Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID ‐19 vaccine safety surveillance: Incidence between 2017 and 2019 and patient profiles from 38.6 million people in six European countries

  1. Edward Burn
  2. Xintong Li
  3. Kristin Kostka
  4. Henry Morgan Stewart
  5. Christian Reich
  6. Sarah Seager
  7. Talita Duarte‐Salles
  8. Sergio Fernandez‐Bertolin
  9. María Aragón
  10. Carlen Reyes
  11. Eugenia Martinez‐Hernandez
  12. Edelmira Marti
  13. Antonella Delmestri
  14. Katia Verhamme
  15. Peter Rijnbeek
  16. Scott Horban
  17. Daniel R. Morales
  18. Daniel Prieto‐Alhambra

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

Background

Thrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus‐vectored COVID‐19 vaccines. In this study, we describe the background incidence of non‐vaccine induced TTS in six European countries.

Methods

Electronic medical records from France, the Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction or ischemic stroke, all with concurrent thrombocytopenia, were estimated among the general population of persons in a database between 2017 and 2019. A range of additional potential adverse events of special interest for COVID‐19 vaccinations were also studied in a similar manner.

Findings

A total of 38 611 617 individuals were included. Background rates ranged from 1.0 (95% CI: 0.7–1.4) to 8.5 (7.4–9.9) per 100 000 person‐years for DVT with thrombocytopenia, from 0.5 (0.3–0.6) to 20.8 (18.9–22.8) for PE with thrombocytopenia, from 0.1 (0.0–0.1) to 2.5 (2.2–2.7) for SVT with thrombocytopenia, and from 1.0 (0.8–1.2) to 43.4 (40.7–46.3) for myocardial infarction or ischemic stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.1–0.2) per 100 000 person‐years. The incidence of non‐vaccine induced TTS increased with age, and was typically greater among those with more comorbidities and greater medication use than the general population. It was also more often seen in men than women. A large proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their event.

Interpretation

Although rates vary across databases, non‐vaccine induced TTS has consistently been seen to be a very rare event among the general population. While still remaining very rare, rates were typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population.

Article activity feed

  1. Version published to 10.1002/pds.5419
  2. Version published to 10.1101/2021.05.12.21257083v3 on medRxiv
  3. ScreenIT

    SciScore for 10.1101/2021.05.12.21257083: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The Clinical Practice Research Datalink (CPRD) GOLD database contains data contributed by general practitioners (GP) from the United Kingdom.14 The Integrated Primary Care Information (IPCI) database is collected from electronic healthcare records of patients registered with GPs throughout the Netherlands.
    GOLD
    suggested: (GOLD, RRID:SCR_000188)
    These definitions were reviewed using the aid of the CohortDiagnostics R package,17 so as to identify additional codes of interest and to remove those highlighted as irrelevant based on feedback from regulators (e.g. puerperium and pregnancy-related disease) through an iterative process during the initial stages of analyses.
    CohortDiagnostics
    suggested: None

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Study limitations: This study relies on routinely-collected health care data and while this has allowed for the inclusion of a large study population, the recording of TTS has not previously been evaluated in the databases used. A degree of measurement error can thus be expected, and further research is required to validate the recording of TTS. The degree to which the TTS events being described after vaccinations against SARS-CoV-2 are comparable to TTS events previously seen in the general population is as yet unclear. TTS after vaccination appears to occur at unusual sites, with a large proportion of spontaneous reports and case series describing cerebral or abdominal thromboses, and with high levels of antibodies to platelet factor 4 often observed despite the absence of an exposure to heparin.28,32 In this study we have focused on specific sites of thrombosis with concomitant thrombocytopenia. We believe that this is more instructive than providing a singular background incidence rate for venous thromboembolism with thrombocytopenia, which would be driven in large part by commonly seen events (such as DVT and PE) and would not necessarily reflect the presentation of TTS after vaccination. As the pathophysiology of TTS after vaccination becomes better understood, definitions of the appropriate historical comparator can also be expected to evolve so as to best match the condition being described among those who have been recently vaccinated.

    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.

    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 10.1101/2021.05.12.21257083v2 on medRxiv
  5. Version published to 10.1101/2021.05.12.21257083v1 on medRxiv