ICU was considerable higher than the reported pulmonary incidence in ICU 100 patients with non-COVID-19 viral pneumonia 18 . This study also showed that pulmonary emboli 101 were confined to peripheral arteries while thrombosis of the leg deep veins was found in less than 102 half of these patients, which suggested in situ formation of thrombi in the pulmonary circulation 18 . 103 The higher incidence of vascular injury and thrombosis in COVID-19 lungs has been postulated to 104 study, ISH revealed SARS-CoV-2 RNA in the microvasculature of endothelial cells and vessel 169 walls of brain stem, leptomeninges, lung, heart, liver, kidney, and pancreas 35 . A separate group 170 identified SARS-CoV-2 RNA by ISH in the alveolar capillary endothelium but not in the endothelium 171 of peripheral organs 16 . In this study, SARS-CoV-2 proteins were detected in skin, brain and liver 172 microvessels by IHC but without corresponding viral RNA by ISH 16 . 173 The many early reports on the pathology of COVID-19 have suggested that vascular injury and 176 and coagulopathy leading to thrombotic occlusion of blood vessels (Fig. 2) . 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