
==== Front
Indian J Community Med
Indian J Community Med
IJCM
Indian J Community Med
Indian Journal of Community Medicine: Official Publication of Indian Association of Preventive & Social Medicine
0970-0218
1998-3581
Wolters Kluwer - Medknow India

IJCM-49-571
10.4103/ijcm.ijcm_676_23
Review Article
Association between COVID-19 Vaccination (ChAdOx1-S) and Thromboembolic, Thrombocytopenic, Hemorrhagic Events: A Systematic Review and Meta-analysis of Analytical Epidemiological Studies
Vaman Raman S. *
Kumar Muthusamy S. 1*
Jeyashree Kathiresan 2
Periasami Ashok
Abdulkader Rizwan S. 3
Murhekar Manoj 4
Scholar, ICMR-School of Public Health, ICMR- National Institute of Epidemiology, Chennai, Tamil Nadu, India
1 Scientist C, ICMR-School of Public Health, ICMR- National Institute of Epidemiology, Chennai, Tamil Nadu, India
2 Scientist E, ICMR-School of Public Health, ICMR- National Institute of Epidemiology, Chennai, Tamil Nadu, India
3 Scientist D, ICMR-School of Public Health, ICMR- National Institute of Epidemiology, Chennai, Tamil Nadu, India
4 Scientist G, ICMR-School of Public Health, ICMR- National Institute of Epidemiology, Chennai, Tamil Nadu, India
Address for correspondence: Dr. Rizwan S. Abdulkader, Scientist D, ICMR-National Institute of Epidemiology, R-127, TNHB Colony, Chennai - 600 077, Tamil Nadu, India. E-mail: sarizwan1986@gmail.com
* Equal contribution.

Jul-Aug 2024
09 7 2024
49 4 571578
30 9 2023
26 3 2024
Copyright: © 2024 Indian Journal of Community Medicine
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
We conducted a systematic review of analytical epidemiological studies to assess the association between ChAdOx1-S vaccination and thromboembolic, thrombocytopenic, and hemorrhagic events. We searched Medline, Embase, Google Scholar, WHO-COVID-19 database, and medRxiv for studies evaluating the association between ChAdOx1-S and vascular events. Primary outcomes of interest were cerebral venous sinus thrombosis, peripheral venous thrombosis (PVT), and thrombocytopenia. Two independent reviewers screened for eligible studies, extracted data, and assessed the risk of bias. The DerSimonian-Laird random effects model was used to pool the incidence rate ratios (IRRs) separately for the first and second doses. Heterogeneity was assessed using I2 statistics. Twenty studies were included, of which 11 were self-controlled case series, and nine were cohort studies (254 million participants). Pooling of 17 studies showed a higher risk of cerebrovascular thrombosis (IRR = 3.5, 95% CI = 2.2–5.4, I2 = 79%), PVT (IRR = 2.0, 95% CI = 1.1–3.5, I2 = 95%) and thrombocytopenia (IRR = 1.6, 95% CI = 1.4–1.9, I2 = 93%) among those who received ChAdOx1-S vaccination as compared to controls. No increased risk was seen after the second dose or for secondary outcomes. There is moderate-to-high certainty of the evidence for the increased risk of cerebral venous sinus thrombosis, PVT, and thrombocytopenia following the first dose of the ChAdOx1-S vaccine.

Systematic Review Registration: PROSPERO CRD42022372768.

Adverse events following immunization
ChAdOx1-S
COVID-19 vaccines
thrombocytopenia
venous thrombosis
==== Body
pmcINTRODUCTION

The global COVID-19 vaccination strategy aims to reduce deaths and severe disease, protect health systems, and resume socioeconomic activities by vaccinating high- to low-priority groups sequentially.[1] As of February 16, 2023, 13.2 billion vaccine doses were administered globally. However, the coverage remains low globally, with 64.9% for the primary series and 30.7% for a booster dose.[2] Of the 13 vaccines approved by the World Health Organization (WHO) for emergency use, four were recombinant, adenoviral vectored. ChAdOx1-S (AstraZeneca COVID-19 vaccine AZD1222 Vaxzevria™, SII COVISHIELD™) is an adenoviral vectored vaccine recommended in a two-dose schedule with an interval of 4–12 weeks.[3]

During early 2021, cases of venous thrombosis with thrombocytopenia were reported within 3–4 weeks of vaccination with ChAdOx1-S.[45] Following these reports, several European countries briefly stopped using ChAdOx1-S.[6] European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee reviewed venous thrombosis cases reported to EudraVigilance, the EU drug safety database. The committee recommended listing thrombosis with thrombocytopenia syndrome (TTS), cerebrovascular and sinus thrombosis, and thrombocytopenia as very rare side effects of ChAdOx1-S in the product information brochure. EMA concluded that the benefits of receiving this vaccine by preventing COVID-19 hospitalizations and deaths outweigh the risks.[7] The WHO’s interim recommendations on ChAdOx1-S listed TTS as a rare adverse event.[3]

Several case reports and case series were published on thromboembolic events during the scale-up of COVID-19 vaccination.[458] To date, 10 systematic reviews have described the clinical features and outcomes of the thromboembolic events following adenoviral COVID-19 vaccines (Supplementary Appendix). These reviews found that most thromboembolic events were reported after vaccination with ChAdOx1 or Ad26.COV2. The most common events were cerebral venous sinus thrombosis, deep vein thrombosis, and pulmonary embolism. The frequency of these events was higher among females and younger adults. Symptoms usually appeared 1–2 weeks after vaccination, with a mortality rate of 16%–39% (Supplementary Appendix). However, none of these reviews was able to provide any epidemiological measure of the strength of association necessary for causal inference because they were all based on case reports/series.

Although case reports and case series are instrumental in generating a hypothesis of a possible association between the adenoviral vectored COVID-19 vaccine and thromboembolic events, they have limited value in establishing a causal linkage. Epidemiological studies such as case-control, cohort, clinical trials, and self-controlled case series are more appropriate for such causal questions. Therefore, we conducted a systematic review and meta-analysis of analytical studies to determine the strength of the association between ChAdOx1-S vaccination and the incidence of thromboembolic, thrombocytopenic, and hemorrhagic events.

METHODS

We registered this review in PROSPERO (CRD42022372768) and reported its findings per the preferred reporting items for systematic reviews and meta-analyses (PRISMA 2020) guidelines.[9]

Study selection

We included case-control studies, cohort studies, self-controlled case series, and randomized controlled trials in this review. The study population in the included studies were all those who were eligible for receiving the COVID-19 vaccine at those particular time points. Our exposure of interest was one or two doses of the ChAdOx1-S vaccine. The control groups comprised either pre-vaccinated or unvaccinated individuals or recipients of other COVID/non-COVID vaccines. We excluded single-group cohorts without a comparison group, case reports, editorials, opinions, letters, and studies done exclusively on children. We grouped studies depending on the dose number of the ChAdOx1-S vaccine. We did not apply any language or time restrictions. More details of the study eligibility criteria can be found in the supplement (Supplementary Appendix).

Information sources and study selection

We searched for eligible studies in Medline (via PubMed), Embase, Google Scholar, the WHO-COVID-19 research database, and medRxiv. In addition, the reference list of all included articles was searched for any additional studies. The search was last performed on November 27, 2022. Details on the search strategy are given in the supplement (Supplementary Appendix). Two independent reviewers (MSK and RSV) conducted the study screening and selection independently using the pre-specified inclusion and exclusion criteria. These reviewers were blinded to each other’s decisions. A third reviewer (SAR) resolved any conflicts in the study selection. We used Rayyan (a web application to manage literature) to conduct the title and abstract screening and full-text inclusion to ensure reproducibility and verification.[10]

Data extraction

We extracted data from the eligible full-text articles by using a pre-tested data abstraction form. Two reviewers independently verified the extracted data for accuracy. We extracted the first author, year of publication, age group of the study population, countries, study design, dose number of the ChAdOx1-S vaccine, comparison group or period, type of outcome, risk period during which the outcome was measured, and the measure of association reported. For the meta-analysis, we extracted the author-reported measures of association, which included odds ratio, relative risk, risk difference, incidence rate ratio (IRR), incidence rate difference, hazard ratio, or standardized mortality ratio (SMR). We also extracted the 95% confidence interval (95% CI) for all measures.

