There is a slightly elevated risk of intracranial thrombosis events following vaccination with the AstraZeneca ChAdOx1-S COVID vaccine, according to two new studies publishing February 22nd in PLOS Medicine. The first paper, by William Whiteley of the University of Edinburgh, UK, and colleagues from the BHF Data Science Centre, UK, analyzed the electronic health records of 46 million adults in England. The second paper, by Steven Kerr of the University of Edinburgh, UK, and colleagues, used a dataset of 11 million adults in England, Scotland, and Wales.
Cases of thromboses—when a blood clot blocks a vein or artery—have been reported after vaccination with the Astra Zeneca ChAdOx1-S COVID-19 vaccine. However, the rates of common venous and arterial events, including stroke, myocardial infarction, deep vein thrombosis and pulmonary embolism, are hard to measure based on case reports alone.
In the first study, Whiteley and colleagues analyzed the electronic health records (EHRs) of 46 million adults living in England, of whom 21 million were vaccinated during the study time span, December 2020 to March 2021. For people aged 70 or over, the risks of arterial and venous thrombotic events were slightly lower in the 28 days following vaccination with either the Pfizer BNT162b2 or ChAdOx1-S vaccine, after adjusting for a range of demographic characteristics and comorbidities. In people under age 70, the risks of arterial and venous thrombotic events were comparable in the 28 days following vaccination, but a small increase in the rate of intracranial venous thrombosis (ICVT) was observed following the ChAdOx1-S vaccine. This corresponded to an estimated excess risk of 0.9–3 per million (varying by age and sex) and was approximately twice the rate compared to unvaccinated people, after adjusting for a range of demographic characteristics and comorbidities. The same effect was not seen after the BNT162b2 vaccine.
“In adults under 70 years, the small increased risks of intracranial venous thrombosis and hospitalization with thrombocytopenia after first vaccination with ChAdOx1-S are likely to be outweighed by the vaccines’ effect in reducing COVID-19 mortality and morbidity,” the authors say.
In the second study, the researchers linked data spanning December 2020 through June 2021 from multiple sources—including primary care, secondary care, mortality and virological testing—for more than 11 million people in England, Scotland and Wales. They compared the rate of cerebral venous sinus thrombosis (CVST) events—a rare type of blood clot in the brain—in the 90 days prior to vaccination and the four weeks following a first dose of ChAdOx1-S or BNT162b2. The authors observed a small elevated risk of CVST events following vaccination with ChAdOx1-S, equivalent to one additional event per 4 million people vaccinated, which was approximately twice as high as before vaccination. The study found no association between the BNT162b2 vaccine and CVST.
“This evidence may be useful in risk-benefit evaluations for vaccine-related policies, and in providing quantification of risks associated with vaccination to the general public,” the authors say.
The authors of both studies caution that the low number of overall events of CVST and other subtypes of thromboses, even in large cohorts, makes precise estimates of the risks difficult. They plan to carry out future studies to include other vaccines as well as second and booster vaccinations.
Whiteley adds, “Because of its very large size, this research study has provided precise results on the risks of rare blood clotting events and of low platelet levels following COVID-19 vaccination. We were able to show that these risks occur only in people under 70 years old with the Oxford-AstraZeneca vaccine and that the increase in risk is extremely small – no more than a few people per million vaccinated.”
Kerr adds, “In this analysis using data from England, Scotland and Wales, we found a roughly two-fold increased risk of a rare form of blood clot in the brain following the Oxford-AstraZeneca vaccine, but we did not see any increased risk for the Pfizer vaccine. We used a novel method that allowed us to do the analysis across several countries without them having to share person-level data with each other, and we hope to take advantage of this in future to allow greater collaboration across the UK.”
