Neutrophil CD14 is a driver and a therapeutic target for deep vein thrombosis.

Clinical Snapshot

Key Findings

• P Value: Not specified

• Effect Size: Not specified in abstract

• Primary Outcome: Significant reduction in thrombus burden and thrombosis incidence with neutrophil-specific CD14 knockdown

• Nnt Or Sensitivity: Reduced intrathrombus neutrophil accumulation and NETosis markers

• Confidence Interval: Not provided

Clinical Application

Requires development of clinically applicable CD14 targeting strategies and extensive safety testing Relevant to Australian DVT management guidelines; would require TGA approval for therapeutic development and PBS consideration for cost-effectiveness Patients at risk of or with established deep vein thrombosis

Abstract

Neutrophil-mediated persistent inflammation and neutrophil extracellular trap formation (NETosis) are critical in the pathogenesis of deep vein thrombosis (DVT). Identifying the mechanisms controlling these proinflammatory and prothrombotic functions is critical for designing and developing new therapeutics for DVT. However, how neutrophils acquire these phenotypes during the early stages of DVT remains poorly understood. Here, multiomic analyses (RNA sequencing, proteomics, and flow cytometry) of bone-marrow neutrophils 3 hours after DVT, revealed consistent overexpression of CD14. Concurrently, mice with DVT exhibited significantly elevated plasma granulocyte colony-stimulating factor (G-CSF) and neutrophil hyperactivation. Mechanistic studies using a geometric deep learning model (DeepPBS) and chromatin immunoprecipitation revealed that elevated G-CSF drives CD14 overexpression by upregulating the transcription factor C/EBPα (leucine zipper CCAAT-enhancer binding protein α). Importantly, neutrophil-specific CD14 knockdown using a novel lentiviral short hairpin RNA approach significantly improved DVT outcomes by lowering thrombus burden, thrombosis incidence, and intrathrombus neutrophil and citrullinated histone H3 accumulation. Studies in G-CSF stimulated primary human neutrophils revealed that CD14 inhibition reduces markers of inflammation and NETosis (activated gasdermin D, citrullinated histone H3, and S100A8/A9), while increasing apoptosis, thus demonstrating translational relevance. Collectively, our study uncovers an essential role of neutrophil CD14 in DVT pathogenesis and establishes it as a promising therapeutic target for DVT.

References

1. 1.Pandey, N., Kaur, H., Mitra, R., Chandaluri, L., Shaaban, N., Martinez, A., Kidder, E., Anand, S. K., Butler, M. E., Zhang, X., Goswami, D., Frausto, L., Kumar, D., Pandit, R., Das, S., Rohilla, S., Mohajan, S., Male, G., Huque, A., Salem, A. R., Magdy, T., Gross, D. S., Stokes, K. Y., Orr, A. W., Tousif, S., Yurdagul, A., Rom, O., & Dhanesha, N. (2026). Neutrophil CD14 is a driver and a therapeutic target for deep vein thrombosis. Blood Advances. https://doi.org/10.1182/bloodadvances.2025017224