Outcomes

Our primary outcomes of interest were central venous thrombosis (CVT), peripheral venous thrombosis (PVT), and thrombocytopenia. Our secondary outcomes of interest were other thrombo-embolic events, such as any type of venous/arterial thromboembolic (VTE/ATE) and hemorrhagic events, myocardial infarction/coronary artery disease (MI/CAD), and stroke.

We included outcomes and risk periods as defined by the individual study authors and did not make any attempts to standardize the diagnostic or clinical criteria across the included studies (Supplementary Appendix). All outcomes were extracted within the specific study-defined risk periods (following the first or second dose). If outcomes were available for multiple periods, all were extracted and aggregated later to match the other studies. Similarly, if outcomes were available for multiple age groups, all the effect sizes were extracted and aggregated for pre-defined age groups. If outcomes were reported against multiple comparison groups, preference was given to pre-vaccinated/unvaccinated first, followed by other types of COVID-19 vaccines and vaccines for other infectious diseases. Within a given study, all available pre-specified outcomes were extracted. We did not attempt to extract outcomes that did not fit our study definitions.

Risk of bias (RoB) assessment

We assessed the risk of bias by using the Newcastle-Ottawa tool for cohort studies and the modified Newcastle-Ottawa tool for self-controlled case series.[11] Details of the tools are given in the supplementary appendix. Two reviewers completed the assessment independently, and a third reviewer resolved discrepancies, if any.

Statistical methods

We planned to pool studies reporting similar measures of association. As most of the studies retrieved were cohorts and self-controlled case series, we used IRR as the effect size for the meta-analysis. For studies that did not directly report an IRR, we calculated the IRR and exact 95% CIs by using the method reported by Miettinen from the reported count of cases and person-years of observation.[12] To avoid unit-of-analysis error, we aggregated effect sizes reported across multiple age groups/time points within a study by using standard inverse-variance weighting and assuming an independent structure for the sampling errors. We used the DerSimonian-Laird random effects model to pool the IRRs separately for one-dose and two-dose studies. Pooling was done on the log-transformed IRRs and their 95% CIs and back-transformed for presentation in forest plots. We planned to conduct subgroup analysis for age, type of comparison, and risk periods if sufficient studies were retrieved. We assessed between-study heterogeneity by using I2 statistics. An I2 value of > 50% was considered evidence of significant heterogeneity. We assessed small-study effects by plotting the effect size against their standard error in funnel plots and examined them for asymmetry. We planned to conduct formal statistical tests such as Egger’s test for publication bias only if there were at least 10 studies per outcome per dose type. We planned to conduct a sensitivity analysis by excluding articles with a high risk of bias. All analysis was performed using R 4.2.2 Statistical significance was set at P < 0.05 (two-sided) for all tests.

We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to rate the certainty of evidence from the meta-analysis for each outcome and dose type. In this approach, we used five domains, namely the risk of bias, inconsistency, indirectness, imprecision and publication bias to quantify the certainity of evience into very low, moderate or high certainity of evidence.[13]

Human participants protection

Ethics committee approval was not obtained as this was only a review of previously published studies.

RESULTS

We identified 328 articles in PubMed and 79 in Embase. After removing duplicates, we screened the titles and abstracts of 380 articles for eligibility. Furthermore, we screened the full text of 36 articles and found 18 that met the eligibility criteria. We identified two additional articles by searching Google Scholar, the WHO-COVID-19 research database, medRxiv, and the reference list of included articles. A total of 20 articles were included in the final analysis [Figure 1].[1415161718192021222324252627282930313233]

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram summarizing identification, screening, and inclusion of studies

All the studies were published during 2021–2022. Of the 20 studies included, 11 were from the United Kingdom, six from other European countries, one each from Argentina and Malaysia, and one with data from Europe and the United States of America [Supplemental Figure 1]. Studies were either self-controlled case series (n = 11) or cohort (n = 9) design. Seventeen studies included individuals aged more than 16 years, and the remaining three had adults and children.

Fourteen studies included individuals after the first dose, five after the first or second dose, and the remaining one after the second dose [Table 1].

Table 1 Characteristics of the studies included in the review

First author	Study design	Sample size	Age group	Doses studied	Comparator	
Schulz JB	Cohort	62	20-89	1	mRNA vaccine	
Pottegard A	Cohort	281,264	18-65	1	Background incidence	
Burn E	Cohort	6,119,754	≥30	1	mRNA vaccine	
Xintong Li	Cohort	32,800,000	≥18	1, 2	mRNA vaccine	
Whiteley WN	Cohort	21,193,814	≥18	1	Pre/Unvaccinated	
Andrews	Cohort	27,378,384	≥15	1	Unvaccinated	
Hviid A	Cohort	355,209	14-63	1	mRNA vaccine	
Vallone MG	Cohort	29,918	≥17	1	Influenza vaccine	
Sturkenboom M	Cohort	12,117,458	0+	1, 2	Pre/Post-vaccination	
McKeigue	Cohort	80,905	NA	1	Post-vaccination	
Hippisley-Cox J	SCCS	29,121,633	≥16	1	Pre/Post-vaccination	
Simpson CR	SCCS	2,530,000	≥18	1	Pre-vaccination	
Patone M	SCCS	32,552,534	≥16	1	Pre-vaccination	
Rahman NA	SCCS	20,202,054	≥18	1, 2	Pre/Post-vaccination	
Higgins H	SCCS	170	≥18	1	Pre/Post-vaccination	
Kerr S	SCCS	11,637,157	≥16	1	Pre-vaccination	
Botton J	SCCS	46,500,000	18-74	1, 2	Pre/Post-vaccination	
Torabi F	SCCS	2,062,144	≥16	1, 2	Pre-vaccination	
Simpson CR	SCCS	3,600,000	≥16	2	Pre/Post-vaccination	
Berild JD	SCCS	5,351,105	≥18	1	Pre-vaccination	
SCCS: Self-controlled case series

All studies except one conducted the analysis using linked electronic health record databases. We observed wide variations in the types of outcomes included across the studies. Thrombocytopenia was included in 14 studies, any venous thromboembolic event in 13, myocardial infarction in 11, stroke and cerebral venous thrombosis in nine, arterial thromboembolic event in eight, and PVT in seven.

Three studies that met the eligibility criteria were not included in the quantitative synthesis because of the different measures of association reported. Pottegård A et al.[26] did a population-based cohort study to compare the adverse events observed within 28 days of vaccination with the expected rates from the general population during the pre-pandemic period and calculated the SMR. The SMR was 1.9 (95% CI: 1.5–2.5) for venous thromboembolic events and 20.3 (95% CI: 8.1–41.7) for cerebral venous thrombosis. Sturkenboom M et al.[30] conducted a cohort study using data from four European countries to monitor 29 adverse events of special interest after COVID-19 vaccination. The pooled random effects IRR for TTS was 2.98 (95% CI: 1.7–5.3). Higgins H et al.[19] assessed the risk of clinically ascertained TTS cases after the first dose of the ChAdOx1-S vaccine by using a self-controlled case series design. The relative incidence of TTS was 5.67 in the age group of 18–39 years during 4–27 days after vaccination compared to the baseline period.

Primary outcomes

Summary estimates indicated a significant increase in risk for central venous thrombosis (CVT) (IRR: 3.5; 95% CI: 2.2–5.4), PVT (IRR: 2; 95% CI: 1.1–3.5) and thrombocytopenia (IRR: 1.6; 95% CI: 1.4–1.9) after vaccination with the first dose of ChAdOx1-S vaccine compared to either pre-vaccinated or unvaccinated individuals or recipients of mRNA vaccines. However, no significant increase in the risk of those events was observed after the second dose [Figure 2]. GRADE approach showed high-to-moderate levels of certainty for the evidence against the first dose of vaccine for all primary outcomes [Table 2].

