1. Epidemiology and Global Health
  2. Medicine
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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
Research Article
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Cite this article as: eLife 2021;10:e64330 doi: 10.7554/eLife.64330

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

Publication 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. Further reading

Further reading

    1. Epidemiology and Global Health
    Andria Mousa et al.
    Research Article

    Background: Transmission of respiratory pathogens such as SARS-CoV-2 depends on patterns of contact and mixing across populations. Understanding this is crucial to predict pathogen spread and the effectiveness of control efforts. Most analyses of contact patterns to date have focussed on high-income settings.

    Methods: Here, we conduct a systematic review and individual-participant meta-analysis of surveys carried out in low- and middle-income countries and compare patterns of contact in these settings to surveys previously carried out in high-income countries. Using individual-level data from 28,503 participants and 413,069 contacts across 27 surveys we explored how contact characteristics (number, location, duration and whether physical) vary across income settings.

    Results: Contact rates declined with age in high- and upper-middle-income settings, but not in low-income settings, where adults aged 65+ made similar numbers of contacts as younger individuals and mixed with all age-groups. Across all settings, increasing household size was a key determinant of contact frequency and characteristics, with low-income settings characterised by the largest, most intergenerational households. A higher proportion of contacts were made at home in low-income settings, and work/school contacts were more frequent in high-income strata. We also observed contrasting effects of gender across income-strata on the frequency, duration and type of contacts individuals made.

    Conclusions: These differences in contact patterns between settings have material consequences for both spread of respiratory pathogens, as well as the effectiveness of different non-pharmaceutical interventions.

    Funding: This work is primarily being funded by joint Centre funding from the UK Medical Research Council and DFID (MR/R015600/1).

    1. Epidemiology and Global Health
    2. Medicine
    ISARIC Clinical Characterisation Group et al.
    Research Article

    Background: There is potentially considerable variation in the nature and duration of the care provided to hospitalised patients during an infectious disease epidemic or pandemic. Improvements in care and clinician confidence may shorten the time spent as an inpatient, or the need for admission to an intensive care unit (ICU) or high density unit (HDU). On the other hand, limited resources at times of high demand may lead to rationing. Nevertheless, these variables may be used as static proxies for disease severity, as outcome measures for trials, and to inform planning and logistics.

    Methods: We investigate these time trends in an extremely large international cohort of 142,540 patients hospitalised with COVID-19. Investigated are: time from symptom onset to hospital admission, probability of ICU/HDU admission, time from hospital admission to ICU/HDU admission, hospital case fatality ratio (hCFR) and total length of hospital stay.

    Results: Time from onset to admission showed a rapid decline during the first months of the pandemic followed by peaks during August/September and December 2020. ICU/HDU admission was more frequent from June to August. The hCFR was lowest from June to August. Raw numbers for overall hospital stay showed little variation, but there is clear decline in time to discharge for ICU/HDU survivors.

    Conclusions: Our results establish that variables of these kinds have limitations when used as outcome measures in a rapidly-evolving situation.

    Funding: This work was supported by the UK Foreign, Commonwealth and Development Office and Wellcome [215091/Z/18/Z] and the Bill and Melinda Gates Foundation [OPP1209135]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.