D-dimer drives immune dysregulation in COVID-19 via chemokine modulation and inflammatory signaling

d-dimer, a fibrin degradation product and established marker of thrombosis, has been strongly associated with disease severity and poor prognosis in COVID-19. However, its role in immune modulation remains underexplored.

In this study, we enrolled 356 participants from Shanghai, including patients with mild and severe COVID-19 and SARS-CoV-2-negative controls. Clinical data were collected to assess correlations between d-dimer and immune-related markers. Public transcriptomic datasets, single-cell RNA sequencing (scRNA-seq), and in vitro stimulation of THP-1 cells with clinically relevant d-dimer concentrations were used to investigate d-dimer-associated immune responses.

d-dimer levels were significantly elevated in severe COVID-19 patients and positively correlated with IL-6 and troponin I, while negatively associated with glomerular filtration rate. Integrated transcriptomic and protein interaction analyses identified IL-6 as a central hub in immune-related gene networks. scRNA-seq revealed tissue- and cell-specific IL-6 expression, predominantly in monocytes and T cells. In vitrod-dimer stimulation did not induce IL-6 expression in THP-1 cells but upregulated chemokines (e.g., CXCL5, CXCL6), and enriched key inflammatory pathways, including IL-17 and PI3K-Akt signaling.

These findings suggest that d-dimer may modulate the immune microenvironment by influencing chemokine-mediated cell recruitment, contributing to immune dysregulation in severe COVID-19. d-dimer functions not only as a clinical biomarker but also as a potential driver of thromboinflammatory responses.