Study population

During the study period from December 1st, 2020, to August 31st, 2022, there were 747,070 subjects at Corewell Health who received mRNA-based vaccines, among which 279,229 (37.38%) had the primary series of mRNA-1273 and 467,841 (62.62%) took BNT162b2. Overall, the number of fully vaccinated patients was 711,460 (95.23%), and 35,610 (4.77%) patients received only one dose. The median age was 57 (with interquartile range [IQR]: 40–69), and 59.81% of patients were female. There were 367,105 patients taking at least one COVID-19 test (antigen or PCR), among which 78,568 (21.4%) patients received positive results. The median age was 52 (with interquartile range [IQR]: 34–67), and 61.44% of patients were female.

In the study cohort of vaccination exposure, there were 16,640 patients who had at least one thromboembolic event and had the first dose of either mRNA-1273 or BNT162b2 vaccine. Patient demographics are presented in Table 1. We identified 2724 events in the control period, 722 events within 28 days after the first dose, and 786 events within 28 days after the second dose.

Table 1 SCCS cohort to study COVID-19 vaccination exposure on thromboembolic events

In the study cohort of COVID-19 exposure, there were 18,004 patients who had a thromboembolic event (cases) and 88,139 patients who had a physical injury (controls) at a hospital visit. 16.96% of cases and 1.48% of controls had COVID-19 within 28 days before the event. Demographics of patients are presented in Table 2.

Table 2 Case-control cohort to study COVID-19 exposure on thromboembolic eventsEstimate effect of mRNA-vaccination on thromboembolic events

Based on the SCCS analysis, we found an increased risk of thromboembolic events 28 days after the first dose (IRR = 1.19, 95% confidence interval (CI): [1.08, 1.31], p-value < 0.001), and after the second dose (IRR = 1.22, 95% CI: [1.11, 1.34], p-value < 0.001) of the mRNA-based vaccines.

We studied the risk of thromboembolic events in a 28-day window after vaccination based on prior research8. An event that occurs in a short period (such as 28 days) is more likely to be attributable to the vaccines. We also conducted a sensitivity analysis using a 60-day window after vaccination. The conclusions remained the same with slightly lower IRRs (IRR = 1.13, 95% CI: [1.03, 1.24] after the first dose, and IRR = 1.14, 95% CI: [1.05, 1.3] after the second dose).

Supplementary Figs. 3 and 4 show the IRRs for subgroup analyses by age (“18–31”, “31–50”, and “≥51”) and gender (female/male). We found that the effects of vaccination on thromboembolic events were similar between age groups and gender groups.

Estimate effect of COVID-19 on thromboembolic events

Naïve SCCS analysis showed a very large increased risk of thromboembolic events associated with COVID-19 (IRR = 19.36, 95% CI: [17.64, 21.26], p-value < 0.001). However, a similar analysis using the physical injury as an event also derived a large increased risk (IRR = 3.31, 95% CI: [3.10, 3.54], p-value < 0.001), indicating misclassification bias as COVID-19 should not substantially increase the risk of physical injury. In the case-control analysis with controls having a physical injury, we found that COVID-19 increased the risk of thromboembolic events but with a much smaller magnitude than the risk in the SCCS analysis (although it is still larger than the vaccination exposure). Moreover, the degree of the increased risks was modified by vaccination status (Fig. 2). The reported OR for the unvaccinated group was 4.65 (95% CI: [4.18, 5.17], p-value < 0.001) compared to 2.77 (95% CI: [2.40, 3.24], p-value < 0.001) for the vaccinated group. We observed the increased risks of thromboembolic events after COVID-19 in both groups, but vaccination appears to confer some protection against infection-associated thromboembolic events, given the lower OR. Alternatively, we divided the vaccinated group into four categories based on the time to the last vaccination (“≥365 days”, “180–365 days”, “90–180 days”, and “<90 days”). The effects of COVID-19 on thromboembolic events were similar across the four vaccinated groups. The results are in Supplementary Fig. 5.

Fig. 2: Forest plot for the case-control study for the association between thromboembolic events and COVID-19.

OR is denoted by a solid circle and a 95% CI is represented by a line. The x-axis is plotted on the natural log scale. CCI Charlson comorbidity index. Infection or non-infection refers to COVID-19.

