This Scottish national population-based analysis among 2.53 million people who received their first doses of SARS-CoV-2 vaccines reveals a potential association between receiving a first-dose ChAdOx1 vaccination and occurrence of ITP, with an incidence of 1.13 cases per 100,000 vaccinations. For ChAdOx1 vaccination, there was suggestive evidence of an association with arterial thromboembolic and hemorrhagic events. For these outcomes, an attenuation of effect was found in the SCCS analysis, which might indicate the presence of residual confounding or confounding by indication. For any venous thromboembolic event, there were more observed than expected events for younger age groups (16–59 years old) associated with ChAdOx1, but this was not seen in our primary incident case–control analysis. Because of our limited ability to match in the observed versus expected analysis, this finding should be treated with considerable caution. There were 19 incident CVST events seen in our study population: 6 of these occurred after vaccination, with these events being seen after both ChAdOx1 and BNT162b2 vaccines. Two individuals with post-vaccination CVST events died. For CVST (and other rare conditions), there were insufficient numbers to draw any reliable conclusions other than, if there is any association, it is likely to represent an extremely rare outcome. For the BNT162b2 vaccine, our analysis found no evidence of increased adverse events for the thrombocytopenic, venous thromboembolic or hemorrhagic outcomes of interest.

To our knowledge, this is the one of the first real-world contemporaneous studies identifying all vaccinated individuals within a national population and assessing COVID-19 vaccine-related thrombocytopenic, venous or arterial thromboembolic and hemorrhagic adverse events. One published study of people aged 18–65 years who received the ChAdOx1 vaccine in Denmark and Norway observed increased rates of venous thromboembolic events, including cerebral venous thrombosis (standardized morbidity ratio of 1.97 and 95% CI, 1.50–2.54) and intracerebral hemorrhage (standardized morbidity ratio of 2.33 and 95% CI, 1.01–4.59)23. In that study, Pottegård et al. found a standardized morbidity ratio for any thrombocytopenia/coagulation disorders of 1.52 (0.97–2.25) and for any bleeding of 1.23 (0.97–1.55).

Our study has several strengths, including our ability to rapidly access and analyze data on vaccination status and medical and death records from linked national databases24,25,26. This study is, therefore, less susceptible to recall or misclassification bias than studies of samples of the population. A large population aided study power to facilitate the analysis of rare events such as ITP. We think that our findings have generalizability across countries using these vaccines as part of national vaccination programs that have prioritized vaccination of high-risk populations.

Our study has several limitations. As few individuals had received two vaccine doses at the time of analysis, this (second-dose) subgroup was not investigated separately. A further analysis on second doses will be conducted in due course. Furthermore, our study included few young vaccinated people (<40 years), especially for the ChAdOx1 vaccine, because the vaccination program has been predominantly targeted by age and underlying comorbidities so far. Although electronic general practice records of hospitalization and deaths were accessible, and linked with hospitalization and mortality records, lags in final coded hospital discharge data and postmortem changes to death certification might have resulted in over-riding of initial recorded causes of hospitalizations and deaths in some instances. However, our sensitivity analysis restricting to an earlier date of follow-up is less subject to such potential biases and found similar results. Additionally, ITP is a diagnosis of exclusion. Given that we based this analysis on clinician-recorded data, we had to assume that clinicians had appropriately investigated patients for their thrombocytopenia before recording this diagnosis. Discussions with Scottish hematologists indicated that this was a reasonable assumption, as the diagnosis of ITP is made only by specialists in a Scottish context. However, there can be uncertainty about the diagnosis of ITP, and published experience indicates that the diagnosis of ITP is often changed when patients are followed by skilled hematologists27,28. There is also the possibility that some of these cases of ITP could have represented reactivation of disease that had been in remission for more than 1 year. We did, however, carry out a post hoc analysis of all post-vaccination ITP events for those with prior available platelet count (tested in the primary care setting) and relevant prescriptions that could cause thrombocytopenia. We also carried out an analysis of ITP-directed therapy after vaccination (including oral corticosteroids). We were unable to access blood smear information as this is not routinely captured in the record systems that we had access to. Furthermore, 48% of patients with post-ChAdOx1 ITP events had prior prescriptions that could induce ITP, compared to 35% of those who were unvaccinated at the time of their ITP event. ITP-directed therapy prescribed by general practitioners in the community to patients with post-vaccination ITP was uncommon (≤10%). The overwhelming majority of ITP-directed therapy (for example, pulsed dexamathasone, prednisolone with or without intravenous immunoglobulin, rituximab and immunosuppressants) is, however, is likely to have been initiated in the hospital setting by hematologists, but these data were not accessible to us, as hospital prescribing in Scotland remains predominantly paper based29. These patients with community prescribing of oral corticosteroids are likely to have had persistent ITP that was managed in primary care.

