Skip to main content
PMC home page
PLOS Medicine logoLink to PLOS Medicine
. 2022 Feb 22;19(2):e1003926. doi: 10.1371/journal.pmed.1003926

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

William N Whiteley 1,2,*, Samantha Ip 3, Jennifer A Cooper 4, Thomas Bolton 3,5, Spencer Keene 3, Venexia Walker 4, Rachel Denholm 4, Ashley Akbari 6, Efosa Omigie 7, Sam Hollings 7, Emanuele Di Angelantonio 3,8, Spiros Denaxas 5,9, Angela Wood 3,8,#, Jonathan A C Sterne 4,10,11,#, Cathie Sudlow 5,#; CVD-COVID-UK consortium
Editor: Suzanne C Cannegieter12
PMCID: PMC8863280  PMID: 35192597

Abstract

Background

Thromboses in unusual locations after the Coronavirus Disease 2019 (COVID-19) vaccine ChAdOx1-S have been reported, although their frequency with vaccines of different types is uncertain at a population level. The aim of this study was to estimate the population-level risks of hospitalised thrombocytopenia and major arterial and venous thromboses after COVID-19 vaccination.

Methods and findings

In this whole-population cohort study, we analysed linked electronic health records from adults living in England, from 8 December 2020 to 18 March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous, and thrombocytopenic outcomes 1 to 28 and >28 days after first vaccination dose for ChAdOx1-S and BNT162b2 vaccines. Analyses were performed separately for ages <70 and ≥70 years and adjusted for age, age2, sex, ethnicity, and deprivation. We also prespecified adjustment for anticoagulant medication, combined oral contraceptive medication, hormone replacement therapy medication, history of pulmonary embolism or deep vein thrombosis, and history of coronavirus infection in analyses of venous thrombosis; and diabetes, hypertension, smoking, antiplatelet medication, blood pressure lowering medication, lipid lowering medication, anticoagulant medication, history of stroke, and history of myocardial infarction in analyses of arterial thromboses. We selected further covariates with backward selection.

Of 46 million adults, 23 million (51%) were women; 39 million (84%) were <70; and 3.7 million (8.1%) Asian or Asian British, 1.6 million (3.5%) Black or Black British, 36 million (79%) White, 0.7 million (1.5%) mixed ethnicity, and 1.5 million (3.2%) were of another ethnicity. Approximately 21 million (46%) adults had their first vaccination between 8 December 2020 and 18 March 2021.

The crude incidence rates (per 100,000 person-years) of all venous events were as follows: prevaccination, 140 [95% confidence interval (CI): 138 to 142]; ≤28 days post-ChAdOx1-S, 294 (281 to 307); >28 days post-ChAdOx1-S, 359 (338 to 382), ≤28 days post-BNT162b2-S, 241 (229 to 253); >28 days post-BNT162b2-S 277 (263 to 291). The crude incidence rates (per 100,000 person-years) of all arterial events were as follows: prevaccination, 546 (95% CI: 541 to 555); ≤28 days post-ChAdOx1-S, 1,211 (1,185 to 1,237); >28 days post-ChAdOx1-S, 1678 (1,630 to 1,726), ≤28 days post-BNT162b2-S, 1,242 (1,214 to 1,269); >28 days post-BNT162b2-S, 1,539 (1,507 to 1,572).

Adjusted HRs (aHRs) 1 to 28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and ≥70 years, respectively, were 0.97 (95% CI: 0.90 to 1.05) and 0.58 (0.53 to 0.63) for venous thromboses, and 0.90 (0.86 to 0.95) and 0.76 (0.73 to 0.79) for arterial thromboses. Corresponding aHRs for BNT162b2 were 0.81 (0.74 to 0.88) and 0.57 (0.53 to 0.62) for venous thromboses, and 0.94 (0.90 to 0.99) and 0.72 (0.70 to 0.75) for arterial thromboses. aHRs for thrombotic events were higher at younger ages for venous thromboses after ChAdOx1-S, and for arterial thromboses after both vaccines.

Rates of intracranial venous thrombosis (ICVT) and of thrombocytopenia in adults aged <70 years were higher 1 to 28 days after ChAdOx1-S (aHRs 2.27, 95% CI: 1.33 to 3.88 and 1.71, 1.35 to 2.16, respectively), but not after BNT162b2 (0.59, 0.24 to 1.45 and 1.00, 0.75 to 1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1 to 28 days after ChAdOx1-S were 0.9 to 3 per million, varying by age and sex.

The main limitations of the study are as follows: (i) it relies on the accuracy of coded healthcare data to identify exposures, covariates, and outcomes; (ii) the use of primary reason for hospital admission to measure outcome, which improves the positive predictive value but may lead to an underestimation of incidence; and (iii) potential unmeasured confounding.

Conclusions

In this study, we observed increases in rates of ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years that were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults aged <40 years are needed. For people aged ≥70 years, rates of arterial or venous thrombotic events were generally lower after either vaccine compared with unvaccinated, suggesting that either vaccine is suitable in this age group.

In a population-based cohort study, William Whiteley and colleagues investigate the association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events in England.

Author summary

Why was this study done

  • Cases of venous and arterial thromboses in unusual locations, such as the cerebral veins, and with low platelet levels, have been reported after vaccination with ChAdOx1-S COVID-19 vaccine.

  • Case finding efforts in vaccinated people may lead to overestimation of risk associated with vaccines, if diagnostic thresholds vary between vaccinated and unvaccinated people.

  • Effects of vaccination on rates of common venous and arterial events—such as stroke, myocardial infarction (MI), deep vein thrombosis (DVT), and pulmonary embolism (PE)—are difficult to measure based on case reports. Population-level data may give better estimates.

What did the researchers do and find

  • We used nationally collated data from electronic health records on 46 million adults, of whom 21 million were vaccinated during the study, and compared the incidence of venous and arterial events before and after the first vaccination with ChAdOx1-S and BNT162b2 COVID-19 vaccines.

  • Overall rates of major arterial and venous events were lower after vaccination with both ChAdOx1-S and BNT162b2, after adjusting for potential confounding factors.

  • In people <70 years, rates of hospitalisation due to intracranial venous thrombosis (ICVT) or due to thrombocytopenia were higher after vaccination with ChAdOx1-S but not BNT162b2, although the absolute increase in the risk of these events was very small.

What do these findings mean

  • In adults ≥70 years, a first vaccination with either ChAdOx1-S and BNT162b2 was not associated with an increase in rates major arterial or venous thrombotic events.

  • In adults <70 years, the small increased risks of ICVT and hospitalisation 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 main limitations of the study were its reliance on the accuracy of coded electronic health records, and the potential for residual confounding.

Introduction

In late February 2021, several groups reported a rare syndrome of thrombosis and thrombocytopenia after vaccination against Severe Acute Respiratory Syndrome Coronavirus-2 Disease 2019 (COVID-19) with ChAdOx1-S (developed by Oxford-AstraZeneca) [1–3]. Thromboses were found in unusual sites such as the cerebral venous sinuses, or mesenteric or portal veins. This syndrome, named “vaccine-induced immune thrombotic thrombocytopenia” (VITT), is probably due to an autoimmune response to platelet factor 4 (PF4) in the absence of exposure to heparin [1]. Whether the risk of common thrombotic illnesses is also increased postvaccination is uncertain, although there have been reports of postvaccination ischaemic stroke and intracerebral haemorrhage [1,3,4].

Estimates of vaccine-associated excess risk based on case reports and routine reporting may be biased if diagnostic thresholds vary between vaccinated and unvaccinated individuals or there is less than population-wide coverage. In England, the National Health Service (NHS) provides almost all healthcare; therefore, linked healthcare records provide comprehensive, population-wide data on outcomes before and after vaccination [5]. Vaccination in England began on 8 December 2020: The first groups vaccinated were care home residents, then those aged ≥80 years and frontline health and social care workers. Those clinically extremely vulnerable were invited alongside people aged ≥70 years, and those with other comorbidities aged <65 alongside people aged >65 years. Consequently, individuals vaccinated earlier are expected to have higher rates of venous and arterial events.

We conducted a new cohort study using routinely collected, linked health data from multiple sources, covering almost the entire English adult population (>46 million). We estimated associations of ChAdOx1-S and BNT162b2 with major venous and arterial events and thrombocytopenic haematological outcomes from the start of the vaccination programme to mid-March 2021, before VITT surveillance was widespread.

Methods

Data were analysed according to a prespecified protocol and analysis plan that was published on GitHub on 5 May 2021 (S1 Protocol) [6]. We used the Strengthening the REporting of studies Conducted using Observational Routinely collected Data (RECORD) guideline to write this paper (S1 Record Checklist).

Population

The study population was adults (aged ≥18 years), alive and registered with an English NHS general practice on 8 December 2020. The data resource [5] includes primary care data (General Practice Extraction Service (GPES) Data for Pandemic Planning and Research (GDPPR)) from 98% of general practices linked at individual-level to nationwide secondary care data including all NHS hospital admissions (Hospital Episode Statistics (HES) and Secondary Uses Service (SUS) data from 1997 onwards), COVID-19 laboratory testing data, COVID-19 vaccination data (NHS England Immunisation Management System), national community drug dispensing data (NHS BSA Dispensed Medicines from 2018), and death registrations. We accessed and analysed pseudonymised data within NHS Digital’s secure, privacy-protecting Trusted Research Environment [7].

Covariates

We defined covariates from primary care, hospital admissions, community drug dispensing, and COVID-19 laboratory testing data, using phenotyping algorithms verified by specialist physicians (see study protocol). Phenotypes for comorbidities, risk factors, and other covariates used Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT) concepts for primary care data, and ICD-10 codes for hospital admission data. We defined sex, age, region, deprivation, and smoking status as the latest recorded in primary care records before 8 December 2020, and the most recently recorded ethnicity in either primary care or hospital admissions records was used. We defined history of diabetes, depression, obesity, cancer, chronic obstructive pulmonary disease, chronic kidney disease, stroke, myocardial infarction (MI), deep vein thrombosis (DVT) or pulmonary embolism (PE), cancer, thrombophilia, liver disease, or dementia as any record in primary care and/or hospital admission data before 8 December 2020. We derived the number of unique diseases in SNOMED-CT for the year before 8 December 2020 from primary care records and major surgery in the previous year from hospital admission records (using the Office of Population Censuses and Surveys classification of surgical procedures).

