Circulating NETs Enable Early Identification of Thrombotic Risk in Sepsis at Emergency Care Onset

Sofía Tejada¹Antonio Clemente^2*Antonia Socias³Maria Aranda³Alberto Del Castillo³Joana Mena³Joana Mª Ribas⁴Luisa Martín⁴Karla Milagritos Llerena⁴María Magdalena Arellano⁴Miguel Agudo⁴Roberto De La Rica⁵Marcio Borges³

• ¹Multidisciplinay Sepsis Group, Fundacio Institut d'Investigacio Sanitaria Illes Balears, Palma, Spain
• ²Group of Innovation in Immunopathology of Infections (GTERi), Fundacio Institut d'Investigacio Sanitaria Illes Balears, Palma, Spain
• ³Multidisciplinay Sepsis Unit, Hospital Son Llatzer, Palma, Spain
• ⁴Emergency Department, Hospital Son Llatzer, Palma, Spain
• ⁵Multidisciplinary Sepsis Group, Fundacio Institut d'Investigacio Sanitaria Illes Balears, Palma, Spain

Introduction: Sepsis involves a dysregulated host response to infection and is frequently complicated by coagulopathy, contributing to organ dysfunction and mortality. Early detection of coagulation disturbances in the emergency department (ED) remains clinically challenging. Neutrophil extracellular traps (NETs) have emerged as key mediators linking inflammation and thrombosis in sepsis, yet their prognostic value during early care is unclear. This study aimed to assess whether circulating NETs measured at sepsis onset are associated with inflammatory biomarkers, sepsis-induced coagulopathy (SIC) status, and clinical outcomes. Methods: We conducted a retrospective study including 212 adult patients with sepsis recruited at the ED presentation. Plasma NETs, IL-6, and MR-ProADM were measured by ELISA. The ISTH SIC score was used to identify early-stage coagulopathy. Results: Circulating NETs were detected in 61 patients (28.8%) and higher NETs levels were significantly associated with elevated D-dimer, LDH, IL-6, PCT, and hypocholesterolemia. NETs positive patients had increased odds of positive blood cultures (OR = 2.3; 95% CI: 1.2–2.5), thromboembolic events (OR = 4.4; 95% CI: 1.0–19.0), and SOFA ≥ 5 (OR = 2.0; 95% CI: 1.1–2.9). Among 202 patients with complete data to SIC evaluation, 49% met SIC criteria. Although NETs were not independently associated with SIC, their inflammatory and clinical impact was significantly amplified in SIC-positive patients, suggesting a synergetic interaction between NETosis and early coagulopathy. Discussion: NETs quantification at ED presentation may help identify a high-risk immunothrombotic phenotype in sepsis and support earlier NETosis-targeted therapies alongside anticoagulation.