Although we used a nested case–control study design matched by age, sex and geography, and adjusted for several confounders, unmeasured confounders could still have influenced our estimates (Supplementary Table 2). To mitigate this risk, where associations between ChAdOx1 and any adverse event were seen (that is, ITP and arterial thromboembolic and hemorrhagic events), we conducted a confirmatory post hoc SCCS analysis. SCCS designs can account for time-invariant confounding but are less suitable where recurrent events are not independent. Although the pattern of findings was largely similar across different analytical approaches, it is worth noting that the magnitude of associations did differ. Estimates tended to be greater in the case–control analysis, which could arise from potential residual confounding by indication that would most likely result in an overestimate of the real effect sizes. By contrast, the SCCS analysis tended to estimate smaller effect sizes, but the potential correlation of outcomes within an individual over time could bias estimates toward the null. The two approaches, therefore, provide reasonable bounds for the true effect, with our primary results potentially overestimating the risk of vaccine-associated harm and, therefore, being the most conservative for decision-making. Owing to the small number of adverse events, to identify predictors among vaccinated individuals we combined the outcomes of interest: ITP and arterial thromboembolic and hemorrhagic events. This as an area for future work, for instance through a meta-analyses of vaccine safety studies. Finally, the EAVE II platform is a national public health surveillance platform that was established at the request of the Scottish Government to help inform the public health response to the pandemic. It brought together a range of national whole-population healthcare datasets for the first time into Public Health Scotland. Ethical permission for this study was granted, and the Public Benefit and Privacy Panel Committee of Public Health Scotland approved the linkage and analysis of the de-identified datasets. As the policy aim was for national coverage, it was not feasible to obtain individual patient consent. This, therefore, restricted our ability to interrogate and report on certain individual record data in detail. For CVST, for instance, there were very few events, and, in keeping with our permissions, we suppressed the actual number of events found to minimize the risk of inadvertent disclosure of identity30. Also, centralized adjudication of our outcomes through case record review by an independent group of experts was not possible because access to data was limited to a small number of approved researchers.

The Centers for Disease Control and Prevention estimated that 60,000–100,000 Americans die annually due to venous thromboembolism (United States of America: 2.8 million deaths annually)31. Venous thromboembolic events are common in patients with COVID-19. Approximately 10% of patients with COVID-19 in hospitals (non-intensive care unit (ICU)) are diagnosed with venous thromboembolism and 28% of those in ICU11,32,33,34. The vaccine-induced adverse events after administration of the adenovirus-based SARS-CoV-2 vaccines (including the ChAdOx1 vaccine) have been described as vaccine-induced immune thrombotic thrombocytopenia (VITT) syndrome or thrombosis with thrombocytopenia syndrome resulting in a venous or arterial thrombosis, including CVST and thrombocytopenia35. The syndrome has been characterized as being similar to heparin-induced thrombocytopenia, a pro-thrombotic adverse drug reaction caused by the transient production of platelet-activating antibodies of IgG class that recognize multi-molecular complexes of (cationic) platelet factor 4 bound to (polyanionic) heparin36. We were insufficiently powered to provide estimates of the rarer VITT CVST and splanchnic vein thrombosis. This is an area for further work likely best pursued through larger datasets and meta-analyses.

ITP has also emerged as an important complication of COVID-19, with early epidemiological evidence suggesting a rate of 0.34% among hospitalized patients. There have also been reports of post-vaccination ITP in patients who received mRNA vaccines (including BNT162b2), and it has been postulated that some individuals might have had mild ‘compensated’ thrombocytopenia of diverse causes, and severe thrombocytopenia might have been induced by enhancement of macrophage‐mediated clearance or impaired platelet production as part of a systemic inflammatory response to vaccination21. ITP, however, as an adverse event after vaccine administration, is very rare. Our study suggests that there might be an increase in the risk of this very rare outcome for ChAdOx1 that is similar to other vaccines, including hepatitis B; measles, mumps and rubella; and influenza37,38. This very small risk is important but needs to be seen within the context of the very clear benefits of the ChAdOx1 vaccine.

As a result of findings from UK pharmacovigilance and surveillance data (including from EAVE II investigators), advice was issued in April 2021 regarding age group limits for the ChAdOx1 vaccine for individuals younger than 30 years of age18 and then, in May 2021, for individuals younger than 40 years of age19. Replication of our study in other countries is needed to confirm our results. We plan to update our analysis as the vaccine program is extended to younger, healthier individuals and as new vaccines become available. We also plan to extend our pharmacovigilance efforts to cover the second doses of these and other vaccines.

In conclusion, we did not identify any overall increased risk in the adverse events of interest in individuals receiving BNT162b2. First dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. Given these small increased risks for ChAdOx1, alternative vaccines for individuals at low COVID-19 risk might be warranted when supply allows.