Endothelial Dysfunction and Thrombosis in Patients With COVID-19—Brief Report

  1. Seigo Nagashima
  2. Monalisa Castilho Mendes
  3. Ana Paula Camargo Martins
  4. Nícolas Henrique Borges
  5. Thiago Mateus Godoy
  6. Anna Flavia Ribeiro dos Santos Miggiolaro
  7. Felipe da Silva Dezidério
  8. Cleber Machado-Souza
  9. Lucia de Noronha

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Abstract

Alveolar-capillary endothelial cells can be activated by severe acute respiratory syndrome coronavirus 2 infection leading to cytokine release. This could trigger endothelial dysfunction, pyroptosis, and thrombosis, which are the vascular changes, commonly referred to as coronavirus disease 2019 (COVID-19) endotheliopathy. Thus, this study aimed to identify tissue biomarkers associated with endothelial activation/dysfunction and the pyroptosis pathway in the lung samples of patients with COVID-19 and to compare them to pandemic influenza A virus H1N1 subtype 2009 and control cases.

Approach and Results:

Postmortem lung samples (COVID-19 group =6 cases; H1N1 group =10 cases, and control group =11 cases) were analyzed using immunohistochemistry and the following monoclonal primary antibodies: anti-IL (interleukin)-6, anti-TNF (tumor necrosis factor)-α, anti-ICAM-1 (intercellular adhesion molecule 1), and anticaspase-1. From the result, IL-6, TNF-α, ICAM-1, and caspase-1 showed higher tissue expression in the COVID-19 group than in the H1N1 and control groups.

Conclusions:

Our results demonstrated endothelial dysfunction and suggested the participation of the pyroptosis pathway in the pulmonary samples. These conditions might lead to systemic thrombotic events that could impair the clinical staff’s efforts to avoid fatal outcomes. One of the health professionals’ goals should be to identify the high risk of thrombosis patients early to block endotheliopathy and its consequences.

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  1. Version published to 10.1161/atvbaha.120.314860
  2. Version published to 10.1101/2020.06.17.20133124v2 on medRxiv
  3. ScreenIT

    SciScore for 10.1101/2020.06.17.20133124: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: The COVID-19 group (n=6) was approved by the National Research Ethics Committee (REC: 3.944.734/2020).
    RandomizationThe HPFs were chosen randomly from the septum and lumen alveolar.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The FFPE lung/heart samples were also performed using immunohistochemical reactions and the primary monoclonal antibodies, anti-CD163 (rabbit polyclonal, clone 14215, Thermo Fisher Scientific, 1:1000)
    anti-CD163
    suggested: (Thermo Fisher Scientific Cat# PA5-14215, RRID:AB_2074541)
    Software and Algorithms
    SentencesResources
    The FFPE lung/heart samples were also performed using immunohistochemical reactions and the primary monoclonal antibodies, anti-CD163 (rabbit polyclonal, clone 14215, Thermo Fisher Scientific, 1:1000)
    FFPE
    suggested: (ffpe, RRID:SCR_001307)
    The measurement was made only in the vascular endothelium, and the positive areas appeared through a semi-automatic segmentation method of quantification, using the Image-Pro Plus software version 4.5
    Image-Pro Plus
    suggested: (Image-Pro Plus, RRID:SCR_007369)
    Data were analyzed using the computer program R Project for Statistical Computing.
    R Project for Statistical
    suggested: (R Project for Statistical Computing, RRID:SCR_001905)
    Data were analyzed using the IBM® SPSS Statistics v.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The main limitations of this study are the small number of cases (n=6)4 and data based on FFPE post-mortem samples that can only provide a piece of static information at the time of the death and cannot reconstruct the evolving disease process. A limitation that might be influencing the expression of biomarkers would be the non-pairing baseline characteristics in the three groups (age and survival times). However, the COVID-19 and H1N1 groups are very different demographically from each other because these two pandemic diseases have marked differences in their risk groups and pathophysiology. In addition, the survival time is quite different between these two groups, since patients in the H1N1 group died earlier than has been observed in patients with COVID-19. We paired these two groups by mechanical ventilation time to minimize the differences in inflammatory response caused by this type of intervention. Our results suggest that endothelial activation/dysfunction and pyroptosis, also called endotheliopathy,59 could lead to a systemic immunothrombotic disease. It is known that thrombogenic conditions are quite characteristic in COVID-193 patients. Understanding the complex events that can be part of an immunothrombosis mechanism might help the health professional identify early patients with the potential of endotheliopathy based on predisposing comorbidities (chronic renal disease, diabetes, and hypertension) and systemic biomarkers, such as D-dimer, angiopoitin-2, and thro...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  4. Version published to 10.1101/2020.06.17.20133124v1 on medRxiv