We defined a history of coronavirus (SARS-CoV-2) infection as either a positive COVID-19 antigen test in national laboratory data covering swab tests performed in the general population and hospitals or a confirmed COVID-19 diagnosis in primary care or hospital admission records. We defined prior medication using community dispensing data on all prescriptions dispensed by community pharmacists, appliance contractors, and doctors in England. British National Formulary (BNF) codes were used to define the total number of types of medication prescribed and dispensed in the following groups: antiplatelets, antihypertensives, lipid lowering agents, oral anticoagulants, combined oral contraceptives, and hormone replacement therapy.

Outcomes

We derived outcomes from primary care data, hospital admission data (SUS dataset), and the national death registry (see S1 Protocol) [8]. We used specialist clinician-verified SNOMED-CT and ICD-10 rule-based phenotyping algorithms to define fatal or nonfatal (i) arterial thrombotic events: MI, ischaemic stroke (ischaemic or unclassified stroke, spinal stroke, or retinal infarction), other nonstroke non-MI arterial thromboembolism; (ii) venous thromboembolic events: PE, lower limb DVT, intracranial venous thrombosis (ICVT), portal vein thrombosis, and venous thrombosis at other sites; (iii) thrombocytopenic haematological events: any thrombocytopenia (idiopathic, primary, secondary, or unspecified), disseminated intravascular coagulation (DIC), and thrombotic thrombocytopenic purpura (TTP); (iv) death from any cause; (v) other vascular outcomes: haemorrhagic stroke (intracerebral or subarachnoid) and mesenteric thrombus for which available codes did not distinguish between arterial or venous causes; and (vi) lower limb fracture as a control condition unlikely to be affected by vaccination. The event date was the earliest of start of hospital episode, death, or recorded date of primary care event or consultation. We identified events within the death registry based on underlying cause of death and in hospital admission data based on the primary cause of the care episode.

Statistical analyses

Follow-up was from 8 December 2020 to 18 March 2021, the date the European Medicine Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) discussed the first reported complications of vaccination, after which diagnostic effort was expected to be concentrated in people receiving ChAdOx1-S [9]. Any cell numbers <5 and any potentially disclosive numbers <10 are not reported exactly but as <5 and <10, respectively.

To allow for varying vaccination dates, we split follow-up from 8 December 2020 for each person into periods before, and 1 to 28, and >28 days after, first vaccination. Censoring was at the earliest of the outcome, death, 18 March 2021 and, in analyses of specific vaccines, receipt of the other vaccine. We estimated incidence rates per 100,000 people per year for each outcome, before and 1 to 28 and >28 days after vaccination.

We fitted Cox models with time zero 8 December 2020, ensuring that all analyses accounted for changes in rates of outcome events with calendar time. We estimated hazard ratios (HRs) comparing the periods 1 to 28 and >28 days after vaccination with unvaccinated or prevaccination person-time (reference). We fitted Cox models separately by age group (<70 and ≥70 years), both overall and separately for males and females. All Cox models were stratified by geographic region. For rare outcomes, sex-specific HRs were estimated from vaccine–sex interaction terms. For computational efficiency, each fitted model used data from all individuals with the outcome of interest and a random 10% sample of all other individuals; analyses incorporated inverse probability weights to account for this sampling [10,11]. We derived confidence intervals with robust standard errors.

Region-; age-sex-region-; and fully adjusted HRs (aHRs) for associations of ChAdOx1-S and BNT162b2 with outcome events were estimated. Analyses were adjusted for age, age2, sex, ethnicity, deprivation, and relevant medical history. Further covariates were selected using backward selection, from models using MI as the outcome. Covariates had few missing values (apart from ethnicity, for which the 5.9% “missing” were included as a separate category); hence, all analyses used “complete-cases”.

Sensitivity analyses examined outcome events recorded as the primary or secondary reason for admission or death in hospital admissions or death records; fatal outcome events (those followed by death from any cause within 28 days); and all venous and all arterial thrombotic outcome events associated with thrombocytopenia. Effect modification by age, sex, ethnicity, deprivation, medication, and medical history was examined for all venous and all arterial thromboses.

We calculated age- and sex-specific absolute excess risks of ICVT in days 1 to 28 following vaccination by multiplying estimated HRs by the average monthly incidence rates of first fatal or nonfatal ICVT; the latter were derived from records during calendar year 2019 in the population-wide data resource.

The study was approved by the Newcastle & North Tyneside 2 Research Ethics Committee (20/NE/0161), the NHS Digital Data Access Request Service (DARS-NIC-381078-Y9C5K), and the British Heart Foundation Data Science Centre CVD-COVID-UK Approvals and Oversight Board.

Information on the data used can be found on the HDR UK Gateway https://web.www.healthdatagateway.org/dataset/7e5f0247-f033-4f98-aed3-3d7422b9dc6d; EHR phenotyping algorithms can be downloaded in machine-readable formats from the HDR UK Phenotype Library http://phenotypes.healthdatagateway.org. Data manipulation and analyses used SQL and Python in Databricks and RStudio (Professional) Version 1.3.1093.1 driven by R Version 4.0.3. All code and phenotypes are available at github.com/BHFDSC/CCU002_02.

Deviations from prespecified protocol

In this paper, we concentrate on the effects of first COVID-19 vaccination on major thrombotic events. The results of analyses on thrombotic events after COVID infection and second vaccination will be presented in future papers.

Results

On 8 December 2020, 46,162,942 eligible adults were registered with an English general practice. By 18 March 2021, 21,193,814 (46%) had received their first vaccination (8,712,477 BNT162b2; 12,481,337 ChAdOx1-S) (S1 Fig). Postvaccination person-years of follow-up for ages <40, 40 to 69, and ≥70 years, respectively, were for ChAdOx1-S: 96,745, 455,122, and 418,942 person-years; for BNT162b2: 165,815, 466,025, and 603,436 person-years. Total unvaccinated follow-up time for ages <40, 40 to 69, and ≥70 years was 4,529,022, 5,026,046, and 1,008,498 person-years, respectively. The median follow-up per person was 101 days.

The risks per 100,000 persons from 8 December 2020 to 18 March 2021 were for the following: any venous thrombosis 45.3; any arterial thrombosis 189; thrombocytopenia 4.2 (Table 1, age-stratified estimates S1 Table). Risks of venous and arterial thromboses were higher in people with comorbidities and with increasing age and deprivation, and varied substantially by ethnicity. Absolute and relative increases in risk with increasing age and deprivation were greater for arterial than for venous thromboses. The risk per 100,000 people during follow-up of venous thromboses was higher in people with prior DVT or PE (541), thrombophilia (327), or oral anticoagulant medication (170), while the risk of arterial thromboses was higher in people with prior stroke (2,955), MI (2,036), or antiplatelet medication (1,451). The risk of thrombocytopenia increased with age and comorbidities but varied less markedly with ethnicity and deprivation than the risk of venous or arterial thromboses.

Table 1. Numbers of patients analysed and (in parentheses) risk per 100,000 people for the whole population during follow-up of venous and arterial events and TCP.

Overall
All Venous Arterial TCP
N 46,162,942 20,903 (45.3) 87,251 (189) 1,926 (4.2)
Sex Male 22,765,779 10,358 (45.5) 51,851 (228) 986 (4.3)
Female 23,397,163 10,545 (45.1) 35,400 (151) 940 (4.0)
Age 18–29 8,821,973 781 (8.9) 400 (4.5) 143 (1.6)
30–49 16,131,025 3,544 (22.0) 6,424 (39.8) 338 (2.1)
50–69 13,791,173 7,510 (54.5) 31,459 (228) 686 (5.0)
70–79 4,674,973 4,820 (103) 22,249 (476) 418 (8.9)
80+ 2,743,798 4,248 (155) 26,719 (974) 341 (12.4)
Ethnicity Asian or Asian British 3,718,442 599 (16.1) 5,325 (143) 152 (4.1)
Black or Black British 1,634,470 654 (40.0) 2,086 (128) 58 (3.5)
Mixed 712,534 182 (25.5) 642 (90.1) 22 (3.1)
Other ethnic groups 1,497,133 217 (14.5) 1,072 (71.6) 39 (2.6)
White 36,446,855 18,995 (52.1) 77,118 (212) 1,643 (4.5)
Unknown or missing 2,153,508 256 (11.9) 1,008 (46.8) 12 (0.6)
Deprivation1 1–2 9,118,746 4,565 (50.1) 18,830 (206) 365 (4.0)
3–4 9,567,633 4,105 (42.9) 17,436 (182) 370 (3.9)
5–6 9,355,549 4,091 (43.7) 17,642 (189) 392 (4.2)
7–8 9,076,313 4,146 (45.7) 16,939 (187) 381 (4.2)
9–10 8,772,902 3,926 (44.8) 16,024 (183) 406 (4.6)
Smoking status Current 7,814,045 3,079 (39.4) 16,115 (206) 260 (3.3)
Former 10,623,072 6,930 (65.2) 31,768 (299) 581 (5.5)
Never 25,722,494 10,667 (41.5) 38,701 (150) 1,053 (4.1)
Medical history Stroke 727,218 1,020 (140) 21,489 (2,955) 104 (14.3)
MI 1,189,182 1,436 (121) 24,212 (2,036) 158 (13.3)
DVT or PE 603,351 3,263 (541) 4,050 (671) 142 (23.5)
Thrombophilia 44,593 146 (327) 202 (453) 23 (51.6)
Coronavirus infection2 1,284,984 1,131 (88.0) 4,167 (324) 101 (7.9)
Diabetes 4,069,412 3,654 (89.8) 25,595 (629) 423 (10.4)
Depression 9,516,020 6,272 (65.9) 24,146 (254) 500 (5.3)
Obesity 10,918,274 8,863 (81.2) 31,194 (286) 679 (6.2)
Cancer 6,609,691 5,674 (85.8) 17,827 (270) 786 (11.9)
COPD 1,582,366 2,497 (158) 12,323 (779) 182 (11.5)
Liver disease 230,243 284 (123) 1,069 (464) 97 (42.1)
CKD 2,934,107 4,467 (152) 25,816 (880) 526 (17.9)
Major surgery3 3,995,870 5,407 (135) 24,164 (605) 763 (19.1)
Dementia 524,293 1,127 (215) 6,073 (1,158) 45 (8.6)
Medications Antiplatelet 2,510,382 2,814 (112) 36,415 (1,451) 218 (8.7)
BP lowering 8,589,860 7,969 (92.8) 55,462 (646) 777 (9.0)
Lipid lowering 6,808,408 5,796 (85.1) 47,859 (703) 564 (8.3)
Anticoagulant 1,338,585 2,278 (170) 12,758 (953) 205 (15.3)
Oral contraceptive 622,529 138 (22.2) 42 (6.7) 8 (1.3)
HRT 540,722 213 (39.4) 516 (95.4) 16 (3.0)
Number of diagnoses 0 36,455,307 12,200 (33.5) 38,617 (106) 980 (2.7)
1–5 9,573,068 8,422 (88.0) 46,012 (481) 925 (9.7)
6+ 134,567 281 (209) 2,622 (1948) 21 (15.6)
Number of medications 0 22,970,920 3,679 (16.0) 9,629 (41.9) 321 (1.4)
1–5 20,875,516 12,872 (61.7) 56,255 (269) 1,210 (5.8)
6+ 2,316,506 4,352 (188) 21,367 (922) 395 (17.1)
Open in a new tab

1Index of Multiple Deprivation deciles where 10 indicates least deprived and 1 indicates most deprived.

