Study examines clinical and genetic risk factors for acute incident venous thromboembolism in ambulatory patients with COVID-19

This population-based cohort study of patients with COVID-19 from UK Biobank included 18,818 outpatients with COVID-19 (mean age, 64.3 years; 56.2% were women) infected between March 1, 2020, and September 3, 2021, who were then propensity score matched to 93,179 COVID-19–naive people during the same period. The primary outcome was a composite VTE, including deep vein thrombosis or pulmonary embolism, which occurred 30 days after the infection.

Overall, a total of 73 and 17 VTE events were seen within 30 days among the ambulatory patients with COVID-19 and matched uninfected individuals, which corresponded to incidence rates of 50.99 and 2.37 per 1,000 person-years, respectively. Survival analyses suggest that severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection was associated with an increased risk of VTE in 30 days (hazard ratio [HR], 21.42; 95% confidence interval [CI], 12.63-36.31). The observed risk was more pronounced in the unvaccinated patients (HR, 27.94; 95% CI, 15.11-51.65) and significantly mitigated in those fully vaccinated (HR, 5.95; 95% CI, 1.82-19.51; interaction P = 0.02).

In patients with COVID-19, older age (adjusted HR, 1.87 per 10 years; 95% CI, 1.50-2.33), male sex (adjusted HR, 1.69; 95% CI, 1.30-2.19), and obesity (adjusted HR, 1.83; 95% CI, 1.28-2.61) were independently associated with higher risk. 

Among 21,055 infected participants with complete genetic data, 1,287 (6.11%) had inherited thrombophilia, with 909 (4.32%) and 392 (1.86%) carrying risk variant/s of factor V Leiden and prothrombin G20210A, respectively. Patients with inherited thrombophilia had a higher risk of VTE following SARS-CoV-2 infection than those without (adjusted HR, 2.05; 95% CI, 1.15-3.66). For each risk variant, the adjusted HR was 2.17 (95% CI, 1.13-4.15) for factor V Leiden carriers and 1.52 (95% CI, 0.48-4.79) for prothrombin G20210A carriers. Also, individuals with higher polygenic risk score (PRS) values had greater VTE risk (adjusted HR per 1-standard deviation increase of PRS, 1.33; 95% CI, 1.11-1.59). 

“The results of this analysis have potentially noteworthy implications. First, VTE risk management needs reevaluation for milder ambulatory COVID-19. With emerging evidence and guidelines focusing on VTE prophylaxis for hospitalized patients with COVID-19, further work is necessary to mitigate the risk in the community … Second, although the etiology of post–COVID-19 VTE is complex and multifaceted, this study’s findings elucidated the role of factor V and possibly prothrombin proteins as contributing factors. Third, although genetic testing of inherited thrombophilia for VTE prevention has been previously discussed in many clinical scenarios, this newly identified association with COVID-19–related VTE, comparable with a 10-year aging risk, supports the potential value of targeted genetic screening for thrombophilia in the infected older adults. Finally, the study data suggest the significant association of vaccination with minimising the risk of COVID-19 VTE,” the authors remarked.

“These findings call for targeted prevention and tailored thromboprophylaxis strategies for post–COVID-19 VTE in outpatient settings and suggest an etiological role of inherited thrombophilia,” the authors concluded.