Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients

  1. Yu Zuo
  2. Mark Warnock
  3. Alyssa Harbaugh
  4. Srilakshmi Yalavarthi
  5. Kelsey Gockman
  6. Melanie Zuo
  7. Jacqueline A. Madison
  8. Jason S. Knight
  9. Yogendra Kanthi
  10. Daniel A. Lawrence

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Abstract

Patients with coronavirus disease-19 (COVID-19) are at high risk for thrombotic arterial and venous occlusions. However, bleeding complications have also been observed in some patients. Understanding the balance between coagulation and fibrinolysis will help inform optimal approaches to thrombosis prophylaxis and potential utility of fibrinolytic-targeted therapies. 118 hospitalized COVID-19 patients and 30 healthy controls were included in the study. We measured plasma antigen levels of tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) and performed spontaneous clot-lysis assays. We found markedly elevated tPA and PAI-1 levels in patients hospitalized with COVID-19. Both factors demonstrated strong correlations with neutrophil counts and markers of neutrophil activation. High levels of tPA and PAI-1 were associated with worse respiratory status. High levels of tPA, in particular, were strongly correlated with mortality and a significant enhancement in spontaneous ex vivo clot-lysis. While both tPA and PAI-1 are elevated among COVID-19 patients, extremely high levels of tPA enhance spontaneous fibrinolysis and are significantly associated with mortality in some patients. These data indicate that fibrinolytic homeostasis in COVID-19 is complex with a subset of patients expressing a balance of factors that may favor fibrinolysis. Further study of tPA as a biomarker is warranted.

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  1. ScreenIT

    SciScore for 10.1101/2020.08.29.20184358: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableThe 30 controls included 20 females and 10 males, mean age of 41.7 ± 14.4.

    Table 2: Resources

    Antibodies
    SentencesResources
    25 μL of 2 μg/mL biotinylated rabbit anti-hPAI-1 or biotinylated rabbit anti-htPA antibody (Molecular Innovations) was added to the plate, followed by incubating with phycoerythrin-conjugated streptavidin.
    anti-hPAI-1
    suggested: None
    anti-htPA
    suggested: None
    Software and Algorithms
    SentencesResources
    Data analysis was with GraphPad Prism software version 8.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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:
    Our study has some limitations. We did not have access to fresh plasma samples each day of a patient’s hospitalization. PAI-1 and tPA levels were therefore not tested on a defined day of hospitalization, but rather when a plasma sample became available to the research laboratory. It should however be noted that when assessing correlations of PAI-1 and tPA with clinical variables, same-day laboratory and clinical status data were used. Due to research restrictions during the pandemic we were not allowed to recruit new healthy controls. Healthy controls were recruited during the pre-COVID-19 era and we were not able to match gender and age to COVID-19 patients. Future studies should endeavor to systematically track PAI-1 and tPA levels over the full course of hospitalization of COVID-19 patients and to compare with gender- and age-matched controls. We also recognize that tPA is not the sole activator of plasminogen, as uPA also plays a role in the fibrinolysis regulation and PAI-1 can also inhibit uPA17. Dysregulation of uPA and its receptor system have been implicated in the pathogenesis of pulmonary fibrosis and ARDS33,34. The role of uPA and its receptor in COVID-19 warrants further investigation. Because the COVID-19 associated prothrombotic risk is known, prophylactic anticoagulation has become part of standard COVID-19 treatment. High rates of thromboembolic events from early studies prompted some experts to recommend a more intensive dose of anticoagulation among COVID-1...

    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

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1038/s41598-020-80010-z
  3. Version published to 10.1101/2020.08.29.20184358 on medRxiv