2After 31 December 2019 and prior to 8 December 2020.

3In the last year.

BP, blood pressure; CKD, chronic kidney disease; COPD, chronic obstructive respiratory disease; DVT, deep vein thrombosis; HRT, hormone replacement therapy; MI, myocardial infarction; PE, pulmonary embolism; TCP, thrombocytopenia.

The additional confounding factors selected using backward selection were as follows: for both sexes and age strata, previous diagnosis of cancer, number of unique diseases in the last year, surgery in the last year, obesity, liver disease; additionally for women aged <70, history of depression, and total number of types of medication (by BNF chapters); additionally for men aged <70, history of SARS-CoV-2 infection and thrombocytopenia; and additionally for men and women aged ≥70, chronic kidney disease, and dementia.

The crude incidence rates of all events varied substantially in unvaccinated and postvaccination (Tables 2 and 3 age-stratified estimates S1 Table), and the crude HRs comparing incidence rates after with before vaccination were substantially attenuated after adjusting for age and further attenuated after adjusting for confounding factors. For example, in <70-year-olds, the HRs 1 to 28 days after vaccination with ChAdOx1-S versus unvaccinated were attenuated from 2.81 (unadjusted) to 2.27 (adjusted) for ICVT; from 4.85 to 1.71 for thrombocytopenia; and from 3.21 to 0.90 for ischaemic stroke (Tables 4 and 5).

Table 2. Numbers and incidence rates pre- and post-first ChAdOx1-S.

Incidence rate per 100,000 person years. Disclosure control prevents presentation of n > 5.

Prevaccination or unvaccinated Postvaccination ≤28 days Postvaccination >28 days
Outcome N (events) Incidence rate (95% CI) N (events) Incidence rate (95% CI) N (events) Incidence rate (95% CI)
All venous 14,769 139.8 (137.6–142.1) 2,006 293.6 (281.0–306.7) 995 359.3 (337.6–382.3)
ICVT 207 1.96 (1.71–2.25) 27 3.95 (2.71–5.76) 9 3.25 (1.69–6.24)
Portal vein thrombosis 121 1.15 (0.96–1.37) 14 2.05 (1.21–3.46) 9 3.25 (1.69–6.24)
PE 8,473 80.2 (78.5–81.9) 1,203 176.0 (166.4–186.3) 587 211.9 (195.4–229.7)
DVT 5,664 53.6 (52.2–55.0) 739 108.1 (100.6–116.2) 374 135.0 (122.0–149.4)
Other 459 4.35 (3.97–4.76) 51 7.46 (5.67–9.82) 30 10.8 (7.6–15.5)
All arterial 57,602 545.6 (541.1–550.0) 8,256 1,210.6 (1184.8–1237.0) 4,634 1,677.8 (1630.2–1726.8)
MI 28,134 266.4 (263.3–269.5) 3,814 558.5 (541.1–576.5) 2,050 740.7 (709.4–773.5)
Ischaemic stroke (ischaemic, unknown, spinal) 28,639 271.2 (268.1–274.3) 4,334 634.8 (616.1–654.0) 2,539 917.9 (882.9–954.3)
Other arterial 1,308 12.4 (11.7–13.1) 189 27.6 (24.0–31.9) 98 35.4 (29.0–43.1)
Haematological    
DIC 13 0.12 (0.07–0.21) <5 0.44 (0.14–1.36) <5 -
TTP 70 0.66 (0.52–0.84) <5 0.59 (0.22–1.56) <5 0.72 (0.18–2.89)
Any thrombocytopenia 1,357 12.8 (12.2–13.5) 200 29.3 (25.5–33.6) 89 32.1 (26.1–39.5)
Other    
Haemorrhagic stroke (intracerebral or subarachnoid) 3,747 35.5 (34.4–36.6) 487 71.2 (65.2–77.9) 289 104.3 (92.9–117.0)
Mesenteric thrombosis 1,170 11.1 (10.5–11.7) 171 25.0 (21.5–29.1) 109 39.3 (32.6–47.5)
Lower limb fracture 18,347 173.7 (171.2–176.3) 2,657 389.0 (374.5–404.0) 1,632 589.7 (561.7–619.0)
Death 123,580 1,169.9 (1163.4–1176.4) 16,192 2,368.5 (2332.3–2405.2) 11,738 4,235.1 (4159.2–4312.4)
Open in a new tab

DIC, disseminated intravascular coagulation; DVT, deep vein thrombosis; ICVT, intracranial venous thrombosis; MI, myocardial infarction; PE, pulmonary embolism; TTP, thrombotic thrombocytopenic purpura.

Table 3. Numbers and incidence rates pre- and post-first BNT162b2. Incidence rate per 100,000 person years.

Disclosure control prevents presentation of n > 5.

Prevaccination or unvaccinated Postvaccination ≤28 days Postvaccination >28 days
Outcome N (events) Incidence rate (95% CI) N (events) Incidence rate (95% CI) N (events) Incidence rate (95% CI)
All venous 14,769 139.8 (137.6–142.1) 1,546 240.8 (229.1–253.1) 1,587 277.1 (263.8–291.0)
ICVT 207 1.96 (1.71–2.25) 13 2.02 (1.18–3.49) 6 1.05 (0.47–2.33)
Portal vein thrombosis 121 1.15 (0.96–1.37) 5 0.78 (0.32–1.87) 12 2.09 (1.19–3.69)
PE 8,473 80.2 (78.5–81.9) 928 144.5 (135.5–154.1) 955 166.7 (156.5–177.6)
DVT 5,664 53.6 (52.2–55.0) 555 86.4 (79.5–93.9) 590 103.0 (95.0–111.6)
Other 459 4.35 (3.97–4.76) 55 8.56 (6.58–11.15) 39 6.81 (4.97–9.31)
All arterial 57,602 545.6 (541.1–550.0) 7,960 1,241.8 (1214.9–1269.4) 8,799 1,539.7 (1507.8–1572.2)
MI 28,134 266.4 (263.3–269.5) 3,722 580.1 (561.8–599.0) 4,023 702.9 (681.5–724.9)
Ischaemic stroke (ischaemic, unknown, spinal) 28,639 271.2 (268.1–274.3) 4,143 645.7 (626.4–665.7) 4,702 821.8 (798.6–845.6)
Other arterial 1,308 12.4 (11.7–13.1) 156 24.3 (20.8–28.4) 167 29.1 (25.0–33.9)
Haematological  
DIC 13 0.12 (0.07–0.21) <5 0.31 (0.08–1.25) <5 0.35 (0.09–1.40)
TTP 70 0.66 (0.52–0.84) <5 0.62 (0.23–1.66) <5 0.35 (0.09–1.40)
Any thrombocytopenia 1,357 12.8 (12.2–13.5) 136 21.2 (17.9–25.1) 144 25.1 (21.3–29.6)
Other  
Haemorrhagic stroke (intracerebral or subarachnoid) 3,747 35.5 (34.4–36.6) 440 68.5 (62.4–75.2) 579 101.0 (93.1–109.6)
Mesenteric thrombosis 1,170 11.1 (10.5–11.7) 161 25.1 (21.5–29.3) 217 37.9 (33.2–43.3)
Lower limb fracture 18,347 173.7 (171.2–176.3) 2,573 400.8 (385.6–416.6) 3,176 554.7 (535.8–574.4)
Death 123,580 1,169.9 (1163.4–1176.4) 9,117 1,419.6 (1390.8–1449.0) 13,935 2,431.7 (2391.7–2472.4)
Open in a new tab

CI, confidence interval; DIC, disseminated intravascular coagulation; DVT, deep vein thrombosis; ICVT, intracranial venous thrombosis; MI, myocardial infarction; PE, pulmonary embolism; TTP, thrombotic thrombocytopenic purpura.

Table 4. HRs (95% CIs) for thrombotic and other outcomes 1–28 and >28 days postvaccination with ChAdOx1-S vaccine, compared with prevaccination rates.

All analyses were stratified on geographical region.