Figure 2 Forest plot for the pooled estimates of primary outcomes of interest among persons vaccinated with ChAdOx1 vaccines a) Central venous thrombosis b) Peripheral venous thrombosis c) Thrombocytopenia

Table 2 GRADE for certainty of evidence for the primary outcomes

Outcomes	IRR (95% CI)	No. of studies	Certainty of evidence (GRADE)	Comments	
CVT after 1 dose	3.5 (2.2-5.4)	8 observational studies	High	First dose of ChAdOx1 results in a large increase in the risk of CVT.	
CVT after 2 doses	0.8 (0.2-4.3)	1 observational study	Very low	The evidence is very uncertain about the effect of second dose of ChAdOx1 on CVT.	
PVT after 1 dose	2.0 (1.1-3.5)	5 observational studies	High	First dose of ChAdOx1 results in a large increase in the risk of PVT.	
PVT after 2 doses	0.9 (0.8-1)	2 observational studies	Moderate	Second dose of ChAdOx1 likely does not increase the risk of PVT.	
Thrombocytopenia after 1 dose	1.6 (1.4-1.9)	10 observational studies	Moderate	First dose of ChAdOx1 likely results in a slight increase in the risk of thrombocytopenia.	
Thrombocytopenia after 2 doses	0.9 (0.8-1.1)	4 observational studies	Low	Second dose of ChAdOx1 likely does not increase the risk of thrombocytopenia.	
CVT: Cerebral venous thrombosis, PVT: Peripheral venous thrombosis

Secondary outcomes

Pooled estimates indicated no significant increase in risk for any of the secondary outcomes of interest: any thromboembolic event (arterial or venous), any hemorrhage, myocardial infarction or coronary artery disease and stroke (hemorrhagic or ischemic or others) post ChAdOx1-S vaccination after the first or second dose [Table 3, Supplemental Figure 2]. The GRADE levels of certainty of the evidence for most secondary outcomes were found to be very low or low [Supplemental Table 1].

Table 3 Pooled incidence rate ratio (IRR) of secondary outcomes post ChAdOx1 vaccination

Outcome	Pooled IRR (95% CI)	
	1 Dose	2 Dose	
Any venous thromboembolic event	1.3 (1.0, 1.7)	0.9 (0.8, 1.0)	
Any arterial thromboembolic event	1.3 (0.9, 1.9)	1.0 (0.9, 1.0)	
Any hemorrhage	1.0 (0.8, 1.3)	0.9 (0.8, 1.1)	
Myocardial infarction/CAD	1.1 (0.8, 1.4)	1.0 (0.8, 1.2)	
Stroke- Hemorrhagic	1.3 (0.9, 1.9)	1.1 (0.9, 1.4)	
Stroke- Ischemic	1.1 (0.7, 1.6)	0.9 (0.9, 1.0)	
Stroke- Others	1.2 (0.8, 1.8)	-	

Supplemental Table 1: GRADE approach for certainty of evidence for secondary outcomes

Outcomes	IRR (95% CI)	No of studies	Certainty of evidence (GRADE)	Comments	
Any VTE after 1 dose	13 (1-17)	10 observational studies	Low	First dose of ChAdOx1 results in little to no difference in the risk of CVT.	
Any VTE after 2 doses	09 (08-1)	4 observational study	Moderate	Second dose of ChAdOx1 likely results in little to no difference in any VTE	
Any ATE after 1 dose	13 (09-19)	6 observational studies	Low	First dose of ChAdOx1 may result in little to no difference in any ATE	
Any ATE after 2 doses	09 (09-1)	3 observational studies	Moderate	Second dose of ChAdOx1 likely results in little to no difference in any ATE	
Any haemorrhage after 1 dose	1 (08-13)	3 observational studies	Very low	The evidence is very uncertain about the effect of first dose of ChAdOx1 on any haemorrhage.	
Any haemorrhage after 2 doses	09 (08-11)	2 observational studies	Very low	The evidence is very uncertain about the effect of second dose of ChAdOx1 on any haemorrhage	
MI or CAD after 1 dose	11 (08-14)	8 observational studies	Very low	The evidence is very uncertain about the effect of first dose of ChAdOx1 on any MI or CAD	
MI or CAD after 2 doses	1 (08-12)	4 observational studies	Very low	The evidence is very uncertain about the effect of second dose of ChAdOx1 on any MI or CAD	
Stroke- Haemorrhagic after 1 dose	13 (09-19)	6 observational studies	Low	First dose of ChAdOx1 may result in little to no difference in Stroke-Haemorrhagic	
Stroke- Haemorrhagic after 1 dose	11 (09-14)	2 observational studies	Very low	The evidence is very uncertain about the effect of second dose of ChAdOx1 on Stroke- Haemorrhagic	
Stroke- Ischemic after 1 dose	11 (07-16)	7 observational studies	Very low	The evidence is very uncertain about the effect of first dose of ChAdOx1 on Stroke-Ischemic	
Stroke- Ischemic after 1 dose	09 (09-1)	3 observational studies	Very low	The evidence is very uncertain about the effect of second dose of ChAdOx1 on Stroke- Ischemic	
Stroke- Others after 1 dose	12 (08-18)	3 observational studies	Very low	The evidence is very uncertain about the effect of first dose of ChAdOx1 on Stroke-Others	

Risk of bias, publication bias, and small study effects

Risk of bias assessment using Newcastle-Ottawa and Modified Newcastle-Ottawa tools found most of the studies (18 of 20) to be of good quality [Supplemental Table 2]. No evidence of significant publication bias could be found by visually examining the funnel plots [Supplemental Figure 3]. Funnel plots for the secondary outcomes showed possible evidence of publication bias for MI/CAD [Supplemental Figure 4].

Supplemental Table 2: Risk of bias in the included studies

Table S1: Assessment of risk of bias of cohort studies using Newcastle-Ottawa quality assessment tool	
Study	Domain wise stars*	Overall stars	Study quality**	
	Selection	Comparability	Outcome			
Schulz 2021	2	1	2	5	Fair	
Pottegard 2021	3	2	2	7	Good	
Li 2022	3	2	2	7	Good	
Vallone 2022	3	1	2	6	Fair	
Andrews 2022	4	2	3	9	Good	
Hviid 2022	3	1	2	6	Good	
Whiteley 2022	3	2	2	7	Good	
Burn 2021	4	1	3	8	Good	
Sturkenboom 2022	3	1	3	7	Good	
*Maximum 4 stars for selection domain; 2 stars for comparability domain and 3 stars for outcome domain. **Good quality: 3 or 4 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome domain. Fair quality: 2 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome domain. Poor quality: 0 or 1 star in selection domain OR 0 stars in comparability domain OR 0 or 1 stars in outcome domain

Table S2: Assessment of risk of bias of SCCS studies using the modified Newcastle-Ottawa quality assessment tool	
Study	Domain wise stars*	Overall stars	Study quality**	
	Selection	Comparability	Outcome			
Simpson 2021	2	1	5	8	Good	
McKeigue 2021	2	1	5	8	Good	
Hippisley-Cox 2021	2	1	5	8	Good	
Berild 2022	3	1	5	9	Good	
Higgins 2022	3	1	5	9	Good	
Rahman 2022	2	1	5	8	Good	
Simpson 2022	2	1	5	8	Good	
Kerr 2022	2	1	5	8	Good	
Botton 2022	2	1	4	7	Good	
Torabi 2022	2	1	5	8	Good	
Patone 2021	2	1	5	8	Good	
*Maximum 3 stars for selection domain; 2 stars for comparability domain and 5 stars for outcome domain. **Good quality: Overall 7-10 stars; Fair quality: Overall 4-6 stars; Poor quality: 3 stars and below

DISCUSSION

Although several systematic reviews synthesized information from case reports and case series on demographics, clinical profile, and mortality due to vascular events following vaccination with ChAdOx1-S, ours is the first study that systematically reviewed all analytical studies testing the association between ChAdOx1-S vaccination and vascular events. We found that the first dose of the ChAdOx1-S vaccine was positively associated with CVT, PVT, and thrombocytopenia. The certainty of evidence using the GRADE approach was moderate to high. Our finding supports the recommendation to list cerebral venous sinus thrombosis and thrombocytopenia as very rare adverse events of ChAdOx1-S in the product information brochure,[7] and the recommendation to include thrombosis with TTS was listed as a very rare adverse event following the ChAdOx1-S vaccination.[3]

