Neutrophil Extracellular Traps Are Markers of Wound Healing Impairment in Patients with Diabetic Foot Ulcers Treated in a Multidisciplinary Setting

Objective: Neutrophil extracellular traps (NETs) are associated with impaired wound healing in diabetes. This study evaluates the association between NET-specific markers and wound healing among diabetic foot ulcer (DFU) patients treated in a multidisciplinary setting. Approach: Clinical data of diabetic patients with active foot ulcers who presented to our team between January 1, 2016 and June 30, 2017 were recorded. The diabetic ulcer severity score (DUSS) and wound, ischemia, and foot infection (WIfI) score were calculated. NET-specific markers in plasma and wound tissues were tested. The capacity for plasma and platelets to prime neutrophils to release NETs was assessed. The prognostic value of NET-specific markers for wound healing was evaluated. Results: NET-specific markers were significantly higher in DFU patients than in diabetic patients without DFU or healthy controls and were found to correlate positively with DUSS or WIfI score. Elastase levels in ulcer tissue significantly increased in wounds with infections and delayed healing. Higher levels of NET release were observed after the stimulation of plasma or platelets from ulcer-related vessels than from nonulcer-related vessels of the DFU patients. Citrullinated histone 3 (citH3) was identified as a risk factor for wound healing impairment and amputation. The patients with the highest quartile of citH3 levels presented significantly lower healing rates and higher amputation rates than those with the lower three quartiles. Innovation: This study extended current knowledge of NETs on wound healing in DFU patients. Conclusion: NET-specific markers negatively correlated with wound healing in DFU patients, and citH3 is a potential marker.