1. Epidemiology and Global Health
  2. Medicine

SARS-CoV-2 suppresses anticoagulant and fibrinolytic gene expression in the lung

  1. Alan E Mast
  2. Alisa S Wolberg
  3. David Gailani
  4. Michael R Garvin
  5. Christiane Alvarez
  6. J Izaak Miller
  7. Bruce Aronow
  8. Daniel Jacobson  Is a corresponding author
  1. Medical College of Wisconsin, United States
  2. UNC Blood Research Center, United States
  3. Vanderbilt University Medical Center, United States
  4. Oak Ridge National Laboratory, United States
  5. Cincinnati Children's Hospital Research Foundation, United States
https://doi.org/10.7554/eLife.64330
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Cite this article
  1. Alan E Mast
  2. Alisa S Wolberg
  3. David Gailani
  4. Michael R Garvin
  5. Christiane Alvarez
  6. J Izaak Miller
  7. Bruce Aronow
  8. Daniel Jacobson
(2021)
SARS-CoV-2 suppresses anticoagulant and fibrinolytic gene expression in the lung
eLife 10:e64330.
https://doi.org/10.7554/eLife.64330
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Abstract

Extensive fibrin deposition in the lungs and altered levels of circulating blood coagulation proteins in COVID-19 patients imply local derangement of pathways that limit fibrin formation and/or promote its clearance. We examined transcriptional profiles of bronchoalveolar lavage fluid (BALF) samples to identify molecular mechanisms underlying these coagulopathies. mRNA levels for regulators of the kallikrein-kinin (C1-inhibitor), coagulation (thrombomodulin, endothelial protein C receptor), and fibrinolytic (urokinase and urokinase receptor) pathways were significantly reduced in COVID-19 patients. While transcripts for several coagulation proteins were increased, those encoding tissue factor, the protein that initiates coagulation and whose expression is frequently increased in inflammatory disorders, were not increased in BALF from COVID-19 patients. Our analysis implicates enhanced propagation of coagulation and decreased fibrinolysis as drivers of the coagulopathy in the lungs of COVID-19 patients.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Data for control and COVID-19 bronchoalveolar lavage samples are available in the Sequence Read Archive at NCBI.

The following previously published data sets were used

Article and author information

Author details

  1. Alan E Mast

    Versiti Blood Research Institute, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    Alan E Mast, receives research funding from Novo Nordisk and has received honoraria for serving on Novo Nordisk advisory boards..

  2. Alisa S Wolberg

    Department of Pathology and Laboratory Medicine, UNC Blood Research Center, Chapel Hill, United States
    Competing interests
    Alisa S Wolberg, receives research funding from Takeda and Bristol Myers Squibb.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2845-2303

  3. David Gailani

    3Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    David Gailani, receives research funding from Bayer and has received honoraria for serving on Anthos, Bristol-Myers Squibb, Ionis and Janssen advisoryboards..

  4. Michael R Garvin

    Biosciences, Oak Ridge National Laboratory, Oak Ridge, United States
    Competing interests
    No competing interests declared.

  5. Christiane Alvarez

    Biosciences, Oak Ridge National Laboratory, Oak Ridge, United States
    Competing interests
    No competing interests declared.

  6. J Izaak Miller

    Biosciences, Oak Ridge National Laboratory, Oak Ridge, United States
    Competing interests
    No competing interests declared.

  7. Bruce Aronow

    Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, Cincinnati, United States
    Competing interests
    No competing interests declared.