Most of the studies included in this review were done in European countries. A study on the geographical distribution of TTS cases using the AstraZeneca global safety database (till August 31, 2021) found the rates (cases per million doses administered per 21 days) ranging between 17.6 in Nordic countries and 0.2 in Asia and Brazil. The difference in rates could be due to variations in reporting.[34] Countries like India used SII COVISHIELD™ (same formulation as ChAdOx1-S) to administer approximately 1.7 billion doses. However, few case reports on VITT were publicly available. A lack of proper reporting mechanisms from India led to gaps in diagnosis, surveillance, and reporting.[35]

Apart from vaccination, infection with SAR-CoV-2 was also identified as a risk factor for thromboembolic events. Katsoularis I et al.[36] did a self-controlled case series study and estimated the IRR of 5.9 for deep vein thrombosis, 31.6 for pulmonary embolism, and 2.5 for bleeding during 1–30 days after COVID-19. Knight R et al.[37] did a population-based cohort study and found that the hazard ratio for first arterial thrombosis after COVID-19 compared to no COVID-19 declined from 21.7 in the first week after COVID-19 to 1.34 in weeks 27–49. Similarly, the hazard ratio for the first venous thromboembolic event declined from 33.2 in week 1 after COVID-19 to 1.8 in weeks 27–49.

A few studies have compared the risk of thromboembolic events after ChAdOx1-S vaccination and SARS-CoV-2 infection. A self-controlled case series study conducted in England reported a higher IRR for venous thromboembolism 8–14 days after SARS-CoV-2 infection (13.86) than after ChAdOx1-S vaccination (1.10).[20] A cohort study estimated that the risk of cerebral venous sinus thrombosis after SARS-CoV-2 infection was 2.3 times higher than following ChAdOx1-S vaccination.[38] Risk-benefit analysis of ChAdOx1-S using a modeling approach found that the probability of dying from thrombosis after COVID-19 infection was 58–126 times higher than dying from TTS.[39] Therefore, the risk of thromboembolic events after ChAdOx1-S vaccination was lower than the risk after COVID-19 infection.

Limitations

Our review had several limitations. First, we did not include Ad26.COV2, an adenoviral vaccine, in our review. We restricted our analysis to the ChAdOx1-S vaccine as most of the population had this vaccine, and only three of the studies included in our review evaluated the association between Ad26.COV2 vaccine and vascular events. Second, we used a RoB assessment tool proposed for self-controlled case series published in preprint.[11] The tool is not validated; thus, our RoB assessment may not be accurate in judging the quality of the included self-controlled case series. There is a need to validate the RoB assessment tool for self-controlled case series considering a recent increase in their application to assess vaccine safety.[40] Third, we did not account for variations in the comparison group chosen in different studies due to the lack of a sufficient number of studies in different subgroups. Finally, the lack of studies from low- and middle-income countries has implications for understanding the actual rates of thromboembolic events and establishing the cause-effect relationship in such populations.

CONCLUSIONS

This systematic review and meta-analysis found that the first dose of the ChAdOx1-S vaccine increased the risk of CVT, PVT, and thrombocytopenia by 2–3 times. For secondary outcomes such as any venous, arterial thromboembolic and hemorrhagic events, myocardial infarction, or coronary artery disease, we found no association or the certainty of the evidence was low to very low. As most studies were done in Europe, there is a need to establish databases at the national level in low- and middle-income countries to monitor rare adverse events in the post-marketing phase.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Supplemental Figure 1 Countries where the studies were conducted. Note: Green dots mark the country where the included studies were primarily carried out

Supplemental Figure 2 Forest plots showing pooled IRR for secondary outcomes by dose a) Any venous thromboembolism b) Any arterial thromboembolism c) Any hemorhage d) Myocardial infarction or Coronary artery disease e) Stroke- Hemorrhagic f) Stroke- Ischemic g) Stroke- Others

Supplemental Figure 3 Funnel plots for the primary outcomes a) Central venous thrombosis b) Peripheral venous thrombosis c) Thrombocytopenia

Supplemental Figure 4 Funnel plots for secondary outcomes a) Any venous thromboembolism b) Any arterial thromboembolism c) Any hemorhage d) Myocardial infarction or Coronary artery disease e) Stroke- Hemorrhagic f) Stroke- Ischemic g) Stroke- Others

Acknowledgment

We thank Dr Rajiv Bahl, Director General of the Indian Council of Medical Research, for his support.

SUPPLEMENTARY APPENDIX

Association between COVID-19 vaccination (ChAdOx1-S) and thromboembolic, thrombocytopenic, haemorrhagic events: A systematic review and meta-analysis of analytical epidemiological studies

Table of contents

Appendix 1: Systematic reviews of case reports/series of thromboembolic events following COVID-19 vaccination	2	
Appendix 2: Details about the study eligibility criteria and study selection	5	
Appendix 3: Search strategy details	6	
Appendix 4: Risk and comparison period in self-controlled case series	11	
Appendix 5: Description of the risk of bias assessment tools used	12	
Supplemental Figure 1: Countries where the studies were conducted	18	
Supplemental Figure 2: Forest plots showing pooled IRR for secondary outcomes by dose	19	
Supplemental Figure 3: Funnel plots for the primary outcomes CVT, PVT and Thrombocytopenia	26	
Supplemental Figure 4: Funnel plots for secondary outcomes	27	
Supplemental Table 1: GRADE approach for certainty of evidence for secondary outcomes	22	
Supplemental Table 2: Risk of bias in the included studies	24	

Appendix 1: Systematic reviews of case reports/series of thromboembolic events following COVID-19 vaccination[12345678910]

Author	Vaccine	Outcome	# studies	# cases	Key findings	
Sharifian- Dorche M 2021	ChAdOx1, Ad26.COV2	Vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis	14	49	• 36 cases after ChAdOx1, 13 cases after Ad26.COV2 vaccination
• Majority females
• Symptom onset within 1 week after 1st dose (range 4-19 days)
• Headache was most common presenting symptom
• Of the 49 cases, 24 had intracranial and subarachnoid haemorrhage
• PF4 IgG Assay and d-Dimer was positive in most cases
• Out of 49 cases, 19 died due to complications	
Waqar U 2021	ChAdOx1, Ad26.COV2	Thrombosis with thrombocytopenia syndrome	62	160	• 67 8% (101/160) were females
• Median age 42 5 years (IQR: 22)
• TTS onset occurred in a median of 9 days after vaccination
• 140 of 160 cases received ChAdOx1 vaccine
• Venous thrombosis was most common (97/160[61 0%])
• Most cases had cerebral venous sinus thrombosis (106/160[66 3%])
• Female and individuals <45 years were more likely to have cerebral venous sinus thrombosis compared to male and ≥45 years
• 47 (36 2%) died	
Matar RH 2021	ChAdOx1	Outcomes of thromboembolic events	45	144	• 64 6% women
• Mean age 21-68 years
• Head ache, intracerebral haemorrhage, hemiparesis were common presenting adverse events
• Cerebral venous sinus thrombosis (38 5%) followed by deep vein thrombosis/pulmonary embolism (21 1%) were common thromboembolic events
• 39 patients died	
Jaiswal V 2022	ChAdOx1, Ad26.COV2, mRNA	Cerebral Venous Sinus Thrombosis	25	80	• 59 (73 8%) were male
• Mean age 42 9±13 9 years
• 70 received adenoviral vector and the rest had mRNA vaccine
• Mean time for onset of symptoms after vaccination was 11 1±5 3 days
• Intracerebral haemorrhage occurred in 35 cases
• Anti-PF-4 was positive in 45 cases
• 31 died (39 2%)	
Elberry MH 2022	ChAdOx1, Ad26.COV2	Thrombosis and thrombocytopenia	26	173	• 157 had ChAdOx1 and 16 had Ad26.COV2
• 74 6% were female and mean age was 43 2 (±16 7)
• Average time from vaccination to admission was 10 5 to 15 9 days
• Common thromboembolic events reported were cerebral venous sinus thrombosis, deep vein thrombosis, and pulmonary embolism
• 52 were positive for antibodies against PF4
• 28 (16 2%) died	
Kim AY 2022	ChAdOx1, Ad26.COV2	Vaccine induced immune thrombotic thrombocytopenia	18	664	• Mean age was 45 6 years
• 70% were females
• 54% had cerebral venous thrombosis
• 91% was positive for anti-PF4 antibody test
• 32% died
• Incidence of total venous thrombosis was 28 (95% CI: 12-52) per 100,000 doses administered	
Saluja P 2022	ChAdOx1, Ad26.COV2 mRNA vaccine	Thrombotic thrombocytopenic purpura	23	27	• Mean age was 51 3 years
• 51 1% were female
• TTP episodes were mostly after BNT162b2 vaccine followed by mRNA-1273 vaccine
• One died	
Saluja P 2022	ChAdOx1, Ad26.COV2 mRNA vaccine	Post-vaccine immune thrombocytopenia	43	66	• Median age 52 years (range: 19-86 years)
• 60 6% were females
• Mean time from vaccine administration and symptom onset was 8 4 days
• 73% cases were after first dose
• More ITP events after mRNA vaccines compared to adenoviral
• No deaths	
Bidari A 2022	ChAdOx1, Ad26.COV2 mRNA vaccine	Immune thrombocytopenic purpura after COVID-19 vaccination	41	77	• Median age was 54 years (IQR: 36-72 years)
• 75 4% cases were reported after mRNA vaccines
• 79 2% cases were after first dose of vaccination
• 75% developed ITP within 12 days of vaccination
• One case died due to intracranial haemorrhage	
Song TJ 2023	ChAdOx1	Thrombosis with thrombocytopenia syndrome (TTS)	19	64	• 38 (59 3%) had cerebral venous thrombosis
• Median age of patients with CVT was 36 5 years and 73 3% were female
• Patients with CVT were younger and had lower fibrinogen levels than those without CVT	

