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. 2022 Oct 1;182(10):1063-1070.
doi: 10.1001/jamainternmed.2022.3858.

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

JunQing Xie  1 , Albert Prats-Uribe  1 , Qi Feng  2 , YunHe Wang  2 , Dipender Gill  3   4   5 , Roger Paredes  6 , Dani Prieto-Alhambra  1
Affiliations

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

JunQing Xie et al. JAMA Intern Med. .

Erratum in

  • Omission in Data Sharing Statement.
    [No authors listed] [No authors listed] JAMA Intern Med. 2022 Nov 1;182(11):1234. doi: 10.1001/jamainternmed.2022.5153. JAMA Intern Med. 2022. PMID: 36342480 Free PMC article. No abstract available.

Abstract

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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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. Cumulative Incidence Curves of Venous Thromboembolism Within 30 Days Overall and in Subgroups by Vaccination Status
Figure 2.
Figure 2.. Hazard Ratio of Clinical Risk Factors for Venous Thromboembolism (VTE) Among Patients With COVID-19
Covariates included in the single multivariable Cox regression model were age, sex, race and ethnicity, socioeconomic status, obesity, vaccination status, cancer, fall, fracture, and number of comorbidities. The estimate of hazard ratios for other VTE was calculated among the uninfected group, which was predefined as a negative control outcome analysis. BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); IMD, index of multiple deprivation.
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