Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs

Taejoon Won; Megan K. Wood; David M. Hughes; Monica V. Talor; Zexu Ma; Jowaly Schneider; John T. Skinner; Beejan Asady; Erin Goerlich; Marc K. Halushka; Allison G. Hays; Deok-Ho Kim; Chirag R. Parikh; Avi Z. Rosenberg; Isabelle Coppens; Roger A. Johns; Nisha A. Gilotra; Jody E. Hooper; Andrew Pekosz; Daniela Čiháková

EBioMedicine (Jan 2022)

Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs

Taejoon Won,
Megan K. Wood,
David M. Hughes,
Monica V. Talor,
Zexu Ma,
Jowaly Schneider,
John T. Skinner,
Beejan Asady,
Erin Goerlich,
Marc K. Halushka,
Allison G. Hays,
Deok-Ho Kim,
Chirag R. Parikh,
Avi Z. Rosenberg,
Isabelle Coppens,
Roger A. Johns,
Nisha A. Gilotra,
Jody E. Hooper,
Andrew Pekosz,
Daniela Čiháková

Affiliations

Taejoon Won: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Megan K. Wood: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
David M. Hughes: Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA
Monica V. Talor: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Zexu Ma: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
Jowaly Schneider: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
John T. Skinner: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Beejan Asady: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
Erin Goerlich: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Marc K. Halushka: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Allison G. Hays: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Deok-Ho Kim: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA
Chirag R. Parikh: Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Avi Z. Rosenberg: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Isabelle Coppens: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
Roger A. Johns: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Nisha A. Gilotra: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Jody E. Hooper: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Andrew Pekosz: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA
Daniela Čiháková: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA; Corresponding author at: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 648, Baltimore, MD 21205; ORCID ID 0000-0002-8713-2860.

Journal volume & issue: Vol. 75
p. 103812

Abstract

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Summary: Background: Thromboembolism is a life-threatening manifestation of coronavirus disease 2019 (COVID-19). We investigated a dysfunctional phenotype of vascular endothelial cells in the lungs during COVID-19. Methods: We obtained the lung specimens from the patients who died of COVID-19. The phenotype of endothelial cells and immune cells was examined by flow cytometry and immunohistochemistry (IHC) analysis. We tested the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the endothelium using IHC and electron microscopy. Findings: The autopsy lungs of COVID-19 patients exhibited severe coagulation abnormalities, immune cell infiltration, and platelet activation. Pulmonary endothelial cells of COVID-19 patients showed increased expression of procoagulant von Willebrand factor (VWF) and decreased expression of anticoagulants thrombomodulin and endothelial protein C receptor (EPCR). In the autopsy lungs of COVID-19 patients, the number of macrophages, monocytes, and T cells was increased, showing an activated phenotype. Despite increased immune cells, adhesion molecules such as ICAM-1, VCAM-1, E-selectin, and P-selectin were downregulated in pulmonary endothelial cells of COVID-19 patients. Notably, decreased thrombomodulin expression in endothelial cells was associated with increased immune cell infiltration in the COVID-19 patient lungs. There were no SARS-CoV-2 particles detected in the lung endothelium of COVID-19 patients despite their dysfunctional phenotype. Meanwhile, the autopsy lungs of COVID-19 patients showed SARS-CoV-2 virions in damaged alveolar epithelium and evidence of hypoxic injury. Interpretation: Pulmonary endothelial cells become dysfunctional during COVID-19, showing a loss of thrombomodulin expression related to severe thrombosis and infiltration, and endothelial cell dysfunction might be caused by a pathologic condition in COVID-19 patient lungs rather than a direct infection with SARS-CoV-2. Funding: This work was supported by the Johns Hopkins University, the American Heart Association, and the National Institutes of Health.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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