References

1. Sharifian-Dorche M Bahmanyar M Sharifian-Dorche A Mohammadi P Nomovi M Mowla A Vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis post COVID-19 vaccination; a systematic review J Neurol Sci 2021 428 117607 https://doi.org/10.1016/j.jns.2021.117607 34365148
2. Waqar U Ahmed S Gardezi SMHA Tahir MS Abidin ZU Hussain A , Thrombosis with Thrombocytopenia Syndrome After Administration of AZD1222 or Ad26.COV2.S Vaccine for COVID-19: A Systematic Review Clin Appl Thromb Hemost 2021 27 10760296211068488 https://doi.org/10.1177/10760296211068487
3. Matar RH Than CA Nakanishi H Daniel RS Smayra K Sim BL , Outcomes of patients with thromboembolic events following coronavirus disease 2019 AstraZeneca vaccination: A systematic review and meta-analysis Blood Coagul Fibrinolysis 2022 33 90 112 https://doi.org/10.1097/MBC.0000000000001113 34980833
4. Jaiswal V Nepal G Dijamco P Ishak A Dagar M Sarfraz Z , Cerebral Venous Sinus Thrombosis Following COVID-19 Vaccination: A Systematic Review J Prim Care Community Health 2022 13 21501319221074450 https://doi.org/10.1177/21501319221074450 35142234
5. Elberry MH Abdelgawad HAH Hamdallah A Abdella WS Ahmed AS Ghaith HS , A systematic review of vaccine-induced thrombotic thrombocytopenia in individuals who received COVID-19 adenoviral-vector-based vaccines J Thromb Thrombolysis 2022 53 798 823 https://doi.org/10.1007/s11239-021-02626-w 35157188
6. Kim AY Woo W Yon DK Lee SW Yang JW Kim JH , Thrombosis patterns and clinical outcome of COVID-19 vaccine-induced immune thrombotic thrombocytopenia: A Systematic Review and Meta-Analysis Int J Infect Dis 2022 119 130 9 https://doi.org/10.1016/j.ijid.2022.03.034 35339716
7. Saluja P Amisha F Gautam N Goraya H A Systematic Review of Reported Cases of Immune Thrombocytopenia after COVID-19 Vaccination Vaccines (Basel) 2022 10 1444 https://doi.org/10.3390/vaccines10091444 36146522
8. Saluja P Gautam N Yadala S Venkata AN Thrombotic thrombocytopenic purpura (TTP) after COVID-19 vaccination: A systematic review of reported cases Thromb Res 2022 214 115 21 https://doi.org/10.1016/j.thromres.2022.04.020 35533526
9. Bidari A Asgarian S Pour Mohammad A Naderi D Anaraki SR Gholizadeh Mesgarha M , Immune thrombocytopenic purpura secondary to COVID-19 vaccination: A systematic review Eur J Haematol 2023 110 335 53 https://doi.org/10.1111/ejh.13917 36562217
10. Song T-J Shin JI Yon DK Lee SW Hwang SY Hwang J , Cerebral venous thrombosis after ChAdOx1 nCoV-19 vaccination: A systematic review Eur Rev Med Pharmacol Sci 2023 27 404 10 https://doi.org/10.26355/eurrev_202301_30894 36647889
11. Wachira VK Peixoto HM Oliveira MRF de Proposal of a Quality Assessment tool for the Evaluation of the Methodological Quality of Self-Controlled Case Series and Self-Controlled Risk Interval Study Designs 2022 https://doi.org/10.1590/SciELOPreprints.4141
Appendix 2: Details about the study eligibility criteria and study selection

	Inclusion criteria	
Population	Populations eligible for Covid-19 vaccine	
Intervention	ChadOx1 Covid-19 vaccine	
Control groups	Unvaccinated/pre-vaccination/post-vaccination/other vaccines	
Outcomes	Thromboembolic/thrombocytopenic/Haemorrhagic events	
Study designs	Case control/two-group cohort/single group cohort with background incidence/self-controlled case series (SCCS)*/clinical trials	
Time period	No restrictions	
Language	No restrictions	
Note: *Self-controlled case series (SCCS): The self-controlled case series (SCCS) method is an epidemiological study design originally developed for evaluation of vaccine safety for which individuals act as their own control and all time invariant confounding is eliminated.1 Petersen I, Douglas I, Whitaker H. Self-controlled case series methods: An alternative to standard epidemiological study designs. BMJ [Internet]. 2016 Sep 12 [cited 2023 Mar 27];354:i4515. Available from: https://www.bmj.com/content/354/bmj.i4515.

	Exclusion criteria	
Population	Studies exclusively on children or special populations	
Intervention	Other covid vaccines	
Outcomes	Non-thromboembolic or non-haemorrhagic outcomes	
Study designs	Single group cohort with no comparison group	

APPENDIX 3: SEARCH STRATEGY DETAILS

Embase: Carried out on 17/10/2022

‘vaxzevria’/exp

‘covid-19 vaccine astrazeneca’ OR ‘covid-19 vaccine astrazeneca-oxford’ OR ‘covid-19 vaccine oxford-astrazeneca’ OR ‘astrazeneca covid-19 vaccine’ OR ‘astrazeneca-oxford covid-19 vaccine’ OR ‘azd 1222’ OR ‘azd1222’ OR ‘chadox 1’ OR ‘chadox1 ncov 19’ OR ‘chadox1 covid-19 vaccine’ OR ‘chadox1 ncov 19’ OR ‘chadox1 ncov 19 vaccine’ OR ‘chadox1 ncov-19’ OR ‘chadox1 ncov19’ OR ‘chadox1 s’ OR ‘chadox1-s’ OR ‘covishield’ OR ‘oxford-astrazeneca covid-19 vaccine’ OR ‘vaxzevria’ OR covishield:ti, ab

1 OR 2

‘thromboembolism’/exp

‘cerebral embolism and thrombosis’ OR ‘embolism and thrombosis’ OR ‘embolism, thrombo’

‘intracranial embolism and thrombosis’ OR ‘thrombo embolic disease’ OR ‘thrombo embolism’ OR ‘thrombo-emboli’ OR ‘thrombo-embolus’ OR ‘thromboemboli’ OR ‘thromboembolic’ OR ‘thromboembolic complication’ OR ‘thromboembolic disease’ OR ‘thromboembolic process’ OR ‘thromboembolism’ OR ‘thromboembolus’ OR ‘thromboemboly’

