Examining Transcriptomic Markers Associated With Neutrophil Extracellular Traps to Predict Mortality Risk in Neonatal Sepsis

Background Neonates are highly susceptible to sepsis, which is often accompanied by fatal coagulopathy. Anticoagulant therapies have not reduced sepsis-related mortality in clinical trials, possibly due to patient heterogeneity. Neutrophil extracellular traps (NETs) enhance coagulation by activating platelets, suggesting that NET-specific biomarkers may identify patients who may benefit from targeted anticoagulant treatment. This study evaluated the association between NET gene expression and adverse outcomes in neonatal sepsis. Methods We analyzed whole blood transcriptomes from 123 neonates with sepsis and developed a predictive model, the NET score, based on NET-related gene expression. Model performance was assessed in two independent validation sets. Mediation and correlation analyses explored the relationship between the NET score and a coagulation score. Temporal transcriptomic data from septic shock cases further tested this interaction. Results The NET score achieved AUCs of 88.7% and 85.4% in validation Sets 1 and 2, respectively, indicating strong predictive performance. Mediation and temporal analyses supported a sequential relationship between NETosis and coagulation in sepsis. Age-specificity of the model was confirmed using pediatric (n = 163) and adult (n = 86) sepsis transcriptomic datasets. Neonates with disseminated intravascular coagulation exhibited a trend toward elevated NET scores. Conclusions Our findings support a novel risk stratification approach using the NET score to identify neonates at increased risk for sepsis-associated coagulopathy and poor outcomes, potentially guiding targeted therapeutic strategies.