Mediation of the sex disparity in COVID-19 mortality by arterial and venous thromboembolism: a multicenter cohort study the Dutch COVID & Thrombosis Coalition.

BACKGROUND: Previous studies have demonstrated a notable sex difference in Coronavirus Disease 2019 (COVID-19) mortality without a clear explanation. Concurrent thrombosis could underlie this sex disparity. OBJECTIVE: To investigate whether differentially occurring venous and arterial thromboembolic events (VTE and ATE, respectively) explain the association between sex and mortality in COVID-19 patients. METHODS: A multicenter cohort study in the Netherlands was conducted between February 2020 and May 2022. Suspected or confirmed COVID-19 patients admitted to the ward or Intensive Care Unit (ICU) were included. All-cause mortality, VTE, and ATE were the primary outcomes. Counterfactual mediation analyses with a random intercept for center were performed to decompose the total effect of sex on mortality into the natural direct effect (NDE; i.e. the effect of sex on mortality not operating through VTE/ATE) and natural indirect effect (NIE; i.e. the effect of sex on mortality mediated by VTE/ATE), and to estimate the proportion mediated (PM; fraction of the total effect explained by VTE/ATE) through VTE and ATE. RESULTS: 3255 COVID-19 patients were included. Females showed lower cumulative incidences of mortality (15 vs. 22%), VTE (10 vs. 16%), and ATE (1.4 vs. 3%) than males. Females demonstrated lower OR for mortality (OR 0.59 (95%CI 0.49-0.72)), VTE (OR 0.57 (95%CI 0.46-0.72)) and ATE (OR 0.64 (95%CI 0.39-1.03)) than males. Counterfactual mediation analyses showed that the proportions mediated were 7.95% (95%CI 3.01-17.63%) for VTE and 3.28% (95%CI 0.42-8.68%) for ATE, respectively. CONCLUSION: The lower incidence of VTE and ATE in females explains the sex difference in mortality in hospitalized COVID-19 patients, only to a minor extent. Further investigation is warranted to unravel sex-related factors in COVID-19.