Thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2: a population-based cohort analysis

  1. Edward Burn
  2. Xintong Li
  3. Antonella Delmestri
  4. Nathan Jones
  5. Talita Duarte-Salles
  6. Carlen Reyes
  7. Eugenia Martinez-Hernandez
  8. Edelmira Marti
  9. Katia MC Verhamme
  10. Peter R Rijnbeek
  11. Victoria Y Strauss
  12. Daniel Prieto-Alhambra

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Abstract

Objectives

To calculate the observed rates of thrombosis and thrombocytopenia following vaccination against SARS-CoV-2, infection with SARS-CoV-2, and to compare them to background (expected) rates in the general population.

Design

Cohort study using routinely collected primary care records.

Setting

Routine practice in the United Kingdom.

Participants

Two mutually exclusive vaccinated cohorts included people vaccinated with either ChAdOx1 or BNT162b2 between 8 December 2020 and 6 March 2021. A third cohort consisted of people newly infected with SARS-Cov-2 identified by a first positive RT-PCR test between 1 September 2020 and 28 February 2021. The fourth general population cohort for background rates included those people with a visit between 1 January 2017 and 31 December 2019. In total, we included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees, 299,311 people infected with SARS-CoV-2, and 2,290,537 people from the general population.

Interventions

First-dose of either ChAdOx1 or BNT162b2

Main outcome measures

Outcomes included venous thrombosis, arterial thrombosis, thrombocytopenia, and thrombosis with thrombocytopenia. Outcome rates were estimated for recipients of the ChAdOx1 or BNT162b2 vaccines, for people infected with SARS-CoV-2, and background rates in the general population. Indirectly standardized incidence ratios (SIR) were estimated.

Results

We included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees, 299,311 people infected with SARS-CoV-2, and 2,290,537 people from the general population for background rates. The SIRs for pulmonary embolism were 1.23 [95% CI, 1.09-1.39] after vaccination with ChAdOx1, 1.21 [1.07-1.36] after vaccination with BNT162b2, and 15.31 [14.08 to 16.65] for infection with SARS-CoV-2. The SIRs for thrombocytopenia after vaccination were 1.25 [1.19 to 1.31] for ChAdOx1 and 0.99 (0.94 to 1.04) for BNT162b2. Rates of deep vein thrombosis and arterial thrombosis were similar among those vaccinated and the general population.

Conclusions

ChAdOx1 and BNT162b2 had broadly similar safety profiles. Thrombosis rates after either vaccine were mostly similar to those of the general population. Rates of pulmonary embolism increased 1.2-fold after either vaccine and 15-fold with SARS-CoV-2 infection. Thrombocytopenia was more common among recipients of ChAdOx1 but not of BNT162b2.

Summary box

What is already known on this topic

  • Spontaneous reports of unusual and severe thrombosis with thrombocytopenia syndrome (TTS) raised concerns regarding the safety of adenovirus-based vaccines against SARS-CoV-2

  • In a cohort study including over 280,000 people aged 18-65 years vaccinated with ChAdOx1 in Denmark and Norway, Pottegård et al reported increased rates of venous thromboembolic events as well as thrombocytopenia among vaccine recipients.

What this study adds

  • In this cohort study, ChAdOx1 and BNT162b2 were seen to have broadly similar safety profiles.

  • Rates of thrombosis after either vaccine were generally similar to those of the general population. Rates of pulmonary embolism were though 1.2-fold higher than background rates after either vaccine, which compared to 15-fold higher after SARS-CoV-2 infection.

  • Thrombocytopenia was more common among recipients of ChAdOx1 but not of BNT162b2.

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  1. ScreenIT

    SciScore for 10.1101/2021.07.29.21261348: (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
    AURUM and GOLD are established primary care databases broadly representative of the UK population,13, 14 and previous research has demonstrated their validity for vaccine safety surveillance.15, 16 Both databases were mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) for analysis.
    GOLD
    suggested: (GOLD, RRID:SCR_000188)

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Study strengths and limitations: Our study has limitations. The time period studied covered the initial phases of vaccination in the UK, when vaccines were prioritized for older, more vulnerable populations and healthcare staff.24 We therefore saw a higher prevalence of conditions such as asthma and diabetes in those vaccinated than in the general population. Although we used indirect standardization to account for differences in the four cohorts’ age distributions, remaining residual confounding could explain some of our findings. Such bias could result in overestimated safety signals due to remaining imbalances in the baseline outcome risk when comparing vaccinated and background populations. Measurement error is unavoidable in observational studies. However, any errors are likely to have been non-differential across our vaccinated and unvaccinated cohorts and should therefore not have affected our relative rate estimates. As we only used primary care data, we may have underestimated absolute risks due to a lack of hospital linkage. However, previous studies have shown that CPRD captures rare events well, even without linkage to Hospital Episode Statistics.25 Although within-database comparisons are preferred,16 we had to use two slightly different primary care databases. However, one study found that these databases gave similar results.26 We also used the OMOP common data model to maximize the comparability of the two databases irrespective of differences in their coding ...

    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

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  2. Version published to 10.1101/2021.07.29.21261348v1 on medRxiv