Outcome Age 1–28 days postvaccination >28 days postvaccination
Unadjusted1 Age and sex adjusted2 Fully adjusted3 Unadjusted1 Age and sex adjusted2 Fully adjusted3
All venous events <70 2.33 (2.16–2.51) 1.32 (1.22–1.43) 0.97 (0.90–1.05) 2.74 (2.39–3.14) 1.60 (1.38–1.84) 0.94 (0.81–1.08)
≥70 0.65 (0.59–0.72) 0.64 (0.59–0.70) 0.58 (0.53–0.63) 0.67 (0.59–0.76) 0.58 (0.52–0.65) 0.49 (0.44–0.55)
ICVT <70 2.81 (1.70–4.64) 2.99 (1.75–5.09) 2.27 (1.33–3.88) 2.37 (0.91–6.12) 2.47 (0.95–6.42) 1.72 (0.66–4.49)
≥70 0.62 (0.17–2.23) 0.65 (0.19–2.21) 0.67 (0.20–2.18) 1.35 (0.13–13.46) 1.13 (0.14–9.20) 1.11 (0.14–9.02)
Portal vein thrombosis <70 2.49 (1.20–5.14) 1.56 (0.72–3.40) 1.00 (0.24–4.15) 2.76 (0.73–10.51) 1.99 (0.53–7.52) 1.00 (0.06–18.18)
≥70 0.66 (0.11–4.06) 0.67 (0.10–4.24) 0.61 (0.10–3.71) 2.72 (0.49–15.02) 3.00 (0.48–18.99) 2.61 (0.41–16.52)
PE <70 2.54 (2.30–2.80) 1.28 (1.15–1.43) 0.95 (0.85–1.05) 3.12 (2.61–3.73) 1.63 (1.34–1.96) 0.95 (0.79–1.15)
≥70 0.62 (0.55–0.70) 0.60 (0.54–0.68) 0.54 (0.48–0.61) 0.61 (0.52–0.72) 0.54 (0.46–0.62) 0.45 (0.39–0.53)
DVT <70 2.08 (1.85–2.34) 1.34 (1.18–1.52) 0.99 (0.87–1.12) 2.37 (1.90–2.96) 1.58 (1.25–1.99) 0.97 (0.77–1.22)
≥70 0.73 (0.62–0.86) 0.71 (0.61–0.83) 0.63 (0.54–0.74) 0.71 (0.57–0.88) 0.62 (0.51–0.75) 0.51 (0.42–0.62)
Other <70 2.48 (1.70–3.62) 1.60 (1.06–2.40) 1.02 (0.69–1.52) 3.04 (1.54–6.00) 2.04 (1.01–4.09) 0.94 (0.47–1.91)
≥70 0.46 (0.21–1.01) 0.46 (0.21–0.99) 0.43 (0.20–0.92) 1.13 (0.50–2.54) 1.03 (0.48–2.21) 0.93 (0.42–2.03)
All arterial events <70 3.02 (2.90–3.14) 1.25 (1.20–1.31) 0.90 (0.86–0.95) 3.55 (3.29–3.83) 1.57 (1.45–1.70) 0.91 (0.84–1.00)
≥70 0.89 (0.85–0.93) 0.84 (0.80–0.87) 0.76 (0.73–0.79) 1.03 (0.97–1.10) 0.83 (0.78–0.87) 0.72 (0.68–0.77)
MI <70 2.85 (2.70–3.01) 1.24 (1.17–1.32) 0.88 (0.83–0.94) 2.93 (2.63–3.26) 1.40 (1.24–1.56) 0.83 (0.73–0.93)
≥70 0.86 (0.80–0.92) 0.83 (0.78–0.88) 0.76 (0.71–0.81) 0.97 (0.89–1.07) 0.83 (0.76–0.90) 0.74 (0.68–0.81)
Ischaemic stroke4 <70 3.21 (3.02–3.41) 1.25 (1.17–1.34) 0.90 (0.84–0.96) 4.36 (3.91–4.86) 1.76 (1.56–1.98) 0.94 (0.84–1.07)
≥70 0.92 (0.87–0.98) 0.85 (0.81–0.90) 0.77 (0.73–0.82) 1.08 (0.99–1.18) 0.83 (0.77–0.90) 0.72 (0.67–0.78)
Other arterial <70 3.18 (2.48–4.07) 1.24 (0.93–1.64) 0.82 (0.63–1.07) 4.20 (2.62–6.73) 1.68 (0.99–2.86) 0.77 (0.46–1.30)
≥70 0.44 (0.33–0.59) 0.45 (0.34–0.59) 0.41 (0.31–0.53) 0.55 (0.38–0.79) 0.49 (0.35–0.70) 0.44 (0.31–0.63)
Haematological events
Any thrombocytopenia <70 4.85 (3.87–6.07) 3.00 (2.34–3.85) 1.71 (1.35–2.16) 7.48 (5.31–10.53) 4.68 (3.24–6.77) 1.69 (1.16–2.46)
≥70 0.92 (0.65–1.29) 0.87 (0.63–1.22) 0.79 (0.56–1.10) 1.14 (0.66–1.95) 0.99 (0.59–1.65) 0.84 (0.50–1.41)
Other events
Haemorrhagic stroke5 <70 2.25 (1.88–2.69) 1.05 (0.86–1.27) 1.00 (0.73–1.37) 2.87 (2.10–3.92) 1.39 (1.00–1.93) 1.00 (0.51–1.95)
≥70 0.83 (0.69–1.00) 0.78 (0.66–0.92) 0.73 (0.62–0.87) 1.09 (0.84–1.40) 0.84 (0.67–1.04) 0.76 (0.61–0.95)
Mesenteric thrombosis <70 3.25 (2.42–4.37) 1.24 (0.89–1.73) 0.84 (0.61–1.16) 5.47 (3.33–8.99) 2.16 (1.24–3.77) 1.04 (0.60–1.80)
≥70 0.66 (0.49–0.89) 0.60 (0.46–0.79) 0.53 (0.41–0.70) 0.95 (0.64–1.43) 0.74 (0.52–1.05) 0.62 (0.43–0.89)
Lower limb fracture <70 1.71 (1.55–1.87)
 1.01 (0.91–1.11) 0.85 (0.77–0.93) 2.26 (1.91–2.67) 1.35 (1.13–1.60) 0.98 (0.83–1.17)
≥70 1.11 (1.02–1.21) 0.94 (0.88–1.01) 0.83 (0.78–0.89) 1.56 (1.39–1.76) 0.95 (0.87–1.04) 0.78 (0.71–0.85)
Death <70 1.96 (1.87–2.06) 0.60 (0.57–0.63) 0.37 (0.35–0.39) 4.51 (4.20–4.85) 1.41 (1.30–1.53) 0.51 (0.47–0.56)
≥70 0.35 (0.34–0.36) 0.34 (0.33–0.35) 0.28 (0.28–0.29) 0.49 (0.47–0.51) 0.38 (0.37–0.39) 0.27 (0.26–0.28)
Open in a new tab

1Stratifed by region.

2Adjusted for age, age2, sex, and stratified by region.

3Adjusted for age, age2, sex, ethnicity, deprivation, smoking, previous diagnosis of cancer, number of unique diseases in the last year, surgery in the last year, obesity, liver disease; additionally for women aged <70, history of depression and total number of types of medication (by BNF chapters); additionally for men aged <70, history of SARS-CoV2 infection and thrombocytopenia; and additionally for men and women aged ≥70, chronic kidney disease and dementia. Venous events adjusted for: anticoagulant medication, combined oral contraceptive medication, hormone replacement therapy medication, history of PE or DVT, and history of coronavirus infection. Arterial thromboses adjusted for: diabetes, hypertension, smoking, antiplatelet medication, blood pressure lowering medication, lipid lowering medication, anticoagulant medication, history of stroke, and history of MI. All analyses stratified by region.

4Ischaemic stroke: including ischaemic stroke, stroke of uncertain cause, and spinal stroke.

5Haemorrhagic stroke: including intracranial haemorrhage and subarachnoid haemorrhage.

BNF, British National Formulary; CI, confidence interval; DVT, deep vein thrombosis; HR, hazard ratio; ICVT, intracranial venous thrombosis; MI, myocardial infarction; PE, pulmonary embolism; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

Table 5. HRs (95% CIs) for thrombotic and other outcomes 1–28 and >28 days postvaccination with BNT162b2 vaccine, compared with prevaccination rates.

All analyses were stratified on geographical region.

