Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases Journal Article


Authors: Magro, C.; Mulvey, J. J.; Berlin, D.; Nuovo, G.; Salvatore, S.; Harp, J.; Baxter-Stoltzfus, A.; Laurence, J.
Article Title: Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases
Abstract: Acute respiratory failure and a systemic coagulopathy are critical aspects of the morbidity and mortality characterizing infection with severe acute respiratory distress syndrome-associated coronavirus-2, the etiologic agent of Coronavirus disease 2019 (COVID-19). We examined skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3). COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the complement pathways. The purpuric skin lesions similarly showed a pauci-inflammatory thrombogenic vasculopathy, with deposition of C5b-9 and C4d in both grossly involved and normally-appearing skin. In addition, there was co-localization of COVID-19 spike glycoproteins with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature of 2 cases examined. In conclusion, at least a subset of sustained, severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state. It provides a foundation for further exploration of the pathophysiologic importance of complement in COVID-19, and could suggest targets for specific intervention. © 2020 Elsevier Inc.
Keywords: immunohistochemistry; adult; clinical article; human tissue; aged; middle aged; case report; diarrhea; hepatitis c; nonhuman; metabolism; skin biopsy; bleeding; thrombocytopenia; myalgia; obesity; smoking; creatinine; creatinine blood level; kidney failure; pathology; physiology; virology; coughing; dyspnea; fever; purpura; disease severity; shock; thrombosis; hyperplasia; diabetes mellitus; blood vessel injury; hydroxychloroquine; thorax radiography; autopsy; echocardiography; microvasculature; microvessels; hypoxemia; azithromycin; hemodialysis; atrial fibrillation; coronary artery disease; artery thrombosis; virus pneumonia; enoxaparin; platelet count; partial thromboplastin time; brain infarction; respiratory insufficiency; artificial ventilation; respiratory failure; d dimer; complement; fibrin; medical history; lung parenchyma; sleep disordered breathing; acute respiratory failure; complication; lung injury; impaired glucose tolerance; heart left ventricle function; respiratory distress; international normalized ratio; pandemic; virus pathogenesis; hypercapnia; endotracheal intubation; lung alveolus cell; hemosiderin; lung alveolus wall; pneumonia, viral; lung capillary; virus envelope protein; neutrophilia; end stage renal disease; thrombogenicity; complement system proteins; complement membrane attack complex; complement activation; humans; human; male; female; priority journal; article; complement component c3d; complement component c4d; fibrin deposition; coronavirus infections; complement deposition; betacoronavirus; coronavirus infection; pandemics; severe acute respiratory syndrome coronavirus 2; coronavirus disease 2019; remdesivir; heart failure with preserved ejection fraction; lung dead space; purpuric rash
Journal Title: Translational Research
Volume: 220
ISSN: 1931-5244
Publisher: Elsevier Science, Inc.  
Date Published: 2020-06-01
Start Page: 1
End Page: 13
Language: English
DOI: 10.1016/j.trsl.2020.04.007
PUBMED: 32299776
PROVIDER: scopus
PMCID: PMC7158248
DOI/URL:
Notes: Article -- Export Date: 1 September 2020 -- Source: Scopus
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  1. Joseph Justin Mulvey
    13 Mulvey