‘cerebrovascular accident’/exp

‘cva’ OR ‘accident, cerebrovascular’ OR ‘acute cerebrovascular lesion’ OR ‘acute focal cerebral vasculopathy’ OR ‘acute stroke’ OR ‘apoplectic stroke’ OR ‘apoplexia’ OR ‘apoplexy’ OR ‘blood flow disturbance, brain’ OR ‘brain accident’ OR ‘brain attack’ OR ‘brain blood flow disturbance’ OR ‘brain insult’ OR ‘brain insultus’ OR ‘brain vascular accident’ OR ‘cerebral apoplexia’ OR ‘cerebral insult’ OR ‘cerebral stroke’ OR ‘cerebral vascular accident’ OR ‘cerebral vascular insufficiency’ OR ‘cerebro vascular accident’ OR ‘cerebrovascular accident’ OR ‘cerebrovascular arrest’ OR ‘cerebrovascular failure’ OR ‘cerebrovascular injury’ OR ‘cerebrovascular insufficiency’ OR ‘cerebrovascular insult’ OR ‘cerebrum vascular accident’ OR ‘cryptogenic stroke’ OR ‘insultus cerebralis’ OR ‘ischaemic seizure’ OR ‘ischemic seizure’ OR ‘stroke’ OR ‘thrombotic stroke’

4 OR 5 OR 6 OR 7 OR 8

‘heart infarction’/exp

‘cardiac infarct’ OR ‘cardiac infarction’ OR ‘cardial infarct’ OR ‘heart attack’ OR ‘heart infarct’ OR ‘heart infarction’ OR ‘heart micro infarction’ OR ‘heart muscle infarction’ OR ‘infarction, heart’ OR ‘myocardial infarct’ OR ‘myocardial infarction’ OR ‘myocardium infarct’ OR ‘myocardium infarction’ OR ‘premonitory infarction sign’ OR ‘second heart attack’ OR ‘subendocardial infarction’ OR ‘transmural cardiac infarction’ OR ‘transmural heart infarction’ OR ‘transmural infarction, heart’

‘acute coronary syndrome’/exp

‘acute coronary syndrome’ OR ‘acute coronary syndromes’

10 OR 11 OR 12 OR 13

‘deep vein thrombosis’/exp

‘dvt (deep vein thrombosis)’ OR ‘acute dvt’ OR ‘acute deep venous thrombosis’ OR ‘deep thrombo-phlebitis’ OR ‘deep thrombophlebitis’ OR ‘deep vein blood clots’ OR ‘deep vein thrombophlebitis’ OR ‘deep vein thrombosis’ OR ‘deep vein thrombus’ OR ‘deep venous thrombophlebitis’ OR ‘deep venous thrombosis’ OR ‘deep venous thrombus’ OR ‘recurrent dvt’ OR ‘thrombosis, acute deep venous’

15 OR 16

‘lung embolism’/exp

‘chronic lung embolism’ OR ‘embolism, lung’ OR ‘lung embolism’ OR ‘lung embolization’ OR ‘lung embolus’ OR ‘lung embolus recurrence’ OR ‘lung emboly’ OR ‘lung microembolism’ OR ‘lung microembolization’ OR ‘lung microembolus’ OR ‘lung thromboembolism’ OR ‘microembolus, lung’ OR ‘pulmonary embolism’ OR ‘pulmonary embolization’ OR ‘pulmonary embolus’ OR ‘pulmonary microembolism’ OR ‘pulmonary thromboembolic disease’ OR ‘pulmonary thromboembolism’ OR ‘thromboembolism, lung’

18 OR 19

‘thrombocyte disorder’/exp OR ‘blood platelet disorders’ OR ‘congenital thrombocytopathy’ OR ‘platelet storage pool deficiency’ OR ‘thrombocyte disease’ OR ‘thrombocyte disorder’ OR ‘thrombocytopathia’ OR ‘thrombocytopathy’

9 OR 14 OR 17 OR 20 OR 21

‘case control study’/exp

‘case control study’ OR ‘case-control studies’ OR ‘case-control study’ OR ‘control study, case’ OR ‘matched case control’ OR ‘matched case control studies’ OR ‘matched case control study’

23 OR 24

‘cohort analysis’/exp

‘analysis, cohort’ OR ‘cohort analysis’ OR ‘cohort fertility’ OR ‘cohort life cycle’ OR ‘cohort studies’ OR ‘cohort study’

26 OR 27

‘self controlled case series’/exp

‘controlled clinical trial’/exp

‘clinical trial, controlled’ OR ‘controlled clinical comparison’ OR ‘controlled clinical drug trial’ OR ‘controlled clinical experiment’ OR ‘controlled clinical study’ OR ‘controlled clinical test’ OR ‘controlled clinical trial’

30 OR 31

‘analytical study’/exp

25 OR 28 OR 29 OR 32 OR 33

3 AND 22 AND 34.

PubMed: Carried out on 18/10/2022

‘vaxzevria’

‘covid-19 vaccine astrazeneca’ OR ‘covid-19 vaccine astrazeneca-oxford’ OR ‘covid-19 vaccine oxford-astrazeneca’ OR ‘astrazeneca covid-19 vaccine’ OR ‘astrazeneca-oxford covid-19 vaccine’ OR ‘azd 1222’ OR ‘azd1222’ OR ‘chadox1’ OR ‘chadox1 ncov 19’ OR ‘chadox1 covid-19 vaccine’ OR ‘chadox1 ncov 19’ OR ‘chadox1 ncov 19 vaccine’ OR ‘chadox1 ncov-19’ OR ‘chadox1 ncov19’ OR ‘chadox1 s’ OR ‘chadox1-s’ OR ‘covishield’ OR ‘oxford-astrazeneca covid-19 vaccine’ OR ‘vaxzevria’ OR covishield:ti,ab

1 OR 2

‘thromboembolism’

‘cerebral embolism and thrombosis’ OR ‘embolism and thrombosis’ OR ‘embolism, thrombo’

‘intracranial embolism and thrombosis’ OR ‘thrombo embolic disease’ OR ‘thrombo embolism’ OR ‘thrombo-emboli’ OR ‘thrombo-embolus’ OR ‘thromboemboli’ OR ‘thromboembolic’ OR ‘thromboembolic complication’ OR ‘thromboembolic disease’ OR ‘thromboembolic process’ OR ‘thromboembolism’ OR ‘thromboembolus’ OR ‘thromboemboly’

‘cerebrovascular accident’

‘cva’ OR ‘accident, cerebrovascular’ OR ‘acute cerebrovascular lesion’ OR ‘acute focal cerebral vasculopathy’ OR ‘acute stroke’ OR ‘apoplectic stroke’ OR ‘apoplexia’ OR ‘apoplexy’ OR ‘blood flow disturbance, brain’ OR ‘brain accident’ OR ‘brain attack’ OR ‘brain blood flow disturbance’ OR ‘brain insult’ OR ‘brain insultus’ OR ‘brain vascular accident’ OR ‘cerebral apoplexia’ OR ‘cerebral insult’ OR ‘cerebral stroke’ OR ‘cerebral vascular accident’ OR ‘cerebral vascular insufficiency’ OR ‘cerebro vascular accident’ OR ‘cerebrovascular accident’ OR ‘cerebrovascular arrest’ OR ‘cerebrovascular failure’ OR ‘cerebrovascular injury’ OR ‘cerebrovascular insufficiency’ OR ‘cerebrovascular insult’ OR ‘cerebrum vascular accident’ OR ‘cryptogenic stroke’ OR ‘insultus cerebralis’ OR ‘ischaemic seizure’ OR ‘ischemic seizure’ OR ‘stroke’ OR ‘thrombotic stroke’

4 OR 5 OR 6 OR 7 OR 8

‘heart infarction’

‘cardiac infarct’ OR ‘cardiac infarction’ OR ‘cardial infarct’ OR ‘heart attack’ OR ‘heart infarct’ OR ‘heart infarction’ OR ‘heart micro infarction’ OR ‘heart muscle infarction’ OR ‘infarction, heart’ OR ‘myocardial infarct’ OR ‘myocardial infarction’ OR ‘myocardium infarct’ OR ‘myocardium infarction’ OR ‘premonitory infarction sign’ OR ‘second heart attack’ OR ‘subendocardial infarction’ OR ‘transmural cardiac infarction’ OR ‘transmural heart infarction’ OR ‘transmural infarction, heart’

