Antibody-induced procoagulant platelets in severe COVID-19 infection

  1. Karina Althaus
  2. Irene Marini
  3. Jan Zlamal
  4. Lisann Pelzl
  5. Anurag Singh
  6. Helene Häberle
  7. Martin Mehrländer
  8. Stefanie Hammer
  9. Harald Schulze
  10. Michael Bitzer
  11. Nisar Malek
  12. Dominik Rath
  13. Hans Bösmüller
  14. Bernard Nieswandt
  15. Meinrad Gawaz
  16. Tamam Bakchoul
  17. Peter Rosenberger

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Abstract

The pathophysiology of COVID-19–associated thrombosis seems to be multifactorial. We hypothesized that COVID-19 is accompanied by procoagulant platelets with subsequent alteration of the coagulation system. We investigated depolarization of mitochondrial inner transmembrane potential (ΔΨm), cytosolic calcium (Ca2+) concentration, and phosphatidylserine (PS) externalization. Platelets from COVID-19 patients in the intensive care unit (ICU; n = 21) showed higher ΔΨm depolarization, cytosolic Ca2+, and PS externalization compared with healthy controls (n = 18) and non-ICU COVID-19 patients (n = 4). Moreover, significant higher cytosolic Ca2+ and PS were observed compared with a septic ICU control group (ICU control; n = 5). In the ICU control group, cytosolic Ca2+ and PS externalization were comparable with healthy controls, with an increase in ΔΨm depolarization. Sera from COVID-19 patients in the ICU induced a significant increase in apoptosis markers (ΔΨm depolarization, cytosolic Ca2+, and PS externalization) compared with healthy volunteers and septic ICU controls. Interestingly, immunoglobulin G fractions from COVID-19 patients induced an Fcγ receptor IIA–dependent platelet apoptosis (ΔΨm depolarization, cytosolic Ca2+, and PS externalization). Enhanced PS externalization in platelets from COVID-19 patients in the ICU was associated with increased sequential organ failure assessment score (r = 0.5635) and D-dimer (r = 0.4473). Most importantly, patients with thrombosis had significantly higher PS externalization compared with those without. The strong correlations between markers for apoptosic and procoagulant platelets and D-dimer levels, as well as the incidence of thrombosis, may indicate that antibody-mediated procoagulant platelets potentially contributes to sustained increased thromboembolic risk in ICU COVID-19 patients.

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  1. ScreenIT

    SciScore for 10.1101/2020.09.03.20187286: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: Written informed consent was obtained from all volunteers prior to any study-related procedure.
    IRB: The study protocol of patient material was approved by the Institutional Review Board of the University of Tuebingen.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Statistical analyses: The statistical analysis was performed using GraphPad Prism, Version 7.0 (GraphPad, La Jolla, USA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    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 is subjected to limitations. First, as an observational study, we cannot conclude that the reported associations between platelet markers and laboratory parameters as well as clinical outcomes are causal or specific for infection with SARS-CoV-2. Second, we cannot exclude the possibility of remaining residual confounding or unmeasured potential confounders. Third, the low number of patients does not enable a final and robust multivariate statistical analysis. In addition, we observed a small difference in age between ICU COVID-19 patients and controls. However, age of the patient is not classically associated, and little is known on the impact of age on platelet apoptosis. It should also be emphasized that it is not clear whether the platelet apoptosis described here are drivers of disease severity or a mere consequence of hypercoagulation in severe (ICU) COVID-19 patients. Indeed, the definitive pathophysiology of COVID-19 and answering questions of causality will likely await the development of model systems for the disease. We hope though that our findings present another piece of the puzzle and will motivate further research into the role of platelet apoptosis in COVID-19 associated thromboembolic complications. Data presented in this study may build a basis for future studies to dissect platelet-mediated pathological mechanisms involved in the progression of COVID-19 and a larger and multi-center study is warranted to investigate the predictive power of platele...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT03205345Active, not recruitingEmricasan, a Caspase Inhibitor, for Treatment of Subjects Wi…
    NCT00080236CompletedSafety and Efficacy Study of a Caspase Inhibitor in Patients…

    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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  2. Version published to 10.1182/blood.2020008762
  3. Version published to 10.1101/2020.09.03.20187286v1 on medRxiv