Hypercoagulability Predicts Survival and Reflects NET-Associated Thromboinflammation in Advanced Pancreatic Cancer

Background: Cancer-associated thrombosis is a major complication in pancreatic cancer; however, its true burden and prognostic significance remain unclear, largely owing to under-detection of asymptomatic events. In addition, the clinical relevance of cancer-related hypercoagulability and neutrophil extracellular traps (NETs), which may link thrombosis and tumor biology, has not been adequately evaluated in advanced pancreatic cancer. Methods: In this prospective study, newly diagnosed patients with unresectable pancreatic ductal adenocarcinoma underwent systematic screening for venous thromboembolism (VTE) at baseline, followed by longitudinal surveillance. Circulating coagulation markers and NET-related biomarkers were analyzed. Associations among VTE, hypercoagulability, NET-related biomarkers, and overall survival (OS) were evaluated. Results: Among 134 patients, VTE was detected at diagnosis in 28.4%, with the majority being asymptomatic. Hypercoagulability and NET-related biomarkers were significantly associated with VTE occurrence. Patients with baseline VTE (6.2 vs. 12.1 months, p = 0.002) and hypercoagulability (7.7 vs. 15.2 months, p = 0.002) demonstrated shorter OS. In multivariate analysis, hypercoagulability, but not baseline VTE, remained independently associated with inferior OS (hazard ratio 2.03, 95% confidence interval 1.27–3.27). Notably, the adverse prognostic impact of hypercoagulability was consistently observed across nearly all predefined clinical subgroups. Furthermore, a reduction in or normalization of D-dimer levels following anticoagulant therapy was associated with prolonged survival. Conclusions: Hypercoagulability, rather than overt thrombotic events, independently predicts survival outcomes in advanced pancreatic cancer. These findings support a biology-driven approach to thrombosis assessment and indicate that monitoring and therapeutic modulation of hypercoagulability may improve risk stratification and clinical management in this population.