Journal of the American Heart Association · 2026
Soluble Thrombomodulin Links Viremia and Mortality During COVID-19: Results From the ACTIV-4a Trial.
СтатьяРандомизированное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Zuchelkowski Benjamin E, Inman Kyle W, Nouraie S Mehdi, Beru Neeharika, Naqvi Asma, Qin Shulin, Yeh Calvin H, Zhang Yingze, Shah Faraaz A, Sharma Lokesh, Dela Cruz Charles S, Zhang Lianghui, McVerry Bryan J, Morris Alison, Neal Matthew D, Seheult Jansen, Kitsios Georgios D, Mellors John W, Lawrence Daniel A, Kim Paul Y, Jacobs Jana L, Bain William G
Аннотация
BACKGROUND: COVID-19 and other respiratory viral infections can cause cardiovascular complications. SARS-CoV-2 virions are found in the blood, and circulating viral RNA levels are associated with death. We hypothesized that viremia can induce thrombotic endotheliopathy that contributes to death and studied this relationship in patients hospitalized for COVID-19 and enrolled in the ACTIV-4a (Accelerating COVID-19 Therapeutic Interventions and Vaccines) randomized trial of antithrombotic therapy.
METHODS: We quantified SARS-CoV-2 nucleocapsid RNA and protein in plasma and measured their associations with clinical outcomes and biomarkers of thromboinflammation and endotheliopathy. We used Cox regression and Fine-Gray competing risk models to analyze survival and thrombosis. We conducted causal mediation analysis to explore whether thrombotic endotheliopathy mediates the relationship between viral RNA and death.
RESULTS: In 93 patients, SARS-CoV-2 RNA and N-antigen were higher in nonsurvivors. Baseline viral RNA levels were associated with increased 90-day death (hazard ratio [HR], 1.31 [95% CI, 1.17-1.46]) and thrombosis (HR, 1.35 [95% CI, 1.24-1.47]). Viral RNA more effectively predicted survivorship than N-antigen levels. Soluble thrombomodulin, a biomarker of thrombotic endotheliopathy, positively correlated with viral RNA levels. Mediation analysis revealed that soluble thrombomodulin accounts for 12.2% (95% CI, 0.1%-32.3%; P=0.048) after adjustment for age and sex of the relationship between viral RNA and the 90-day mortality rate.
CONCLUSIONS: Elevated plasma SARS-CoV-2 RNA levels are associated with death in ACTIV-4a, which is causally mediated in part by soluble thrombomodulin. We propose that lung-blood viral dissemination is a potential mechanism for cardiovascular complications of respiratory viruses.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04505774.
METHODS: We quantified SARS-CoV-2 nucleocapsid RNA and protein in plasma and measured their associations with clinical outcomes and biomarkers of thromboinflammation and endotheliopathy. We used Cox regression and Fine-Gray competing risk models to analyze survival and thrombosis. We conducted causal mediation analysis to explore whether thrombotic endotheliopathy mediates the relationship between viral RNA and death.
RESULTS: In 93 patients, SARS-CoV-2 RNA and N-antigen were higher in nonsurvivors. Baseline viral RNA levels were associated with increased 90-day death (hazard ratio [HR], 1.31 [95% CI, 1.17-1.46]) and thrombosis (HR, 1.35 [95% CI, 1.24-1.47]). Viral RNA more effectively predicted survivorship than N-antigen levels. Soluble thrombomodulin, a biomarker of thrombotic endotheliopathy, positively correlated with viral RNA levels. Mediation analysis revealed that soluble thrombomodulin accounts for 12.2% (95% CI, 0.1%-32.3%; P=0.048) after adjustment for age and sex of the relationship between viral RNA and the 90-day mortality rate.
CONCLUSIONS: Elevated plasma SARS-CoV-2 RNA levels are associated with death in ACTIV-4a, which is causally mediated in part by soluble thrombomodulin. We propose that lung-blood viral dissemination is a potential mechanism for cardiovascular complications of respiratory viruses.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04505774.