‘acute coronary syndrome’

‘acute coronary syndrome’ OR ‘acute coronary syndromes’

10 OR 11 OR 12 OR 13

‘deep vein thrombosis’

‘dvt (deep vein thrombosis)’ OR ‘acute dvt’ OR ‘acute deep venous thrombosis’ OR ‘deep thrombo-phlebitis’ OR ‘deep thrombophlebitis’ OR ‘deep vein blood clots’ OR ‘deep vein thrombophlebitis’ OR ‘deep vein thrombosis’ OR ‘deep vein thrombus’ OR ‘deep venous thrombophlebitis’ OR ‘deep venous thrombosis’ OR ‘deep venous thrombus’ OR ‘recurrent dvt’ OR ‘thrombosis, acute deep venous’

15 OR 16

‘lung embolism’

‘chronic lung embolism’ OR ‘embolism, lung’ OR ‘lung embolism’ OR ‘lung embolization’ OR ‘lung embolus’ OR ‘lung embolus recurrence’ OR ‘lung emboly’ OR ‘lung microembolism’ OR ‘lung microembolization’ OR ‘lung microembolus’ OR ‘lung thromboembolism’ OR ‘microembolus, lung’ OR ‘pulmonary embolism’ OR ‘pulmonary embolization’ OR ‘pulmonary embolus’ OR ‘pulmonary microembolism’ OR ‘pulmonary thromboembolic disease’ OR ‘pulmonary thromboembolism’ OR ‘thromboembolism, lung’

18 OR 19

‘thrombocyte disorder’OR ‘blood platelet disorders’ OR ‘congenital thrombocytopathy’ OR ‘platelet storage pool deficiency’ OR ‘thrombocyte disease’ OR ‘thrombocyte disorder’ OR ‘thrombocytopathia’ OR ‘thrombocytopathy’

9 OR 14 OR 17 OR 20 OR 21

‘case control study’

‘case control study’ OR ‘case-control studies’ OR ‘case-control study’ OR ‘control study, case’ OR ‘matched case control’ OR ‘matched case control studies’ OR ‘matched case control study’

23 OR 24

‘cohort analysis’

‘analysis, cohort’ OR ‘cohort analysis’ OR ‘cohort fertility’ OR ‘cohort life cycle’ OR ‘cohort studies’ OR ‘cohort study’

26 OR 27

‘self controlled case series’

‘controlled clinical trial’

‘clinical trial, controlled’ OR ‘controlled clinical comparison’ OR ‘controlled clinical drug trial’ OR ‘controlled clinical experiment’ OR ‘controlled clinical study’ OR ‘controlled clinical test’ OR ‘controlled clinical trial’

30 OR 31

‘analytical study’

25 OR 28 OR 29 OR 32 OR 33

3 AND 22 AND 34.

WHO Covid-19 database: Carried out on 26/11/2022

(chadox OR azd 1222 OR “Oxford-Astrazeneca”) AND (thromboembolism OR “Central venous thrombosis” OR thrombocytopenia OR stroke OR “Myocardial infarction” OR hemorrhage) AND type_of_study:(“observational_studies” OR “cohort_studies”).

Google Scholar: Carried out on 26/11/20221

(chadox OR azd 1222 OR “Oxford-Astrazeneca”) AND (thromboembolism OR “Central venous thrombosis” OR thrombocytopenia OR stroke OR “Myocardial infarction” OR hemorrhage) AND type_of_study:(“observational_studies” OR “cohort_studies”).

medRxiv: Carried out on 27/11/2022

Chadox OR AZD 1222 OR Oxford-Aztrazeneca

Chadox AND Thrombocytopenia

Chadox AND Thromboembolism

Chadox AND Adverse events

Chadox AND Myocardial infarction

Chadox AND Hemorrhage

Chadox AND Stroke.

Appendix 4: Risk and comparison period in self-controlled case series

Study	Risk period	Comparison	
Berild JD	28 days following vaccination	Pre-vaccination period (2020-21) covering four seasons (March-May, June-August, September-November, Dec-Feb)	
Botton J	3 weeks after vaccination with first/second dose	All other period of observation from 6 Feb 2021 to 20 July 2021	
Rahman N	21 days post vaccination	All other period between 1 Feb and 30 Sept 2021	
Higgins	27 days post vaccination	All other period between Jan 1 to March 31	
Kerr S	28 days post vaccination	90 days before vaccination	
Hippisley-Cox	28 days post vaccination	All other period between 1 Dec 2020 and 24 April 2021	
Simpson CR	28 days post vaccination	15 to 104 days before receipt of vaccination	
Torabi F	28 days post vaccination	15 to 104 days before receipt of vaccination	
Patone M	28 days post vaccination	All other period between 1 Dec 2020 to 31 May 2021	

APPENDIX 5: DESCRIPTION OF THE RISK OF BIAS ASSESSMENT TOOLS USED

Ottawa-Newcastle tool for ROB assessment of cohort studies

Note: A study can be given a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability.

Selection

Representativeness of the exposed cohort

Truly representative (one star)

Somewhat representative (one star)

Selected group

No description of the derivation of the cohort.

Selection of the non-exposed cohort

Drawn from the same community as the exposed cohort (one star)

Drawn from a different source

No description of the derivation of the non-exposed cohort.

Ascertainment of exposure

Secure record (e.g., surgical record) (one star)

Structured interview (one star)

Written self-report

No description

Other.

Demonstration that outcome of interest was not present at start of study

Yes (one star)

No.

Comparability

Comparability of cohorts on the basis of the design or analysis controlled for confounders

The study controls for age, sex, and marital status (one star)

Study controls for other factors (list) _________________________________ (one star)

Cohorts are not comparable on the basis of the design or analysis controlled for confounders.

Outcome

Assessment of outcome

Independent blind assessment (one star)

Record linkage (one star)

Self report

No description

Other.

Was follow-up long enough for outcomes to occur

Yes (one star)

No.

Indicate the median duration of follow-up and a brief rationale for the assessment above: ____________________

Adequacy of follow-up of cohorts

Complete follow up- all subject accounted for (one star)

Subjects lost to follow up unlikely to introduce bias- number lost less than or equal to 20% or description of those lost suggested no different from those followed. (one star)

Follow up rate less than 80% and no description of those lost

No statement.

Thresholds for converting the Newcastle-Ottawa scales to AHRQ standards (good, fair, and poor):

Good quality: 3 or 4 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome/exposure domain.

Fair quality: 2 stars in selection domain AND 1 or 2 stars in comparability domain AND 2 or 3 stars in outcome/exposure domain.

Poor quality: 0 or 1 star in selection domain OR 0 stars in comparability domain OR 0 or 1 stars in outcome/exposure domain.

APPENDIX 6: REFERENCES OF THE ARTICLES INCLUDED IN THE SYSTEMATIC REVIEW AND META-ANALYSIS[1213141516171819202122232425262728293031]