  8. Daniel Jacobson

    Biosciences, Oak Ridge National Laboratory, Oak Ridge, United States
    For correspondence
    jacobsonda@ornl.gov
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9822-8251

Funding

Oak Ridge National Laboratory (LOIS:10074)

  • Michael R Garvin
  • Christiane Alvarez
  • J Izaak Miller
  • Daniel Jacobson

National Institutes of Health (U24 HL148)

  • Bruce Aronow

National Institutes of Health (HL068835)

  • Alan E Mast

National Institutes of Health (HL143403)

  • Alisa S Wolberg

National Institutes of Health (HL126974)

  • Alisa S Wolberg

National Institutes of Health (HL140025)

  • David Gailani

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Noriaki Emoto, Kobe Pharmaceutical University, Japan

Version history

  1. Received: October 26, 2020
  2. Accepted: March 6, 2021
  3. Accepted Manuscript published: March 8, 2021 (version 1)
  4. Accepted Manuscript updated: March 9, 2021 (version 2)
  5. Version of Record published: April 15, 2021 (version 3)

Copyright

© 2021, Mast et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Alan E Mast
  2. Alisa S Wolberg
  3. David Gailani
  4. Michael R Garvin
  5. Christiane Alvarez
  6. J Izaak Miller
  7. Bruce Aronow
  8. Daniel Jacobson
(2021)
SARS-CoV-2 suppresses anticoagulant and fibrinolytic gene expression in the lung
eLife 10:e64330.
https://doi.org/10.7554/eLife.64330

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Further reading

    1. Microbiology and Infectious Disease

    Comment on ‘SARS-CoV-2 suppresses anticoagulant and fibrinolytic gene expression in the lung’

    Ethan S FitzGerald, Amanda M Jamieson
    Scientific Correspondence

    Mast et al. analyzed transcriptome data derived from RNA-sequencing (RNA-seq) of COVID-19 patient bronchoalveolar lavage fluid (BALF) samples, as compared to BALF RNA-seq samples from a study investigating microbiome and inflammatory interactions in obese and asthmatic adults (Mast et al., 2021). Based on their analysis of these data, Mast et al. concluded that mRNA expression of key regulators of the extrinsic coagulation cascade and fibrinolysis were significantly reduced in COVID-19 patients. Notably, they reported that the expression of the extrinsic coagulation cascade master regulator Tissue Factor (F3) remained unchanged, while there was an 8-fold upregulation of its cognate inhibitor Tissue Factor Pathway Inhibitor (TFPI). From this they conclude that “pulmonary fibrin deposition does not stem from enhanced local [tissue factor] production and that counterintuitively, COVID-19 may dampen [tissue factor]-dependent mechanisms in the lungs”. They also reported decreased Activated Protein C (aPC) mediated anticoagulant activity and major increases in fibrinogen expression and other key regulators of clot formation. Many of these results are contradictory to findings in most of the field, particularly the findings regarding extrinsic coagulation cascade mediated coagulopathies. Here, we present a complete re-analysis of the data sets analyzed by Mast et al. This re-analysis demonstrates that the two data sets utilized were not comparable between one another, and that the COVID-19 sample set was not suitable for the transcriptomic analysis Mast et al. performed. We also identified other significant flaws in the design of their retrospective analysis, such as poor-quality control and filtering standards. Given the issues with the datasets and analysis, their conclusions are not supported.

    1. Epidemiology and Global Health
    2. Medicine
    3. Microbiology and Infectious Disease

    COVID-19: A Collection of Articles

    Edited by Diane M Harper et al.
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    1. Epidemiology and Global Health
    2. Medicine

    Association between bisphosphonate use and COVID-19 related outcomes

    Jeffrey Thompson, Yidi Wang ... Ulrich H von Andrian
    Research Article Updated

    Background:

    Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19.

    Methods:

    A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak.

    Results:

    A total of 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. A total of 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR = 0.22; 95%CI:0.21–0.23; p<0.001), COVID-19 diagnosis (OR = 0.23; 95%CI:0.22–0.24; p<0.001), and COVID-19-related hospitalization (OR = 0.26; 95%CI:0.24–0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR = 0.23; 95%CI:0.22–0.23; p<0.001) or pneumonia (OR = 0.32; 95%CI:0.31–0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2.

    Conclusions:

    Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes.

    Funding:

    This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to UHvA) and a CRI Irvington postdoctoral fellowship, CRI2453 (to PH).