von Willebrand Factor Multimer Formation Contributes to Immunothrombosis in Coronavirus Disease 2019

  1. Adrian A. N. Doevelaar
  2. Martin Bachmann
  3. Bodo Hölzer
  4. Felix S. Seibert
  5. Benjamin J. Rohn
  6. Frederic Bauer
  7. Oliver Witzke
  8. Ulf Dittmer
  9. Michael Bachmann
  10. Serap Yilmaz
  11. Rita Dittmer
  12. Sonja Schneppenheim
  13. Nina Babel
  14. Ulrich Budde
  15. Timm H. Westhoff

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Abstract

Prevention and therapy of immunothrombosis remain crucial challenges in the management of coronavirus disease 2019, since the underlying mechanisms are incompletely understood. We hypothesized that endothelial damage may lead to substantially increased concentrations of von Willebrand factor with subsequent relative deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13).

DESIGN:

Prospective controlled cross-over trial.

SETTING:

Blood samples of patients with confirmed coronavirus disease 2019 and healthy controls were obtained in three German hospitals and analyzed in a German hemostaseologic laboratory.

PATIENTS:

Seventy-five patients with confirmed coronavirus disease 2019 of mild to critical severity and 30 healthy controls.

MEASUREMENTS AND MAIN RESULTS:

von Willebrand factor antigen, ADAMTS13, and von Willebrand factor multimer formation were analyzed. von Willebrand factor antigen was 4.1 times higher in COVID-19 patients compared with healthy controls ( p < 0.0001), whereas ADAMTS13 activities were not significantly different ( p = 0.18). The ADAMTS13/von Willebrand factor antigen ratio was significantly lower in COVID-19 than in the control group (24.4 ± 20.5 vs 82.0 ± 30.7; p < 0.0001). Fourteen patients (18.7%) undercut a critical ratio of 10 as described in thrombotic thrombocytopenic purpura. Gel analysis of multimers resembled a thrombotic thrombocytopenic purpura pattern with loss of the largest multimers in 75% and a smeary triplet pattern in 39% of the patients. The ADAMTS13/von Willebrand factor antigen ratio decreased continuously from mild to critical disease (analysis of variance p = 0.026). Furthermore, it differed significantly between surviving patients and those who died from COVID-19 ( p = 0.001) yielding an area under the curve of 0.232 in receiver operating characteristic curve curve analysis.

Conclusion:

COVID-19 is associated with a substantial increase in von Willebrand factor levels, which can exceed the ADAMTS13 processing capacity resulting in the formation of large von Willebrand factor multimers indistinguishable from thrombotic thrombocytopenic purpura. The ADAMTS13/von Willebrand factor antigen ratio is an independent predictor of severity of disease and mortality. These findings provide a rationale to consider plasma exchange as a therapeutic option in COVID-19 and to include von Willebrand factor and ADAMTS13 in the diagnostic workup.

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  1. ScreenIT

    SciScore for 10.1101/2020.08.23.20177824: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was approved by the ethical committees of Ruhr-University Bochum (20–6886), University Hospital Essen (20–9214-BO) and the Medical Association Hamburg.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Statistical analyses were performed using SPSS Statistics 25 (IBM, Chicago, USA) and Prism 8 (Graph Pad, San Diego, USA).
    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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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  2. Version published to 10.1097/ccm.0000000000004918
  3. Version published to 10.1101/2020.08.23.20177824v1 on medRxiv