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
Share this article
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
  2. Download BibTeX
  3. Download .RIS

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 HL148865)

  • 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.

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.

Download links

Share this article

https://doi.org/10.7554/eLife.64330

Categories and tags

Research organism

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.
    Collection

    eLife has published the following articles on SARS-CoV-2 and COVID-19.

    1. Epidemiology and Global Health

    Lifestyles and their relative contribution to biological aging across multiple-organ systems: Change analysis from the China Multi-Ethnic Cohort study

    Yuan Zhang, Dan Tang ... Xing Zhao
    Research Article

    Background:

    Biological aging exhibits heterogeneity across multi-organ systems. However, it remains unclear how is lifestyle associated with overall and organ-specific aging and which factors contribute most in Southwest China.

    Methods:

    This study involved 8396 participants who completed two surveys from the China Multi-Ethnic Cohort (CMEC) study. The healthy lifestyle index (HLI) was developed using five lifestyle factors: smoking, alcohol, diet, exercise, and sleep. The comprehensive and organ-specific biological ages (BAs) were calculated using the Klemera–Doubal method based on longitudinal clinical laboratory measurements, and validation were conducted to select BA reflecting related diseases. Fixed effects model was used to examine the associations between HLI or its components and the acceleration of validated BAs. We further evaluated the relative contribution of lifestyle components to comprehension and organ systems BAs using quantile G-computation.

    Results:

    About two-thirds of participants changed HLI scores between surveys. After validation, three organ-specific BAs (the cardiopulmonary, metabolic, and liver BAs) were identified as reflective of specific diseases and included in further analyses with the comprehensive BA. The health alterations in HLI showed a protective association with the acceleration of all BAs, with a mean shift of –0.19 (95% CI −0.34, –0.03) in the comprehensive BA acceleration. Diet and smoking were the major contributors to overall negative associations of five lifestyle factors, with the comprehensive BA and metabolic BA accounting for 24% and 55% respectively.

    Conclusions:

    Healthy lifestyle changes were inversely related to comprehensive and organ-specific biological aging in Southwest China, with diet and smoking contributing most to comprehensive and metabolic BA separately. Our findings highlight the potential of lifestyle interventions to decelerate aging and identify intervention targets to limit organ-specific aging in less-developed regions.

    Funding:

    This work was primarily supported by the National Natural Science Foundation of China (Grant No. 82273740) and Sichuan Science and Technology Program (Natural Science Foundation of Sichuan Province, Grant No. 2024NSFSC0552). The CMEC study was funded by the National Key Research and Development Program of China (Grant No. 2017YFC0907305, 2017YFC0907300). The sponsors had no role in the design, analysis, interpretation, or writing of this article.