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Citation 1: Whiteley WN, Ip S, Cooper JA, Bolton T, Keene S, Walker V, et al. (2022) Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events: A population-based cohort study of 46 million adults in England. PLoS Med 19(2): e1003926. https://doi.org/10.1371/journal.pmed.1003926
Citation 2: Kerr S, Joy M, Torabi F, Bedston S, Akbari A, Agrawal U, et al. (2022) First dose ChAdOx1 and BNT162b2 COVID-19 vaccinations and cerebral venous sinus thrombosis: A pooled self-controlled case series study of 11.6 million individuals in England, Scotland, and Wales. PLoS Med 19(2): e1003927. https://doi.org/10.1371/journal.pmed.1003927
Author Countries: United Kingdom
Funding 1: The British Heart Foundation Data Science Centre (grant No SP/19/3/34678 awarded to Health Data Research (HDRUK) funded co-development (with NHS Digital) of the trusted research environment provision of linked datasets, data access, user software licences, computational usage, and data management and wrangling support. Support was also provided through the Data and Connectivity and Longitudinal Health and Wellbeing National Core Studies, which were established through the UK Government’s Chief Scientific Adviser’s National Core Studies program to coordinate COVID-19 priority research. Consortium partner organisations funded the time of contributing data analysts, biostatisticians, epidemiologists, and clinicians. WW is supported by the Chief Scientist’s Office (CAF/01/17). CS, AW and WW are supported by Stroke Association (SA CV 20/100018). AMW is supported by the BHF-Turing Cardiovascular Data Science Award (BCDSA/100005) and by core funding from UK MRC (MR/L003120/1), BHF (RG/13/13/30194, RG/18/13/33946), and NIHR Cambridge Biomedical Research Centre (BRC/1215/20014). AMW is part of the BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No 116074. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. JAC, JS, and RD are supported by the Health Data Research (HDR) UK South West Better Care Partnership, and the NIHR Bristol Biomedical Research Centre at University Hospitals Bristol, and Weston NHS Foundation Trust and the University of Bristol. VMW is supported by the MRC Integrative Epidemiology Unit, which receives its funding from the Medical Research Council and the University of Bristol (MC/UU/00011/4). AA, SD is supported by Health Data Research UK (grant number HDR/9006), which receives its funding from the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation (BHF) and the Wellcome Trust, and Administrative Data Research UK, which is funded by the Economic and Social Research Council (grant number ES/S007393/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding 2: This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20029, AS). EAVE II is funded by the Medical Research Council (https://mrc.ukri.org/) (UKRI MC_PC 19075, AS) with the support of BREATHE, The Health Data Research Hub for Respiratory Health (MC_PC_19004, AS), which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. This work was supported by the Con-COV team funded by the Medical Research Council (grant number: MR/V028367/1, RL). This work was supported by Health Data Research UK, which receives its funding from HDR UK Ltd (HDR-9006, RL) funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation (BHF) and the Wellcome Trust. This work was supported by the ADR Wales programme of work (https://www.adruk.org/). The ADR Wales programme of work is aligned to the priority themes as identified in the Welsh Government’s national strategy: Prosperity for All. ADR Wales brings together data science experts at Swansea University Medical School, staff from the Wales Institute of Social and Economic Research, Data and Methods (WISERD) at Cardiff University and specialist teams within the Welsh Government to develop new evidence which supports Prosperity for All by using the SAIL Databank at Swansea University, to link and analyse anonymised data. ADR Wales is part of the Economic and Social Research Council (part of UK Research and Innovation) funded ADR UK (grant ES/S007393/1, RL). SVK acknowledges funding from NHS Research Scotland Senior Clinical Fellowship (SCAF/15/02, SVK), the MRC (MC_UU_00022/2, SVK), and the Scottish Government Chief Scientist Office (SPHSU17, SVK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Competing Interests 1: I have read the journal’s policy and the authors of this manuscript have the following competing interests: WW has given expert testimony to UK courts. WW served on a advisory board for Bayer. CS is Director of the BHF Data Science Centre (at Health Data Research UK), which worked with NHS Digital to develop its Trusted Research Environment. CS leads the CVD COVID UK consortium which has enabled access to the linked population health data that enabled this study. No other authors declared conflicts of interest. Competing Interests 2: I have read the journal’s policy and the authors of this manuscript have the following competing interests. AS is a member of the Scottish Government Chief Medical Officer’s COVID-19 Advisory Group and the New and Emerging Respiratory Virus Threats (NERVTAG) Risk Stratification Subgroup and AstraZeneca’s COVID-19 Thrombocytopenia Taskforce; all roles are remunerated to AS or his institution. AS and SS are members of the editorial board of PLOS Medicine. CRS declares funding from the MRC, NIHR, CSO and New Zealand Ministry for Business, Innovation and Employment and Health Research Council during the conduct of this study. SVK is co-chair of the Scottish Government’s Expert Reference Group on COVID-19 and ethnicity, is a member of the Scientific Advisory Group on Emergencies (SAGE) subgroup on ethnicity and acknowledges funding from a NRS Senior Clinical Fellowship, MRC and CSO. CR is a member of the Scottish Government Chief Medical Officer’s COVID-19 Advisory Group, SPI-M, MHRA Vaccine Benefit and Risk Working Group. HRS is an advisor to the Scottish Parliament’s COVID-19 Committee. RKO is a member of the National Institute for Health and Care Excellence (NICE) Technology Appraisal Committee. DB is employed by Queen’s University Belfast, the Public Health Agency and the Department of Health (Northern Ireland). DB is a member of several Northern Ireland and UK government COVID-19 advisory boards, including the Scientific Pandemic Influenza Group on Modelling and the UK Vaccine Effectiveness Expert Panel, and has represented Northern Ireland on the UK Scientific Advisory Group for Emergencies and its subgroups. SdeL through his University holds grants from AstraZeneca, Eli-Lilly, GSK, MSD, Sanofi and Seqirus. He has been advisory board members for Astra Zeneca, Sanofi and Seqirus. MW is a member of UK government COVID-19 advisory group, SPI-M, and a member of Scottish Government COVID-19 Advisory Group. All other authors report no conflicts of interest.