Outcome Age 1–28 days postvaccination >28 days postvaccination
Unadjusted1 Age and sex adjusted2 Fully adjusted3 Unadjusted1 Age and sex adjusted2 Fully adjusted3
All venous events <70 1.47 (1.35–1.61) 1.01 (0.93–1.11) 0.81 (0.74–0.88) 1.14 (1.01–1.29) 0.88 (0.77–1.00) 0.73 (0.64–0.83)
≥70 0.65 (0.60–0.71) 0.56 (0.52–0.61) 0.57 (0.53–0.62) 0.68 (0.62–0.75) 0.50 (0.46–0.55) 0.50 (0.45–0.55)
ICVT <70 0.76 (0.31–1.85) 0.72 (0.29–1.78) 0.59 (0.24–1.45) 0.65 (0.20–2.13) 0.59 (0.18–1.93) 0.51 (0.16–1.68)
≥70 1.65 (0.64–4.29) 1.25 (0.48–3.26) 1.43 (0.55–3.75) 1.13 (0.13–9.75) 0.71 (0.08–6.56) 0.88 (0.10–7.52)
Portal vein thrombosis <70 0.58 (0.15–2.30) 0.44 (0.11–1.72) 0.29 (0.07–1.17) 3.06 (1.29–7.24) 2.84 (1.19–6.74) 2.19 (0.89–5.37)
≥70 0.49 (0.10–2.28) 0.43 (0.10–1.87) 0.42 (0.09–1.91) 0.67 (0.23–1.97) 0.54 (0.19–1.56) 0.48 (0.17–1.38)
PE <70 1.52 (1.36–1.71) 0.99 (0.87–1.11) 0.78 (0.69–0.88) 1.20 (1.02–1.43) 0.89 (0.75–1.06) 0.71 (0.60–0.85)
≥70 0.61 (0.55–0.68) 0.53 (0.48–0.59) 0.54 (0.49–0.60) 0.61 (0.54–0.69) 0.45 (0.40–0.51) 0.45 (0.39–0.50)
DVT <70 1.38 (1.21–1.59) 1.03 (0.89–1.18) 0.82 (0.71–0.95) 1.05 (0.86–1.28) 0.85 (0.69–1.04) 0.73 (0.59–0.89)
≥70 0.69 (0.60–0.79) 0.58 (0.51–0.67) 0.61 (0.53–0.70) 0.81 (0.69–0.96) 0.59 (0.50–0.70) 0.61 (0.52–0.73)
Other <70 2.16 (1.47–3.19) 1.60 (1.07–2.37) 1.18 (0.79–1.77) 1.64 (0.93–2.90) 1.34 (0.75–2.40) 1.03 (0.57–1.87)
≥70 1.13 (0.66–1.94) 0.97 (0.58–1.64) 1.01 (0.60–1.72) 0.86 (0.39–1.88) 0.66 (0.31–1.41) 0.67 (0.30–1.47)
All arterial events <70 2.21 (2.12–2.31) 1.31 (1.25–1.37) 0.94 (0.90–0.99) 1.45 (1.35–1.55) 1.08 (1.01–1.16) 0.88 (0.82–0.95)
≥70 0.90 (0.87–0.93) 0.69 (0.66–0.71) 0.72 (0.70–0.75) 1.15 (1.10–1.20) 0.69 (0.66–0.72) 0.71 (0.68–0.74)
MI <70 2.24 (2.12–2.37) 1.39 (1.30–1.47) 0.94 (0.88–1.00) 1.42 (1.29–1.55) 1.14 (1.04–1.26) 0.88 (0.80–0.97)
≥70 0.93 (0.88–0.98) 0.74 (0.71–0.78) 0.74 (0.70–0.78) 1.19 (1.12–1.27) 0.78 (0.73–0.83) 0.75 (0.70–0.80)
Ischaemic stroke4 <70 2.18 (2.05–2.33) 1.23 (1.14–1.31) 0.90 (0.83–0.97) 1.46 (1.32–1.62) 1.00 (0.89–1.11) 0.80 (0.72–0.90)
≥70 0.88 (0.84–0.93) 0.65 (0.63–0.68) 0.71 (0.68–0.75) 1.13 (1.06–1.19) 0.64 (0.60–0.67) 0.69 (0.66–0.73)
Other arterial <70 1.72 (1.28–2.31) 0.95 (0.70–1.30) 0.69 (0.50–0.94) 1.63 (1.10–2.43) 1.13 (0.74–1.72) 0.85 (0.55–1.32)
≥70 0.59 (0.46–0.76) 0.51 (0.40–0.65) 0.52 (0.41–0.67) 0.64 (0.47–0.85) 0.47 (0.35–0.62) 0.46 (0.34–0.62)
Haematological events
Any thrombocytopenia <70 2.10 (1.60–2.77) 1.48 (1.11–1.97) 1.00 (0.75–1.34) 2.03 (1.42–2.92) 1.54 (1.07–2.23) 0.97 (0.66–1.41)
≥70 0.85 (0.64–1.13) 0.72 (0.54–0.95) 0.68 (0.51–0.90) 1.22 (0.87–1.71) 0.90 (0.64–1.25) 0.79 (0.56–1.12)
Other events
Haemorrhagic stroke5 <70 1.39 (1.13–1.71) 0.83 (0.67–1.03) 0.77 (0.62–0.96) 1.31 (1.00–1.73) 0.90 (0.68–1.19) 0.86 (0.65–1.15)
≥70 0.80 (0.69–0.91) 0.59 (0.52–0.68) 0.65 (0.57–0.74) 1.28 (1.09–1.50) 0.72 (0.62–0.84) 0.80 (0.68–0.94)
Mesenteric thrombosis <70 1.61 (1.10–2.36) 0.84 (0.56–1.26) 0.65 (0.43–0.97) 1.77 (1.11–2.84) 1.08 (0.66–1.75) 0.83 (0.50–1.37)
≥70 0.72 (0.57–0.90) 0.54 (0.43–0.67) 0.54 (0.44–0.68) 1.06 (0.81–1.37) 0.61 (0.48–0.78) 0.59 (0.45–0.76)
Lower limb fracture <70 1.44 (1.31–1.59) 1.03 (0.93–1.14) 0.93 (0.84–1.02) 1.24 (1.08–1.42) 0.95 (0.83–1.09) 0.89 (0.78–1.03)
≥70 0.99 (0.93–1.05) 0.65 (0.62–0.69) 0.69 (0.66–0.73) 1.48 (1.38–1.59) 0.67 (0.63–0.72) 0.71 (0.66–0.76)
Death <70 0.74 (0.69–0.79) 0.35 (0.32–0.37) 0.24 (0.22–0.26) 0.91 (0.84–1.00) 0.52 (0.48–0.57) 0.33 (0.30–0.37)
≥70 0.22 (0.22–0.23) 0.16 (0.16–0.16) 0.19 (0.19–0.20) 0.30 (0.29–0.31) 0.16 (0.16–0.16) 0.19 (0.18–0.19)
Open in a new tab

1Stratifed by region.

2Adjusted for age, age2, sex, and stratified by region.

3Adjusted for age, age2, sex, ethnicity, deprivation, smoking, previous diagnosis of cancer, number of unique diseases in the last year, surgery in the last year, obesity, liver disease; additionally for women aged <70, history of depression and total number of types of medication (by BNF chapters); additionally for men aged <70, history of SARS-CoV2 infection and thrombocytopenia; and additionally for men and women aged ≥70, chronic kidney disease and dementia. Venous events adjusted for: anticoagulant medication, combined oral contraceptive medication, hormone replacement therapy medication, history of PE or DVT, and history of coronavirus infection. Arterial thromboses adjusted for: diabetes, hypertension, smoking, antiplatelet medication, blood pressure lowering medication, lipid lowering medication, anticoagulant medication, history of stroke, and history of MI. All analyses stratified by region.

4Ischaemic stroke: including ischaemic stroke, stroke of uncertain cause, and spinal stroke.

5Hemorrhagic stroke: including intracranial haemorrhage and subarachnoid haemorrhage.

BNF, British National Formulary; CI, confidence interval; DVT, deep vein thrombosis; HR, hazard ratio; ICVT, intracranial venous thrombosis; MI, myocardial infarction; PE, pulmonary embolism; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

In people aged <70 years, the fully adjusted HR for any venous thrombosis was 0.97 (95% confidence interval (CI): 0.90 to 1.05) 1 to 28 days after ChAdOx1-S compared with before vaccination, with similar aHRs for PE and DVT. Compared with before vaccination, the hazard of any venous thrombosis was lower 1 to 28 days after ChAdOx1-S in people aged ≥70 (aHR 0.58, 95% CI: 0.53 to 0.63) and 1 to 28 days after BNT162b2 (<70: HR 0.81, 0.74 to 0.88; ≥70 HR: 0.57, 0.53 to 0.62), with similar aHRs for PE and DVT. (Fig 1, Tables 4 and 5).

Fig 1. aHRs for all venous thromboses, intracranial venous thromboses, PE, and deep vein thromboses after ChAdOx1-S or BNT162b2 vaccine.

Fig 1

Open in a new tab

aHR, adjusted HR; CI, confidence interval; PE, pulmonary embolism.

In people aged <70 years, aHRs for ICVT were 2.27 (95% CI: 1.32 to 3.88) 1 to 28 days after ChAdOx1-S and 0.59 (0.24 to 1.45) 1 to 28 days after BNT162b2 compared with before vaccination. HRs were similar in men and women (Fig 1, Tables 4 and 5). In a post hoc analyses, in people aged <40 years, the aHRs for ICVT 1 to 28 days after vaccination were 3.73 (1.58 to 8.83) and 1.07 (0.33 to 3.48) for ChAdOx1-S and BNT162b2, respectively, compared with before vaccination. The same estimates for people 40 to 69 years were 1.93 (1.19 to 2.13) and 0.74 (0.29 to 1.87). In people aged ≥70 years, associations of vaccination with ICVT were estimated imprecisely (<10 events for ChAdOx1-S and 8 for BNT162b2).

aHRs for any arterial thrombosis 1 to 28 days after ChAdOx1-S were 0.90 (95% CI: 0.86 to 0.95) and 0.76 (0.73 to 0.79) in people aged <70 and ≥70 years, respectively, compared with before vaccination. Corresponding aHRs 1 to 28 days after BNT162b2 were 0.94 (0.90 to 0.99) and 0.72 (0.70 to 0.75). HRs were similar for MI and ischaemic stroke, and >28 days after vaccination (Fig 2, Tables 4 and 5).

Fig 2.

Fig 2

Open in a new tab

aHRs for all arterial thromboses, MI, ischaemic stroke, and other arterial thromboses after ChAdOx1-S or BNT162b2 vaccine. aHR, adjusted HR; CI, confidence interval; MI, myocardial infarction.

In people aged <70 years, aHRs for thrombocytopenia were 1.71 (95% CI:1.35 to 2.16) 1 to 28 days and 1.69 (1.16 to 2.46) >28 days after ChAdOx1-S compared with before vaccination. Corresponding HRs after BNT162b2 were 1.00 (0.75 to 1.34) and 0.97 (0.66 to 1.41). For those aged ≥70 years, aHRs for thrombocytopenia 1 to 28 days after vaccination were similar for ChAdOx1 (0.79, 95% CI: 0.56 to 1.10) and BNT162b2 (0.68, 0.51 to 0.90) (Fig 3, Tables 4 and 5).

Fig 3. aHRs for thrombocytopenia, haemorrhagic stroke, mesenteric thrombosis, and lower limb fracture after ChAdOx1-S or BNT162b2 vaccine.

Fig 3

Open in a new tab

CI, confidence interval.

aHRs for the control condition lower limb fracture 1 to 28 days after ChAdOx1-S were 0.85 (95% CI: 0.77 to 0.93), and 0.83 (0.78 to 0.89) in people aged <70 and ≥70 years, respectively, compared with before vaccination. Corresponding aHRs after BNT162b2 were 0.93 (0.84 to 1.02) and 0.69 (0.66 to 0.73). (Fig 3, Tables 4 and 5). aHRs for all-cause mortality 1 to 28 days after ChAdOx1-S were 0.37 (95% CI: 0.35 to 0.39), and 0.28 (0.28 to 0.29) in people aged <70 and ≥70 years, respectively. Corresponding aHRs after BNT162b2 were 0.24 (0.22 to 0.26) and 0.19 (0.19 to 0.20) (S2 Fig, Tables 4 and 5).

Subgroup analyses

aHRs for all venous and for all arterial thrombotic events 1 to 28 days after vaccination compared with before vaccination were lower in older age groups for each vaccine (all interaction p-values <0.001) (S2 Table). HRs for venous thromboses were >1 1 to 28 days after compared with before vaccination in people aged <50 years for ChAdOx1-S but not BNT162b2. aHRs for arterial thromboses were >1 1 to 28 days after compared with before vaccination in people aged <50 years for both ChAdOx1-S and BNT162b2. Less marked trends for lower HRs in older individuals were observed for HRs >28 days after vaccination. A higher proportion of venous thromboses in those aged <40 years (7%) compared with those aged ≥40 years were due to ICVT (40 to 59: 1.6%, 60 to 69: 0.9%, and 70+: 0.5%). A higher proportion of arterial thromboses at age <40 (49%) was due to stroke than at ages 40 to 59 (40%) and 60 to 69 (44%) years.

