Abstract
BACKGROUND: The aim of this study is to explore how neutrophil extracellular traps (NETs) and phosphatidylserine exposure contribute to hypercoagulability in periodontitis with type 2 diabetes (T2D).
METHODS: Ninety-six participants were divided into groups with periodontitis (CP), T2D, periodontitis with type 2 diabetes (DP), and a healthy control (CTR). Coagulation profiles were assessed using coagulation time and fibrin generation tests. Confocal microscopy and flow cytometry measured phosphatidylserine (PS)-exposed cells and NETs in blood samples. The impact of NETs on endothelial cells was evaluated through Western blot, confocal microscopy, and angiogenesis tests. We evaluated the NETs levels in patients before and after treatment through blood glucose control or periodontitis treatment.
RESULTS: DP patients showed shorter coagulation times, higher fibrinogen levels, and more blood cells (e.g., platelets and neutrophils) with PS exposure, along with increased NETs release. Activated platelets were found to stimulate NETs release more than microparticle-poor plasma. NETs damage vascular endothelial cells, leading to increased vascular cell adhesion molecule-1 (VCAM-1), decreased vascular endothelial cadherin (VE-cadherin), actin reorganization, reduced tube formation, and higher procoagulant activity in endothelial cells. After periodontal treatment or blood sugar control, the levels of NETs decreased significantly in patients with DP.
CONCLUSIONS: In patients with DP, activated platelets trigger neutrophils to release excess NETs, which create a pro-thrombotic state by damaging endothelial cells. Small-scale clinical trials underscore the value of controlling local infection and hyperglycemia as first-line "NET-modulating" strategies.
PLAIN LANGUAGE SUMMARY: The hypercoagulability of DP patient can be partially explained by the activated platelet-promoted excess NETs providing a scaffold for clotting factors, damaging endothelial cells intercellular connections, converting of endothelial cells to pro-coagulant phenotype, and impairing of endothelial cells tube formation capacity. Blood sugar control and periodontal treatment can regulate the levels of NETs which represents the generation of new promising DP treatment options. In the future, efforts should be made to develop therapeutic strategies targeting NETs or PS.