Supplemental Table 2: Risk of bias in the included studies

REFERENCES

1. Sharifian-Dorche M Bahmanyar M Sharifian-Dorche A Mohammadi P Nomovi M Mowla A Vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis post COVID-19 vaccination; a systematic review J Neurol Sci 2021 428 117607 https://doi.org/10.1016/j.jns.2021.117607 34365148
2. Waqar U Ahmed S Gardezi SMHA Tahir MS Abidin ZU Hussain A , Thrombosis with Thrombocytopenia Syndrome After Administration of AZD1222 or Ad26.COV2.S Vaccine for COVID-19: A Systematic Review Clin Appl Thromb Hemost 2021 27 10760296211068488 https://doi.org/10.1177/10760296211068487
3. Matar RH Than CA Nakanishi H Daniel RS Smayra K Sim BL , Outcomes of patients with thromboembolic events following coronavirus disease 2019 AstraZeneca vaccination: A systematic review and meta-analysis Blood Coagul Fibrinolysis 2022 33 90 112 https://doi.org/10.1097/MBC.0000000000001113 34980833
4. Jaiswal V Nepal G Dijamco P Ishak A Dagar M Sarfraz Z , Cerebral Venous Sinus Thrombosis Following COVID-19 Vaccination: A Systematic Review J Prim Care Community Health 2022 13 21501319221074450 https://doi.org/10.1177/21501319221074450 35142234
5. Elberry MH Abdelgawad HAH Hamdallah A Abdella WS Ahmed AS Ghaith HS , A systematic review of vaccine-induced thrombotic thrombocytopenia in individuals who received COVID-19 adenoviral-vector-based vaccines J Thromb Thrombolysis 2022 53 798 823 https://doi.org/10.1007/s11239-021-02626-w 35157188
6. Kim AY Woo W Yon DK Lee SW Yang JW Kim JH , Thrombosis patterns and clinical outcome of COVID-19 vaccine-induced immune thrombotic thrombocytopenia: A Systematic Review and Meta-Analysis Int J Infect Dis 2022 119 130 9 https://doi.org/10.1016/j.ijid.2022.03.034 35339716
7. Saluja P Amisha F Gautam N Goraya H A Systematic Review of Reported Cases of Immune Thrombocytopenia after COVID-19 Vaccination Vaccines (Basel) 2022 10 1444 https://doi.org/10.3390/vaccines10091444 36146522
8. Saluja P Gautam N Yadala S Venkata AN Thrombotic thrombocytopenic purpura (TTP) after COVID-19 vaccination: A systematic review of reported cases Thromb Res 2022 214 115 21 https://doi.org/10.1016/j.thromres.2022.04.020 35533526
9. Bidari A Asgarian S Pour Mohammad A Naderi D Anaraki SR Gholizadeh Mesgarha M , Immune thrombocytopenic purpura secondary to COVID-19 vaccination: A systematic review Eur J Haematol 2023 110 335 53 https://doi.org/10.1111/ejh.13917 36562217
10. Song T-J Shin JI Yon DK Lee SW Hwang SY Hwang J , Cerebral venous thrombosis after ChAdOx1 nCoV-19 vaccination: A systematic review Eur Rev Med Pharmacol Sci 2023 27 404 10 https://doi.org/10.26355/eurrev_202301_30894 36647889
11. Wachira VK Peixoto HM Oliveira MRF de Proposal of a Quality Assessment tool for the Evaluation of the Methodological Quality of Self-Controlled Case Series and Self-Controlled Risk Interval Study Designs 2022 https://doi.org/10.1590/SciELOPreprints.4141
Modified Ottawa-Newcastle tool for ROB assessment of Self-controlled cases series

Section	Explanation/Guide	Assessment	
Selection		Three stars maximum	
1) Representativeness of the cases	The study should show the representativeness of the cases in terms of all cases from the study population. For example, in vaccine safety studies, were the selected cases (people with the outcome of interest) representative of all cases originating from the study population?	One star maximum	
a) Truly representative of the average _______________ (describe) in the community *
b) Somewhat representative of the average -_________ in the community *
c) Selected group of users, example, volunteers
d) No description of the derivation of the cases in the study	a) Were all eligible cases included in the study? In the case of vaccine safety studies, were all cases registered for example in a data base of adverse events, reference institution or hospital or was there a clear method of defining who was to be included in the study?
b) In case of random sampling, was there a clear method used to define the cases included in the study? Example, In the case of vaccine safety studies were the adverse effects analyzed reported at a predetermined period of interest?
c) Was there a certain group of individuals who qualified to be the cases after an exposure and were there any justifications of why that was done?	A study gets a star if meets the requirements for item a or b	
d) No explanation whatsoever of how the cases were included in the follow up.	
2) Ascertainment of exposure	The study should report how the exposure was ascertained	One star maximum	
a) Secure record (Example, data base) *
b) Structured interview *
c) Written self-report
d) No description	a) Is there a secure record of that shows that there was an exposure? Example, in the case of vaccines, is there a secure database of the vaccines administered, doses, date, batch number?
b) In the absence of a database or secure registries of the exposure of interest, were the cases interviewed to clarify about the exposure, did they show a vaccination card, were the caregivers contacted to confirm the information?
c) Did the cases self-report the exposure with no other physical evidence (like a vaccination card)? Example, a self-report of vaccination
d) No documented evidence of exposure or self-report.	A study gets a star if it meets the requirements of item a or b.	
3) Demonstration that outcome of interest was not present at start of study	There should be evidence that the outcome of interest occurred during the observation period	One star maximum	
a) Yes*
b) No	a) The study should report that the outcome of interest occurred during the observation period	A study gets a star the response is “yes”	
Comparability	One of the most important pillars of self-controlled studies. a) The study should at least report which of the confounding factors that vary over time were controlled for.	Two stars maximum	
1) Comparability of cases on the basis of the design or analysis	The comparability is inherent of the study design and should be evaluated in detail	Two stars maximum	
a) Study controls for _____________ (select the most important factor that varies over time; seasonality or age) or the follow-up period was short enough to mitigate time-confounding issues *
b) Study controls for any additional factor or justifies why the time varying factors were controlled (This criterion could be modified to indicate specific control for a second important factor that varies over time) *	a) e b) The study should report if a time varying factor such as seasonality or age were controlled in the study. (Some exposures depending on the age or seasonality may give biased results of the outcomes evaluated)	A study can get a star if it meets the requirements of item a or b, or two stars if it meets the requirements of the two.	
Outcome	The study should clearly report the outcome of interest	Five stars maximum	
1) Assessment of outcome	The outcome of interest should be evaluated in a valid manner	One star maximum	
a) Independent blind assessment* or outcome was measured in a valid and reliable way
b) Record linkage*
c) Self-report
d) No description	a) Were the outcomes evaluated in an independent way (by specialists who were blinded), was a valid and reliable method of evaluation used like a criterion of confirmation of exposure?
b) In the case of the use of a database, were there any data linkage between the exposure database and that of outcomes?
c) Did the cases self-report the outcomes?
d) No description of how the outcome was assessed.	A study get a star if it meets the requirements of item a or b	
2) Risk period stated	One of the observation periods of the SCCS and SCRI designs	One star maximum	
a) Yes*/justify the period
b) No	a) Was the risk period clearly stated in reference to when the exposure occurred, or the selection of the period justified?
b) No statement of the risk period.	A study get a star if the response is “yes”	
3) Control period stated	One of the observation periods of the SCCS and SCRI designs	Maximum of one star	
a) Yes*
b) No	a) Was the control period clearly stated in reference to the time of exposure or the risk period.
b) No statement of the control period.	A study get a star if the response is “yes”	
4) Risk period and control period long enough for outcomes to occur	The risk and control periods should be long enough to observe the outcomes of interest.	One star maximum	
a) Yes (select an adequate follow up period for outcome of interest/)*
b) No	a) Was there an adequate follow up?
*An adequate follow up is essential to observe the desired outcomes. Generally, the period of risk is determined by previous studies. The study should at least mention why the lengths of the periods of observation were chosen, this information guides in determining if the follow up was sufficient enough for the outcomes to occur.	A study get a star if the response is “yes”	
5) Adequacy of follow up of cases	Significant loss to follow up may be detrimental to the results obtained. A SCCS or SCRI should account for the cases studied.	One star maximum	
a) Complete follow up - all subjects accounted for*
b) Subjects lost to follow up unlikely to introduce bias - small number lost - > ____ % (select an adequate %) follow up, or description provided of those lost)*
c) Follow up rate < ____% (select an adequate %) and no description of those lost
d) No statement	a) Were all cases accounted for at the end of the study period?
*All cases which should be accounted for. In case of a recurrent event or death, this should de clearly reported.
b) If the cases are lost due to other motives like a personal choice to leave the study or lack of information (e.g., no exposure information) in a certain period of the follow up in case of databases, the possible impact should be reported and how it influences in the analysis.
c) the follow up rate should be stated	A study gets a star if it meets the requirements for item a or b	
Source: Wachira VK, Peixoto HM, Oliveira MRF de. Proposal of a Quality Assessment tool for the Evaluation of the Methodological Quality of Self-Controlled Case Series and Self-Controlled Risk Interval Study Designs [Internet]. 2022 May [cited 2023 Mar 27]. Available from: https://preprints.scielo.org/index.php/scielo/preprint/view/4141/version/4377
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