Despite modest differences between the magnitude of HRs in subgroups defined by sex, ethnicity, prior COVID, COCP, diabetes, deprivation or history of MI, DVT, or PE, anticoagulation or antiplatelet medication, aHRs in all of these subgroups were consistent with lower rates of arterial or venous thromboses after vaccination with ChAdOx1-S or BNT162b2 (S2 Table).

Sensitivity analyses

When using a less restrictive outcome definition (outcomes recorded as primary or secondary reason for admission or death), aHRs were consistent with those from analyses of outcomes in the primary position (S3 Fig). Similarly, aHRs for fatal outcomes were similar to HRs for fatal or nonfatal outcomes (S4 Fig). There were very few people for whom outcomes in the primary position were recorded as well as thrombocytopenia in any position in the same hospital admission or death record (after ChAdOx1-S and BNT162b, respectively: ICVT 7 and 0; all arterial thromboses 47 and 58; all venous thromboses 37 and 26).

Intracranial venous thrombosis

Characteristics were similar among patients who developed ICVT while unvaccinated, after ChAdOx1 and after BNT162b. Most were women (60% unvaccinated, 67% ChAdOx1, 79% BNT162b), of white ethnicity (75% unvaccinated, 92% ChAdOx1, 100% BNT162b), and had no prior comorbidities (71% unvaccinated, 50% ChAdOx1, 50% BNT162b). Patients with postvaccination ICVT were older than those with unvaccinated ICVT. Postvaccination, no patients had a recorded history of thrombophilia, and fewer than 5% had a recorded dispensed prescription of oral contraceptive or HRT (S3 Table).

Applying the aHR for ICVT 1 to 28 days after ChAdOx1 to the monthly incidence of ICVT in 2019, the excess risk of ICVT in the month after vaccination with ChAdOx1 among those aged 19 to 30, 31 to 39, 40 to 49, 50 to 59, and 60 to 69 years was estimated to be, respectively: 0.9, 1.1, 1.5, 1.5, and 1.6 per million vaccinated in men and 3.0, 2.7, 2.0, 1.6, and 1.5 per million vaccinated in women.

Discussion

In this cohort study, which included almost all adults alive in England at the start of the national COVID-19 vaccination programme, vaccination with ChAdOx1-S, but not BNT162b2, was associated with approximately 2-fold higher rates of ICVT or hospitalisations due to thrombocytopenia in people aged under 70 years, after adjusting for a comprehensive range of demographic characteristics and comorbidities. The corresponding absolute increases in the risk of these events were very small. ChAdOx1-S and BNT162b2 were associated with lower hazards of major vascular events after vaccination in those aged ≥70 years. Post hoc analyses stratified by age suggest that in people aged <50 years, rates of venous thromboses were higher 1 to 28 days after vaccination with ChAdOx1-S, and that rates of arterial thrombotic events were higher 1 to 28 days after vaccination with ChAdOx1-S or BNT162b2, compared with rates in unvaccinated people.

The large population analysed adds substantial precision to estimated associations of thromboses with vaccination, which is of particular importance for very rare events and associations in subgroups. The extensive data linkages across different healthcare settings enabled adjustment for a wide range of confounding variables. The analysed population is slightly larger than the midyear estimate of the 2020 English population aged ≥18 (44,456,850) that excluded short-term residents and students, and modelled international migrant numbers [12].

Our findings are generally consistent with other studies. Smaller Danish and Norwegian electronic health record studies reported a small excess of intracranial haemorrhage (2 per 100,000 1 to 28 days after ChAdOx1-S), cerebral venous thrombosis (3 per 100,000), and other venous thrombosis (2 per 100,000) [13]. The randomised trials of ChAdOx1-S reported no venous thrombotic events among 8,597 participants who received the vaccine versus 2 among 8,581who received placebo [14]. A Scottish study found a risk of 1.13 (0.62 to 1.63) cases of idiopathic thrombocytopenic purpura per 100,000 after ChAdOx1-S. There was no clear evidence on other outcomes, although the number of postvaccine events was small [15]. A study with English vaccine data linked to other health records used a self-controlled case series (SCCS) analysis and found higher incidence rates following ChAdOx1 of: thrombocytopenia 8 to 14 days and 22 to 28 days postvaccine; of all venous thromboembolism 8 to 14 days postvaccine; and ICVT 8 to 14 days postvaccine (incidence rate ratio 4.01, 95% CI: 2.08 to 7.71); and following BNT162b2 of ICVT 15 to 21 days postvaccine (3.58, 1.39 to 9.27) and of ischaemic stroke 15 to 21 days postvaccine (1.12, 1.04 to 1.20) [16]. We did not find evidence of higher rates of any event in the whole population following BNT162b2. Differences between the results of this SCCS study and our findings may have arisen due to the following: differences in outcome data sources and definitions; inclusion in the SCCS study of outcomes recorded after the potential association of unusual thromboses and thrombocytopenia with COVID-19 vaccination was widely known, introducing possible diagnostic bias; and censoring by death in the SCCS study, a known limitation of the SCCS design for potentially fatal outcomes. Reporting of ICVT cases to the UK Medicines and Healthcare Products Regulatory Agency (MHRA) identified more cases of ICVT with thrombocytopenia after ChAdOx1-S than the present study (44 up to 31 March 2021) [17].

Healthcare systems planning to use ChAdOx1-S should balance the very small harms against the known benefits of the vaccine. For older populations, who are most vulnerable to COVID-19, we found no evidence of increased risk of any event with ChAdOx1-S. In younger populations, who have a lower morbidity and mortality due to COVID-19, other available vaccines might be prioritised, especially when the risk of COVID-19 is otherwise low.

Our study has several limitations. First, identification of exposures, covariates, and outcomes relies on the accuracy of data collected during routine healthcare. Additional data on results of laboratory and radiology investigations would have improved diagnostic coding, particularly for ascertainment of thrombocytopenia. Second, people who were not registered with an NHS GP (for example, the homeless, recent immigrants, those using only private healthcare, and those not eligible for NHS care) or who opted out of their data being provided to NHS Digital were excluded. Third, follow-up ended on 18 March 2021, but a small number of events that occurred before this date may have been excluded because they had yet to be coded or the people affected were still in hospital. Analyses after this date will likely lead to overestimation of associations, because speciality societies recommended further investigations of mild symptoms in vaccinated populations. Fourth, our primary outcome used the primary reason for death or hospital admission, which improves the positive predictive value but may lead to an underestimation of incidence. We believe this is necessary because historical nonincident events are frequently recorded in secondary positions. Analyses of events recorded in any position as fatal within 28 days were consistent with the primary analyses. Fifth, we did not address time-varying confounding, which can occur when factors, which vary during follow-up, such as admission to hospital, predict both vaccination and outcomes of interest. Sixth, comparison of adjusted and unadjusted associations suggests that studies that do not adjust for a comprehensive range of potential confounders will overestimate the thrombotic effects of vaccination. However, adjusted associations in this study may still be biased by unmeasured confounding by patient characteristics that predict both vaccination and thromboses and that are difficult to ascertain in electronic health records. Examples include general health at the time of vaccination, and people at higher risk of thromboses (for example, with end-stage diseases) [18]. There were slightly lower postvaccination rates of the “negative control” outcome lower limb fracture in those aged ≥70 years, which are likely due to unmeasured confounding. This implies that inverse associations of vaccination with thrombotic outcomes in that age group may also be attributable in part to unmeasured confounding.

Associations of vaccination with thromboses varied with age. This may be because in older people, small increases in the risk of major thrombotic events after vaccination with ChAdOx1-S were more than offset by reductions in major thrombotic events (particularly PE) subsequent to COVID-19. By contrast, in younger people, any increase in risk associated with ChAdOx1-S vaccine is less likely to be offset by a lower risk of COVID-associated thrombosis, because the chance of severe COVID disease is lower in younger than older individuals.

Further analyses assessing the effects of other vaccines and the effects of second doses of these vaccines on thrombotic, neurological, and cardiac complications will be important to inform vaccination programmes. Access to data from radiology or laboratory systems (which in the UK will rely on regional rather than national data collection systems) will allow more comprehensive case ascertainment and more granular phenotyping. Such efforts are currently underway across the UK.

In summary, in this study, we observed increases in rates of ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years that were small compared with its previously reported effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults <40 years are needed. For people aged ≥70 years, rates of arterial or venous thrombotic events were generally lower after either vaccine.

Supporting information

S1 Protocol. Prespecified protocol.

(PDF)

Click here for additional data file. (193.8KB, pdf)
S1 RECORD Checklist. The RECORD statement—checklist of items, extended from the STROBE statement, that should be reported in observational studies using routinely collected health data.

(DOCX)

Click here for additional data file. (19.7KB, docx)
S1 Table

Estimates for (a) age-stratified risk of venous and arterial events during follow-up; (b) age-stratified incidence of events pre- and post-first ChAdOx1-S; (c) age-stratified incidence of events pre- and post-first BNT162b2; (d) age- and sex-stratified HR of events 1–28 and >28 days post-ChAdOx1-S vaccine; and (e) age- and sex-stratified HR of events 1–28 and >28 days post-ChAdOx1-S vaccine BNT162b2 vaccine. HR, hazard ratio.

(PDF)

Click here for additional data file. (575.9KB, pdf)
S2 Table. Prespecified subgroup estimates for (a) venous and (b) arterial events.

(PDF)

Click here for additional data file. (187.8KB, pdf)
S3 Table. Characteristics of patient who had an ICVT event before and after vaccination.

Only percentage are presented, as disclosure control does not allow numbers <5 to be released. ICVT, intracranial venous thrombosis.

(PDF)

Click here for additional data file. (95.9KB, pdf)
S1 Fig. Cumulative frequency of vaccines of different types during follow-up.

(PNG)

Click here for additional data file. (60.4KB, png)
S2 Fig. aHRs for portal vein thrombosis, other venous events, and death after ChAdOx1-S or BNT162b2 vaccine.

aHR, adjusted HR; CI, confidence interval.

(PDF)

Click here for additional data file. (118.6KB, pdf)
S3 Fig

HRs for major (A) arterial and (B) venous thrombotic events and (C) haematological events, other events and lower limb fractures recorded in any position in EHR. CI, confidence interval; EHR, electronic health records; HR, hazard ratio.