We also conducted two sensitivity analyses. In the first analysis, rather than adjusting for the CCI, we adjusted individual risk factors that might be related to a thromboembolic event. These are congestive heart failure, peripheral vascular disease, cerebrovascular disease, chronic pulmonary disease, diabetes with complications, cancer, moderate or severe liver disease, and metastatic solid tumors. We included the above eight risk factors (present or absent) in the logistic regression model. The effect of COVID-19 on the outcome of thromboembolic events was similar to the analysis with CCI. Results can be found in Supplementary Fig. 6.

We assumed that patients who visited hospitals were routinely tested for COVID-19, especially during the early pandemic. Based on Corewell Health’s policy, patients who visited the healthcare system before March 1st, 2022, were tested for COVID-19. In our study cohort, 74.05% of participants had a hospital visit before March 1st, 2022. We conducted a sensitivity analysis using only these patients and the conclusions remained the same. See results in Supplementary Fig. 7.

Estimate the net effect of mRNA-vaccination on thromboembolic events: a risk-benefit analysis

Our analysis in the previous sections gave an IRR of 1.22 as the measure of the association between thromboembolic events and the second dose of COVID-19 vaccination, therefore, we set \(}}_}}\) = 1.22. We also obtained odd ratios \(}}_}\bar}}}\) = 4.65 and \(}}_}}\) = 2.82 from the analysis using the case-control design. Since the RR is very close to the OR when the event is rare, we therefore set \(}}_}\bar}}}\) = 4.65 and \(}}_}}\) = 2.82, as the thromboembolic events are rare33. Hence, plugging these estimators into Eq. (2), the \(}}_}}\) becomes

$$}}_}}=\frac}\right)}\left(}|\bar}}\right)}}(}\bar}})}$$

Figure 3 illustrates the \(}}_}}\) of thromboembolic events after COVID-19 vaccination as a function of VE. As VE increases from 0 to 1, \(}}_}}\) decreases and reaches a point where vaccine benefits outweigh the harms. Specifically, vaccines with higher VE offer higher protection against thromboembolic events. For example, the effectiveness of mRNA-based COVID-19 vaccines against infection was 61% during the Delta period and 46% during the Omicron period34,35,36. Given an infection rate of 0.08 among unvaccinated subjects, the risk of thromboembolic events was decreased by 4.62% in the Delta period, which is higher than 2.07% in the Omicron period. Moreover, vaccines offer stronger protection during periods with higher infection rates. For example, with the infection rate of 0.1 in unvaccinated subjects, the reduction of the risk of thromboembolic events was higher (by 9.19% in Delta and 6.23% in the Omicron period), compared to the scenario when the infection rate was 0.08.

Fig. 3: Net RR of thromboembolic events comparing vaccinated and unvaccinated subjects.

The x-axis is VE, and the y-axis is the net RR of thromboembolic events.

The list of ICD-10 codes for thromboembolic events is based on a previous publication8, including old myocardial infarction (I252). Old myocardial infarction (I252) reports for any myocardial infarction described as older than four weeks. However, our study cohort removed subjects with an I252 code who had any thromboembolic event with ICD-10 codes listed in Table S1 in the prior year. Therefore, we can consider observing I252 in the study period as a new incidence. There were 20,002 (18.84%) patients with a hospital visit associated with the I252 code. We conducted a sensitivity analysis by excluding these patients and the conclusions did not change. The estimated IRRs of thromboembolic events are 1.16 and 1.17 after vaccine dose 1 and dose 2, respectively, which are slightly smaller than the original results including the I252 code (IRRs were 1.19 and 1.22 after the first and second dose). The association between COVID-19 and thromboembolic events is higher in the unvaccinated group (OR = 5.77 without I252 and OR = 4.65 with I252) and similar in the vaccinated group (OR = 2.80 without I252 and OR = 2.77 with I252). Hence, given the same infection rate and VE, vaccination offered a stronger protection, compared to the analysis with the I252 codes. For example, given an infection rate in the unvaccinated population of 0.08 and a VE of 0.8, vaccination lowers the risk of thromboembolic events by 17.14% without I252, compared to 6.67% in the analysis with I252. Detailed results are in Supplementary Figs. 8 and 9. We considered the analysis that includes the I252 code as the main analysis to represent more conservative results.