In a cohort of 5.6 million people vaccinated against SARS-CoV-2, 157 (0.003%) more than expected had a VTE in the 28 days following their first dose. Thrombocytopenia was also more common after vaccination, with 1145 (0.021%) more events seen after a first dose of ChAdOx1 or BNT162b2 than would be expected. Rates of CVST were also higher than expected after a fist dose of ChAdOx1 with 12 more events than the 4 that would typically be expected, which equated to a standardized event difference proportion of 0.0003%. Meanwhile, among close to 400,000 people who were not yet vaccinated and who had a positive SARS-CoV-2 PCR positive test, 940 (0.23%) more people had a VTE in the 90 days after their positive test, 151 (0.0027%) had thrombocytopenia, and 4 (0.001%) had CVST. Moreover, this SARS-CoV-2 PCR cohort also had an increased risk of arterial thromboembolism with 53 (0.01%) more cases observed than would normally be expected. Study participants with a positive SARS-CoV-2 PCR positive test were also at increased risk of a VTE with thrombocytopenia with 9 (0.002%) more events observed than would be otherwise expected.
Concerns over thrombosis—alone and with thrombocytopenia—have been raised from spontaneous reports data since March 20216,7,11. Case series have been published, suggesting a new clinical entity known as vaccine-induced immune thrombotic thrombocytopenia (VITT), presenting as unusual thrombosis with raised antibodies against platelet factor 4. To date, thrombosis and thrombocytopenia has primarily been a concern for adenoviral-based vectors12. However, in our study we have seen comparable safety signals for PE and thrombocytopenia for both ChAdOx1 and BNT162b. Thrombocytopenia post vaccination has previously been reported after receipt of other vaccines, such as those against influenza13, measles, mumps, and rubella14, and hepatitis B15. Consequently, the finding from our study is in line with the existing observation that vaccines, as well as infections, initiate immune-mediated mechanisms that can induce protective immunity but may also lead to an autoimmune response16. Indeed, we see in our study a similar increase in risk for thrombocytopenia among COVID-19 cases.
A study of 280,000 vaccinees aged between 18 and 65 in Denmark and Norway assessed the 28-day incidence rates of thromboembolic events and coagulation disorders following ChAdOx117. Similar to our analyses, Pottegård et al applied a historical comparator design with indirect standardization. They found a 2-fold increased rate of VTE, an 80% increase in rates of PE, and a 20-fold increased rate of CVST. The authors also reported a 3-fold higher-than-expected rate of thrombocytopenia. As in our study, they observed similar rates of arterial events among those vaccinated as would be expected given rates in the general population.
Another study using data from the UK, which used a self-controlled case series analysis approach, found ChAdOx1 to be associated with an increased risk of thrombocytopenia, VTE, and CVST, while BNT162b was associated with increased risks of ATE, ischaemic stroke, and CVST18. Meanwhile, a nested case-control study from Scotland found no increase in risk of VTE with either vaccine19. However, the authors of this latter study also reported potential increased risks of ATE and hemorrhagic events with ChAdOx1, although these were not confirmed in subsequent self-controlled case series analysis.
As well as analysing the rates of adverse events, we have also described the characteristics of those persons affected. Study participants with pulmonary embolism and those with thrombocytopenia after vaccination were generally older and more often had a prior history of related conditions or medications, which is similar to the profiles of people with these events in previous years. This is though in contrast to the early case series describing the profiles of patients with vaccine-induced thrombosis with thrombocytopenia, which have often identified patients aged under 60, more often female, and with relatively few comorbidities described. This may in part be explained by selection biases affecting case series, but may also reflect the broader definitions used in this study. For example, we do not have measurements of anti-PF4 antibodies and so could not use this for defining study outcomes.
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. 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 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 studies such as ours based on routinely-collected health care data. 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 Statistics20.
Our study also has strengths. The large sample of 5.6 million vaccinees allowed us to assess very rare events that are generally not observed in clinical trials. While spontaneous reports provide a valuable resource for identifying potential safety signals, population-based studies such as ours allow for further consideration of whether the rates being observed after vaccinations exceed those that would be expected to occur in the absence of any vaccination. We used a well-established source of routinely collected health data previously used for vaccine safety studies21,22. Moreover, including cohorts of people infected with SARS-CoV-2 provided much needed context for interpreting our findings.
In conclusion, in a cohort of 5.6 million people vaccinated against SARS-Cov-2, thrombosis, thrombocytopenia, and thrombosis with thrombocytopenia were very rare events. A similar safety signal was seen for VTE and thrombocytopenia (overall and specifically immune-related) was seen after first dose of both ChAdOx1 and BNT162b2, and of CVST after a first dose of ChAdOx1. Although the occurrence of VTE after vaccination was 1.1-fold above that expected in the general population, among those infected with SARS-CoV-2 it was more than 7-fold the background (expected) rate. Infection with SARS-CoV-2 prior to any vaccination against COVID-19 was also associated with increased risks of thrombocytopenia, arterial thromboembolism, and VTE with thrombocytopenia. These findings underline the relative safety of vaccines compared to the numerous ill-effects of being infected by SARS-CoV-2 for those people that remain unvaccinated.