(PDF)

Click here for additional data file. (343.1KB, pdf)
S4 Fig

HRs for major (A) arterial and (B) venous thrombotic events and (C) haematological events, other events and fractures recorded in death record or in hospital record in first position followed by death <28 days. CI, confidence interval; HR, hazard ratio.

(PDF)

Click here for additional data file. (342.3KB, pdf)

Acknowledgments

This work uses data provided by patients and collected by the NHS as part of their care and support. We would also like to acknowledge all data providers who make anonymised data available for research.

Abbreviations

aHR

adjusted HR

BNF

British National Formulary

CI

confidence interval

COVID-19

Coronavirus Disease 2019

DIC

disseminated intravascular coagulation

DVT

deep vein thrombosis

EMA

European Medicine Agency

GDPPR

GPES Data for Pandemic Planning and Research

GPES

General Practice Extraction Service

HES

Hospital Episode Statistics

HR

hazard ratio

ICVT

intracranial venous thrombosis

MI

myocardial infarction

MHRA

UK Medicines and Healthcare Products Regulatory Agency

NHS

National Health Service

PE

pulmonary embolism

PF4

platelet factor 4

PRAC

Pharmacovigilance Risk Assessment Committee

SCCS

self-controlled case series

SNOMED-CT

Systematized Nomenclature of Medicine Clinical Terms

SUS

Secondary Uses Service

TTP

thrombotic thrombocytopenic purpura

VITT

vaccine-induced immune thrombotic thrombocytopenia

Data Availability

The de-identified data used in this study is available via the CVD-COVID-UK consortium coordinated by BHF Data Science Centre for accredited researchers working on approved projects in the NHS Digital trusted research environment. For information on the access and approvals process, please email bhfdsc@hdruk.ac.uk or see https://web.www.healthdatagateway.org/dataset/7e5f0247-f033-4f98-aed3-3d7422b9dc6d.

Funding Statement

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). SI was funded by a BHF-Turing Cardiovascular Data Science 419 Award (BCDSA\100005) and is funded by the International Alliance for Cancer Early Detection, a partnership between Cancer Research UK C18081/A31373, Canary Center at Stanford University, the University of Cambridge, OHSU Knight Cancer Institute, University College London and the University of Manchester. 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 and SD are 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. SD is funded by the UCL Hospitals Biomedical Research Centre. 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.

References

Decision Letter 0

Louise Gaynor-Brook

19 Aug 2021

Dear Dr Whiteley,

Thank you for submitting your manuscript entitled "Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, and thrombocytopenic events: whole population cohort study in 46 million adults in England" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by Aug 23 2021 11:59PM.

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Louise Gaynor-Brook, MBBS PhD

Senior Editor

PLOS Medicine

Decision Letter 1

Louise Gaynor-Brook

22 Sep 2021

Dear Dr. Whiteley,

Thank you very much for submitting your manuscript "Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, and thrombocytopenic events: whole population cohort study in 46 million adults in England" (PMEDICINE-D-21-03568R1) for consideration at PLOS Medicine.

Your paper was evaluated by three independent reviewers, including a statistical reviewer, and was discussed among all the editors here and with an academic editor with relevant expertise. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Oct 13 2021 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Louise Gaynor-Brook, MBBS PhD

Associate Editor

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Comments from the Academic Editor:

I wonder why the authors didn't add a self controlled case series design as a kind of sensitivity analysis.

Requests from the editors:

General comments:

Throughout the paper, please adapt reference call-outs to the following style: "... intracerebral haemorrhage [1,3,4]." (noting the absence of spaces within the square brackets).

Title: Please revise your title according to PLOS Medicine's style. We suggest “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” or similar

Abstract:

Please combine the Methods and Findings sections into one section, “Methods and Findings”.

Abstract Background: Provide expand on the context of why your study is important. The final sentence should clearly state the study question.

Abstract Methods and Findings:

Please provide brief demographic details of the study population (e.g. sex, age, ethnicity, etc)

Please specify the study design i.e. population-based cohort study

Please clarify what is meant by ‘during follow up’

Please provide the incidence rates and/or absolute risks of relevant outcomes, not just aHRs

Please include more detail on the important dependent variables that are adjusted for in the analyses.

Lines 74, 76 - please clarify whether these are HRs or aHRs

In the last sentence of the Abstract Methods and Findings section, please describe 2-3 of the main limitations of the study's methodology.

Abstract Conclusions:

Please begin your Abstract Conclusions with "In this study, we observed ..." or similar, to summarize the main findings from your study, without overstating your conclusions. Please emphasize what is new and address the implications of your study, being careful to avoid assertions of primacy.

Author Summary:

At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

In the final bullet point of ‘What Do These Findings Mean?’, please describe the main limitations of the study in non-technical language.

Introduction:

Please indicate whether your study is novel, being careful to temper assertions of primacy.

Methods:

Please state that your study had a prospective protocol / analysis plan early in the Methods section; please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study. A legend for this file should be included at the end of your manuscript. Changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale. If a reported analysis was performed based on an interesting but unanticipated pattern in the data, please be clear that the analysis was data-driven.

Thank you for providing a RECORD checklist. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the REporting of studies Conducted using Observational Routinely-collected Data (RECORD) guideline (S1 Checklist)." When completing the checklist, please use section and paragraph numbers, rather than page numbers which will likely no longer correspond to the appropriate sections after copy-editing.

Line 159 - please refer to a specific file in your supporting information e.g. S1 Table

Results:

Please define the length of follow up (eg, in mean, SD, and range).

Line 265 - please clarify which vaccination ‘post-vaccinated’ refers to

Supplementary Table 1 is central to the understanding of the paper. Please incorporate it into the main paper.

Where aHRs are reported, please specify the comparison group.

Discussion:

Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.

Line 354 - please temper assertions of primacy by adding ‘to the best of our knowledge’ or similar

Figures:

Please provide Figures 1 - 3 in your revised manuscript.

Please indicate in the figure caption the meaning of the error bars in Supplementary Figures 2-4

Supplementary Fig. 1 - Please consider avoiding the use of red and green in order to make your figure more accessible to those with colour blindness.

Tables:

Please define all abbreviations used in the table legend of each table.

Table 1 - please clarify whether this is risk per 100,000 people pre- or post-vaccination

Please specify the variables adjusted for in the table legend of Supplementary Table 1.

When a p value is given, please specify the statistical test used to determine it in the table legend.

References:

Please ensure that journal name abbreviations match those found in the National Center for Biotechnology Information (NCBI) databases, and are appropriately formatted and capitalised.

Please also see https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references for further details on reference formatting.

Where websites are cited, please provide date of access.

Supplementary files:

Please see https://journals.plos.org/plosmedicine/s/supporting-information for our supporting information guidelines.

Comments from the reviewers:

Reviewer #1: I confine my remarks to statistical aspects of this paper. The general approach is fine and appropriate but I have a couple issues to resolve before I can recommend publication.

One is that the authors have the entire population. This makes use of p values and confidence intervals problematic. These statistics are about inference from a sample to a population, but you have the population. My preference would be to remove p values and CIs. Some statisticians disagree and say that you can posit a sort of "super population". I don't find their arguments persuasive, but I won't reject an article that uses this idea, but it has to be mentioned.

I would like more explanation of why followup was split up the way it was. Usually, categorizing continuous variables is a bad idea.

Tables: The formatting of the numbers isn't great. Either add commas or remove the last 3 digits and note that the numbers are in thousands. I prefer the latter, and then some numbers will have decimal parts and some won't.

Peter Flom

Reviewer #2: Thank you for the opportunity to review this timely manuscript on a matter of importance to public health. The size of the source data for this study is very impressive. While I commend the authors on providing a wealth of analyses on English data, I have some concerns about the analytical approach and the presentation which I hope can be adressed.

- You state that for computational efficiency only 10% of the almost nationwide data is used. First of all, if this is correct then this is not a nationwide study. Second, how are you ensuring that the 10% selection is random; if you select individuals with equal probability, you are selecting individuals that may not have a lot of follow-up with the same probability as individuals with complete follow-up. Third, you can only be certain that an individual is a "case" or "control" if you look at the whole follow-up period. That is, you are in some way conditioning on the future if we look at the data from a survival analysis perspective. I think you need to provide more detail on this aspect of your analysis and reassure the reader that this is a valid approach for survival data. Please also include references to where this approach has been used before. Alternatively, use another approach such as Poisson regression which should be more computational feasible for all the data.

- You should not use any stepwise selection procedure for covariate inclusion.

- Please elaborate on your approach to absolute excess risk. Is this an observed (post-vac) vs expected (historic) analysis? Please provide 95%CI also when reporting these risks.

- The tables are overloaded, have formatting issues and are difficult to read.

- Why are the main results "hidden" in a supplementary table?

- I am lacking a hierarchy of results. As it stands, you are presenting all possible combinations of analyses. Do all these analytical combinations represent apriori hypotheses?

- You include fractures as a control outcome supposedly not associated with vaccination (which is not entirely clear since fractures and frailty could be associated) and present significantly protective effects of vaccination without comment? Could this protective effect not represent unadjusted confounding/bias, which would also have biased thrombotic outcome risks towards null?

Reviewer #3: This is an interesting comprehensive analysis of the risk of venous and arterial thrombosis, or thrombocytopenia in association with ChAdOx1-S and BNT162b2 vaccination in the English adult population. I have some comments that should be addressed:

The definition of the unvaccinated group is unclear. This group includes pre-vaccination times of later vaccinated persons as well as unvaccinated persons. What was the proportion of pre-vaccination times and unvaccinated persons? How was the observation time defined in the unvaccinated population? How long was the observation time? How were the controls (unvaccinated) selected? This information needs to be provided in much more detail-

Including prevaccination times is of concern. Patients who develop VTE, ATE or thrombocytopenia would probably not get vaccinated. This introduces substantial bias.

„…the monthly incidence of ICVT in 2019.." From where did you derive this data? Please provide information in the Methods.

How did you handle missing data?

„Rates of intracranial venous thrombosis and thrombocytopenia in adults …" This should be „OR" rathern than „AND", since you did not link the two events. In light of VITT, current presentation might be misleading particularly considering the very heterogeneous definition of thrombocytopenia. Please report thrombotic events separately from thrombocytopenia and rephrase.

