Soluble Thrombomodulin Links Viremia and Mortality During COVID-19: Results From the ACTIV-4a Trial

Clinical Snapshot

Key Findings

• P Value: P=0.048 for mediation effect

• Effect Size: Hazard ratio 1.31 for death, 1.35 for thrombosis per unit increase in viral RNA

• Primary Outcome: 90-day mortality associated with baseline SARS-CoV-2 RNA levels

• Nnt Or Sensitivity: Soluble thrombomodulin mediates 12.2% (95% CI 0.1%-32.3%) of the viral RNA-mortality relationship

• Confidence Interval: Death: 95% CI 1.17-1.46; Thrombosis: 95% CI 1.24-1.47

Clinical Application

Viral RNA quantification requires specialized laboratory capabilities; soluble thrombomodulin assays are research-based currently Relevant to Australian ICUs and COVID-19 management protocols. May inform TGA considerations for thromboprophylaxis guidelines and support existing RACGP recommendations for monitoring thrombotic risk in hospitalized COVID-19 patients Hospitalized COVID-19 patients, particularly those with moderate to severe disease requiring antithrombotic consideration

Abstract

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.

References

1. 1.Zuchelkowski, B. E., Inman, K. W., Nouraie, S. M., Beru, N., Naqvi, A., Qin, S., Yeh, C. H., Zhang, Y., Shah, F. A., Sharma, L., Dela Cruz, C. S., Zhang, L., McVerry, B. J., Morris, A., Neal, M. D., Seheult, J., Kitsios, G. D., Mellors, J. W., Lawrence, D. A., Kim, P. Y., Jacobs, J. L., & Bain, W. G. (2026). Soluble thrombomodulin links viremia and mortality during COVID-19: Results from the ACTIV-4a trial. Journal of the American Heart Association. https://doi.org/10.1161/JAHA.125.047693