Emerging molecular targets in deep vein thrombosis: from inflammation to coagulation

Deep vein thrombosis (DVT), a prevalent vascular disorder driven by venous stasis, endothelial injury, and hypercoagulability, imposes a significant global health burden due to life-threatening complications like pulmonary embolism. Recent advances highlight inflammation as a pivotal contributor to DVT pathogenesis, intricately linked with coagulation through immunothrombosis. This review synthesizes emerging molecular targets bridging these pathways, focusing on neutrophil extracellular traps (NETs), peptidylarginine deiminase 4 (PAD4), P-selectin, high-mobility group box 1 (HMGB1), tissue factor (TF), complement C3, and the NLRP3 inflammasome. NETs provide a procoagulant scaffold for fibrin deposition, activate Factor XII, and stabilize thrombi. PAD4 catalyzes NET formation via histone citrullination, while P-selectin mediates leukocyte adhesion and thromboinflammation. HMGB1 amplifies thrombosis by inducing NETosis and TF expression, and leukocyte-derived TF challenges traditional vessel-injury paradigms. Complement C3 and NLRP3 activation further propagate inflammation-coagulation crosstalk. Despite promising preclinical data, therapeutic translation faces challenges, including species differences, off-target effects, and balancing efficacy with immune defense. Innovations in single-cell RNA sequencing and CRISPR screening offer new avenues for target discovery. Targeting these molecules may enable bleeding-sparing therapies, advancing DVT management beyond conventional anticoagulants.