Data on VTE and ATE risks in the general population are important to assess their risks in association with the vaccination. This would also be of interest for immunethrombocytopenia. However, the definition of thrombocytopenia in the present study is a mixed bag and includes a wide range of diseases associated with a low platelet count (e.g. TTP). It is unclear what the relevance of this data is.

„…our primary outcome used the primary reason for death or hospital admission.." Are all DVT treated in the hospital in the UK? Is there the possibility to have missed events that were treated in an outpatient setting?

„In younger populations, who have a lower morbidity and mortality due to COVID-19, other available vaccines might be prioritise, especially when the risk of COVID-19 is otherwise low." Given the low absolute risk this conclusion cannot necessarily be drawn. The decision on the vaccine is influenced by other factors including availability and costs. Also, how would one define an otherwise low risk of COVID-19?

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 2

Louise Gaynor-Brook

24 Nov 2021

Dear Dr. Whiteley,

Thank you very much for submitting your manuscript "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" (PMEDICINE-D-21-03568R2) for consideration at PLOS Medicine.

Your paper was evaluated by an associate editor and discussed among all the editors here. It was also seen again by the reviewers. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

We hope to receive your revised manuscript by Dec 15 2021 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

We look forward to receiving your revised manuscript.

Sincerely,

Callam Davidson (on behalf of Louise Gaynor-Brook, MBBS PhD)

Associate Editor

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

It appears a large amount of content has been duplicated in your responses to the submission form questions, please revise as appropriate.

The lines ‘This work uses data provided by patients and collected by the NHS as part of their care and support. We would also like to acknowledge all data providers who make anonymised data available for research’ from your Financial Disclosure statement would be better placed in the Acknowledgements section in the main text.

In your Data Availability Statement, please additionally provide either a URL or email address that an interested researcher could use to apply for access to the de-identified data (the current URL only describes the project and does not detail the application process).

Please ensure citations throughout the text are in square brackets, are not in sub- or superscript, and appear before punctuation (e.g. ‘…in the absence of exposure to heparin [1].’).

In the interest of brevity, please remove the absolute incidence rates but include a sentence to the effect of ‘Substantial confounding was observed in the absolute incidence rates, but after adjustment…’.

In the interest of brevity, please shorten the list of independent variables adjusted for to ‘Analyses were performed separately for ages <70 and ≥70 years, and adjusted for age, age2, sex, ethnicity, deprivation and relevant medical history. Further covariates were selected using backward selection.’

Lines 129 – 132: please combine these two bullet points that reads ‘We used nationally collated data from electronic health records on 46 million adults, of whom 21 million were vaccinated during the study, and compared the incidence of venous and arterial events before and after the first vaccination with ChAdOx1-S and BNT162b2 COVID-19 vaccines.’

Line 179: When citing your supplementary material, please provide a specific item number (e.g. S1 etc.). See our supporting information guidelines for more details: https://journals.plos.org/plosmedicine/s/supporting-information

Line 197: As above, please cite the specific item within the supporting information (e.g. S1 protocol).

Please ensure all abbreviations are defined on first use (e.g. MI, DVT, PE are all defined in the ‘outcomes’ section currently but are used earlier in the manuscript).

In the results section, please include the relevant quantitative results when stating observations.

Please include the absolute incidence rates in the results (around line 333).

Line 377: Please only report p-values to 3 significant figures (P<0.001 rather than P<0.0001). Please check throughout.

Line 449: Please correct ‘prioritise’ to ‘prioritised’.

Please remove the ‘Data Sharing’, ‘Funding’, Conflicts of interest’ and ‘Contributions’ sections from the end of the main text. In the event of publication this information will be published as metadata based on your responses to the submission form questions.

Reference 15: Please add [preprint] per our referencing guidelines (https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references)

Comments from the reviewers:

Reviewer #1: The authors have addressed my concerns and I now recommend publication

Peter Flom

Reviewer #2: Thank you for the revision. The authors should reference, "Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study - PubMed (nih.gov)" which uses the same data and discuss the differences between their study and the already published study.

My comments to the responses:

35. I do not understand why I am being lectured on IP weights from causal inference when that is not what has been done here, you do not use the probability of treatment/non-treatment in your weights, just the selection probability. Your study is still not a cohort study of 46 million. Your study is essentially a case control study. Please provide a reference for your simulation studies.

36. Stepwise selection is still not a valid approach to confounder control. How does stepwise selection remove collinearity? If too few events are your main concern, why would you use backwards selection - where you are going from a model with (too) many covariates potentially providing unstable estimates.

37. Ok.

38. Can you clarify what has changed. Table 1 and 2(a+b) seems very similar to previous editions.

39-41. Ok.

Reviewer #3: Comments well addressed

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 3

Louise Gaynor-Brook

14 Jan 2022

Dear Dr. Whiteley,

Thank you very much for re-submitting your manuscript "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" (PMEDICINE-D-21-03568R3) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by one reviewer. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Jan 21 2022 11:59PM.   

Sincerely,

Louise Gaynor-Brook, MBBS PhD

Associate Editor 

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

General comments:

Please ensure that a space is added before the reference call-out e.g. “AstraZeneca) [1–3].”

Please be clear when HRs presented are adjusted HRs / aHRs

Abstract Methods and Findings:

Line 69 - please revise to ‘ethnicity and deprivation’

Line 71 - please define PE and DVT at first use

Line 74 - please revise to ‘history of stroke and history of myocardial infarction’

Line 77 - please revise to ‘were <70 years of age’

Line 79 - please revise to ‘mixed ethnicity and 1.5 million’

Line 83 - please define CI at first use

Author Summary:

Please specify the definitions of younger and older used in this study (i.e. younger than 70 years, or 70 years or older)

Please move the limitations to be the final bullet point of ‘What Do These Findings Mean?’

Methods:

Line 221 - please specify supplementary file name (S1 Protocol)

Results:

Line 302 - Tables 1 / S1a do not appear to show that “risks of venous and arterial thromboses were higher in people with… increasing deprivation”; please clarify

Line 331 - please revise to aHR

Line 335 / 344 / 345 / etc - please specify whether HRs presented in the main text are adjusted HRs

Line 336 - please clarify in which table data are presented for the post-hoc analyses; this does not appear to be either of Table 3 or S1 Table (d,e) as stated. Line 371 - please clarify in which table data are presented for the analyses of <40 compared to ≥ 40 years

Lines 375-79 - please refer to the table in which these data are presented

Line 391 - it appears from Table S3 that this should be 60% unvaccinated; please clarify

Discussion:

Lines 435-7 - please revise to ‘days post-vaccine’

Line 468 - is the underlying data for these analyses provided? PLOS do not permit “data not shown”

Tables:

NB) Table under file name ‘S2 Table’ is labelled as S1 table; also for file ‘S3 Table’ / S2 table

S2 Table - please clarify what 1 in superscript after HR (95% CI) refers to

Comments from Reviewers:

Reviewer #2: The authors have addressed my comments satisfactorily.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 4

Louise Gaynor-Brook

21 Jan 2022

Dear Dr Whiteley, 

On behalf of my colleagues and the Academic Editor, Prof. Suzanne Cannegieter, I am pleased to inform you that we have agreed to publish your manuscript "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" (PMEDICINE-D-21-03568R4) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. 

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. 

Sincerely, 

Louise Gaynor-Brook, MBBS PhD 

Associate Editor 

PLOS Medicine

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Protocol. Prespecified protocol.

    (PDF)

    Click here for additional data file. (193.8KB, pdf)
    S1 RECORD Checklist. The RECORD statement—checklist of items, extended from the STROBE statement, that should be reported in observational studies using routinely collected health data.

    (DOCX)

    Click here for additional data file. (19.7KB, docx)
    S1 Table

    Estimates for (a) age-stratified risk of venous and arterial events during follow-up; (b) age-stratified incidence of events pre- and post-first ChAdOx1-S; (c) age-stratified incidence of events pre- and post-first BNT162b2; (d) age- and sex-stratified HR of events 1–28 and >28 days post-ChAdOx1-S vaccine; and (e) age- and sex-stratified HR of events 1–28 and >28 days post-ChAdOx1-S vaccine BNT162b2 vaccine. HR, hazard ratio.

    (PDF)

    Click here for additional data file. (575.9KB, pdf)
    S2 Table. Prespecified subgroup estimates for (a) venous and (b) arterial events.

    (PDF)

    Click here for additional data file. (187.8KB, pdf)
    S3 Table. Characteristics of patient who had an ICVT event before and after vaccination.

    Only percentage are presented, as disclosure control does not allow numbers <5 to be released. ICVT, intracranial venous thrombosis.

    (PDF)

    Click here for additional data file. (95.9KB, pdf)
    S1 Fig. Cumulative frequency of vaccines of different types during follow-up.

    (PNG)

    Click here for additional data file. (60.4KB, png)
    S2 Fig. aHRs for portal vein thrombosis, other venous events, and death after ChAdOx1-S or BNT162b2 vaccine.

    aHR, adjusted HR; CI, confidence interval.

    (PDF)

    Click here for additional data file. (118.6KB, pdf)
    S3 Fig

    HRs for major (A) arterial and (B) venous thrombotic events and (C) haematological events, other events and lower limb fractures recorded in any position in EHR. CI, confidence interval; EHR, electronic health records; HR, hazard ratio.

    (PDF)

    Click here for additional data file. (343.1KB, pdf)
    S4 Fig

    HRs for major (A) arterial and (B) venous thrombotic events and (C) haematological events, other events and fractures recorded in death record or in hospital record in first position followed by death <28 days. CI, confidence interval; HR, hazard ratio.

    (PDF)

    Click here for additional data file. (342.3KB, pdf)
    Attachment

    Submitted filename: Response to reviewers v0.2.docx

    Click here for additional data file. (51.6KB, docx)

    Data Availability Statement

    The de-identified data used in this study is available via the CVD-COVID-UK consortium coordinated by BHF Data Science Centre for accredited researchers working on approved projects in the NHS Digital trusted research environment. For information on the access and approvals process, please email bhfdsc@hdruk.ac.uk or see https://web.www.healthdatagateway.org/dataset/7e5f0247-f033-4f98-aed3-3d7422b9dc6d.

    Articles from PLoS Medicine are provided here courtesy of PLOS

    RESOURCES