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Clinical and Genetic Risk Factors for Acute Incident Venous Thromboembolism in Ambulatory Patients With COVID-19

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To identify the key insights or developments described in this article
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Key Points

Question  What is the 30-day acute risk of venous thromboembolism (VTE) among ambulatory patients with COVID-19, and what are the clinical and genetic risk factors predisposing them to developing post–COVID-19 VTE?

Findings  In this retrospective cohort study of 18 818 outpatients with COVID-19 and 93 179 propensity score–matched noninfected participants, a higher VTE incidence was observed in the former (hazard ratio, 21.42); however, this risk was considerably attenuated among the fully vaccinated, after breakthrough infection. Older age, male sex, obesity, no vaccination or partial vaccination, and inherited thrombophilia were independent risk factors for COVID-19–associated VTE.

Meaning  The results of this study suggest that ambulatory patients with COVID-19, either vaccinated or not, present a clinically relevant increased risk of incident VTE during the acute phase, with the risk pronounced by factors of older age, male sex, obesity, incomplete vaccination, and factor V Leiden thrombophilia.


Importance  The risk of venous thromboembolism (VTE) in ambulatory COVID-19 is controversial. In addition, the association of vaccination with COVID-19–related VTE and relevant clinical and genetic risk factors remain to be elucidated.

Objective  To quantify the association between ambulatory COVID-19 and short-term risk of VTE, study the potential protective role of vaccination, and investigate clinical and genetic risk factors for post–COVID-19 VTE.

Design, Setting, and Participants  This population-based cohort study of patients with COVID-19 from UK Biobank included participants with SARS-CoV-2 infection that was confirmed by a positive polymerase chain test reaction result between March 1, 2020, and September 3, 2021, who were then propensity score matched to COVID-19–naive people during the same period. Participants with a history of VTE who used antithrombotic drugs (1 year before index dates) or tested positive in hospital were excluded.

Exposures  First infection with SARS-CoV-2, age, sex, ethnicity, socioeconomic status, obesity, vaccination status, and inherited thrombophilia.

Main Outcomes and Measures  The primary outcome was a composite VTE, including deep vein thrombosis or pulmonary embolism, which occurred 30 days after the infection. Hazard ratios (HRs) with 95% CIs were calculated using cause-specific Cox models.

Results  In 18 818 outpatients with COVID-19 (10 580 women [56.2%]; mean [SD] age, 64.3 [8.0] years) and 93 179 matched uninfected participants (52 177 women [56.0%]; mean [SD] age, 64.3 [7.9] years), the infection was associated with an increased risk of VTE in 30 days (incidence rate of 50.99 and 2.37 per 1000 person-years for infected and uninfected people, respectively; HR, 21.42; 95% CI, 12.63-36.31). However, risk was substantially attenuated among the fully vaccinated (HR, 5.95; 95% CI, 1.82-19.5; interaction P = .02). In patients with COVID-19, older age, male sex, and obesity were independently associated with higher risk, with adjusted HRs of 1.87 (95% CI, 1.50-2.33) per 10 years, 1.69 (95% CI, 1.30-2.19), and 1.83 (95% CI, 1.28-2.61), respectively. Further, inherited thrombophilia was associated with an HR of 2.05 (95% CI, 1.15-3.66) for post–COVID-19 VTE.

Conclusions and Relevance  In this population-based cohort study of patients with COVID-19, ambulatory COVID-19 was associated with a substantially increased risk of incident VTE, but this risk was greatly reduced in fully vaccinated people with breakthrough infection. Older age, male sex, and obesity were clinical risk factors for post–COVID-19 VTE; factor V Leiden thrombophilia was additionally associated with double the risk, comparable with the risk of 10-year aging. These findings may reinforce the need for vaccination, inform VTE risk stratification, and call for targeted VTE prophylaxis strategies for unvaccinated outpatients with COVID-19.

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Article Information

Accepted for Publication: July 13, 2022.

Published Online: August 18, 2022. doi:10.1001/jamainternmed.2022.3858

Corresponding Author: Dani Prieto-Alhambra, MD, PhD, Professor, Botnar Research Centre, Windmill Road, OX37LD Oxford, England (daniel.prietoalhambra@ndorms.ox.ac.uk).

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Xie J et al. JAMA Internal Medicine.

Author Contributions: Drs Xie and Prats-Uribe had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Xie, Prats-Uribe, Wang, Gill, Prieto-Alhambra.

Acquisition, analysis, or interpretation of data: Xie, Prats-Uribe, Feng, Paredes.

Drafting of the manuscript: Xie, Paredes, Prieto-Alhambra.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Xie.

Obtained funding: Prats-Uribe.

Administrative, technical, or material support: Prieto-Alhambra.

Supervision: Gill, Paredes, Prieto-Alhambra.

Conflict of Interest Disclosures: Dr Gill reported part-time employment with Novo Nordisk outside the submitted work. Dr Prieto-Alhambra reported grants from Amgen, UCB Biopharma, Les Laboratoires Servier, Novartis, and Chiesi-Taylor as well as speaker fees and advisory board membership with AstraZeneca and Johnson and Johnson outside the submitted work in addition to research support from Janssen. No other disclosures were reported.

Funding/Support: Mr Xie is funded through Jardine-Oxford Graduate Scholarship and a titular Clarendon Fund Scholarship. Dr Gill is supported by the British Heart Foundation Research Centre of Excellence (RE/18/4/34215) at Imperial College London and by a National Institute for Health Research Clinical Lectureship (CL-2020-16-001) at St George's, University of London. Prof Prieto-Alhambra is funded through a National Institute of Health Research (NIHR) Senior Research Fellowship (grant SRF-2018-11-ST2-004), and received partial support from the Oxford NIHR Biomedical Research Centre. Dr Prats-Uribe has received funding from the Medical Research Council (MRC) [MR/K501256/1, MR/N013468/1].

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: Bonafide researchers can apply to use the UK Biobank dataset by registering and applying at https://ukbiobank.ac.uk/register-apply/. Any additional summary data generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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