Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study

Dear editor,

The article by Hippisley-Cox et al. compares side effects in first-dose vaccinated people with side effects in vaccinated people suffering from a breakthrough infection with Sars-Cov-2. We know from other studies (e.g. Menni, The Lancet 21 (7), p. 939) that side effects can be much stronger after the second dose. Could unwanted effects after the second dose be as high as they are after breakthrough infection?

Meaningful comparisons would be (i) those between people who have been vaccinated once and twice and those with breakthrough infection or (ii) between those who have been vaccinated and those who are infected, but not vaccinated. The analysis even begs the question of whether the undesirable side effects could be worse after a breakthrough infection than after infection without vaccination. If one takes into account the age-related benefits and risks of vaccination, the result could even argue against vaccination of younger people.

Dear Editor,

The article combines an impressive number of data points but it does not say very much about the quality of a data point. There is reason to question the data quality of this data set.

The article does not explain how the pre-risk period of 1 month (28 days) comes about. I.e. the authors observed an increased risk of adverse outcomes up to 28 days before the exposure. What should be the reason for that except that there is a considerable problem with the exposure dates and/or the outcome dates?

As mentioned in the text and shown in supplementary figure 2a, adverse outcomes for vaccinations preceded the exposure up to 1 month (28 days). This indicates that the exposure dates were accurate only up to plus/minus 1 month. Also, the authors give no explanation how this pronounced 2-peaked form in supplementary figure 2a comes about.

An exposure date accurate only up to plus/minus 1 month is significant because the total observation period is only 5 months. If the data quality of the exposure dates is poor it is difficult to discriminate between positive test and vaccination when it comes to the combined exposure of a positive SARS-CoV2 test and a vaccination. This is what the article is reporting when it comes to test related events, a combined exposure to test and vaccination. A clear differentiation between those events could be possible, if they differ by more than 2 month.

That this is a serious problem can be seen in table 3 of the article where the incidence rate ratio (IRR) of an adverse outcome in the pre-risk phase after (i.e. before) a positive test is up to 5 times higher than baseline. The same elevated pre-risk does not appear after (i.e. before) a vaccinations, for none of the outcomes. That happened because the authors attributed the adverse effect to the positive test exposure only though it was a combined exposure of test and vaccination that relates to an adverse effect. In this sense the authors decided what caused the outcome.

This data set does say something about the combined exposure of vaccination and positive test and the outcome thrombosis like adverse reaction and this gives cause for concern. But it says very little if not nothing about the positive test event alone and the outcome thrombosis like event.

In view of the recent deaths related to vaccinations it would have been desirable if the authors had interpreted their data more conservatively. Caution is advised to conclude from this data set that the risk of vaccination related adverse outcomes is smaller than the risk of positive test related adverse outcomes.

Best regards,
Johannes Kreis

Dear Editor

Shyan Goh writes [1]:

“ Astra Zeneca sure needed better media communication specialists, marketing experts and public relations strategists than what they have so far, considering the discrepancy in public concerns and brand damage in response to vaccine-related adverse events connected to ChAdOx1 nCoV-19 when compared to those of “the other vaccine”.”

Unfortunately “communication specialists, marketing experts and public relations” is what we get from pharmaceutical companies. What the public and the medical profession should expect is not that they do more of it, or do it better, but candour.

[1] Shyan Goh, ‘ One swallow does not a summer make but perhaps fodder for AstraZeneca to improve their brand image’, 27 August 2021, https://www.bmj.com/content/374/bmj.n1931/rr-1

Dear Editor

The risks of thrombocytopenia, venous thromboembolism, and arterial thrombosis as characterized in Table 2, even though broken down by vaccine and positive SARS-CoV-2 test - are all vaccinated populations, according to your study.

Therefore this is the rate of thrombotic events in a vaccinated population who has a "breakthrough" infection.

To my knowledge we do not know the prevalence of blood clots or venous thromboembolism in a vaccine naive population who test positive for SARS-CoV-2, most existing research examine hospitalizations and fail to take into account all infections, including asymptomatic and mild infections.

Please examine this higher risk for blood clots associated with breakthrough infection as this may be a safety signal.