COVID ‐19 Vaccine‐Associated Cerebral Venous Thrombosis in Germany

  1. Jörg B. Schulz
  2. Peter Berlit
  3. Hans‐Christoph Diener
  4. Christian Gerloff
  5. Andreas Greinacher
  6. Christine Klein
  7. Gabor C. Petzold
  8. Marco Piccininni
  9. Sven Poli
  10. Rainer Röhrig
  11. Helmuth Steinmetz
  12. Thomas Thiele
  13. Tobias Kurth
  14. the German Society of Neurology SARS‐CoV‐2 Vaccination Study Group

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Abstract

We aimed to estimate the incidence of cerebral sinus and venous thrombosis (CVT) within 1 month from first dose administration and the frequency of vaccine‐induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA‐1273, in Germany.

Methods

A web‐based questionnaire was e‐mailed to all departments of neurology. We requested a report of cases of CVT occurring within 1 month of a COVID‐19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of 9 German states.

Results

A total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were younger than 60 years. Fifty‐three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%) vaccination, and none after mRNA‐1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within 1 month from first dose administration was 0.55 (95% confidence interval [CI] = 0.38–0.78) per 100,000 person‐months (which corresponds to a risk of CVT within the first 31 days of 0.55 per 100,000 individuals) for all vaccines and 1.52 (95% CI = 1.00–2.21) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (95% CI = 3.46–34.98) for ChAdOx1 compared to mRNA‐based vaccines and 3.14 (95% CI = 1.22–10.65) for females compared to non‐females. In 26 of 45 patients with CVT (57.8%), VITT was graded highly probable.

Interpretation

Given an incidence of 0.02 to 0.15 per 100,000 person‐months for CVT in the general population, these findings point toward a higher risk for CVT after ChAdOx1 vaccination, especially for women. ANN NEUROL 2021;90:627–639

Article activity feed

  1. Version published to 10.1002/ana.26172
  2. Version published to 10.1101/2021.04.30.21256383v2 on medRxiv
  3. ScreenIT

    SciScore for 10.1101/2021.04.30.21256383: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The protocol was approved by the Ethics Committee (Vote-No. 142/21, Ethics Committee of the Medical Faculty at RWTH University).
    Sex as a biological variableWe extracted CC-BY licenced data from the Robert Koch-Institute (RKI) about the number of vaccine shots administered by calendar week, age group, vaccine type, and state separately for only females and for everyone (numbers for non-females were obtained by difference).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    For a subgroup of patients, anti-Heparin/Platelet Factor 4 Antibody (PF4)/polyanion-IgG EIA and a platelet activation assay were performed in the laboratory of the Institute for Immunology and Transfusion Medicine at the University of Greifswald as described12.
    anti-Heparin/Platelet Factor 4
    suggested: None
    For the PF4 antibody results, we used information from the central laboratory in Greifswald, only if missing, we considered test results if positive from the respective local hospitals.
    PF4
    suggested: None
    (a) time after vaccination equals one to 16 days, (b) thrombocytopenia (<150/nL) or relative thrombocytopenia (drop of thrombocytes of at least 50%), (c) positive enzyme-linked immunosorbent assay (ELISA) to detect platelet factor 4 (PF4)-polyanion antibodies, (d) positive modified (PF4-enhanced
    PF4)-polyanion
    suggested: None
    Software and Algorithms
    SentencesResources
    All analyses were performed using R version 4.0.3 and RStudio 1.1.456.
    RStudio
    suggested: (RStudio, RRID:SCR_000432)

    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:
    Limitations of our study include that we only collected information from neurological departments and patients may have been treated at other departments or died without reaching a hospital. We could not collect the brain imaging data to validate the diagnosis of CVT and other cerebral events. Due to public discussions specifically around CVT as a consequence of the ChAdOx1 vaccine, a certain overreporting is possible. We assume that neurologists in Germany would be more aware of cases with CVT after vaccination than of ischemic stroke or cerebral haemorrhage, which may result in underreporting of the latter. We did not have data on the age, sex and vaccine type distribution of vaccinated people from entire Germany but only from 9 states. In the RKI dataset, the vaccine shots administered by general practitioners are not included, probably leading to an overestimation of the true risk. Furthermore, we had to compute the overall amount of person-years spent at risk by subgroup relying on a crude approximation of the number of first doses administered. Lastly, we cannot exclude in this retrospective survey that some transferred data were misclassified or differentially missing. Two of the cases included in this report were also presented in the first description of VITT by Greinacher and colleagues12 Implications: Findings of our study imply further careful considerations in the administration of ChAdOx1 especially for women and risk-benefit considerations when considering this...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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.

    Results from scite Reference Check: We found no unreliable references.

    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.

  4. Version published to 10.1101/2021.04.30.21256383v1 on medRxiv