Venous Thromboembolism and Chronic Pain After Major Limb Trauma

Major limb trauma triggers a complex cascade of physiological responses, including systemic inflammation, endothelial injury, activation of coagulation pathways, and prolonged immobilization. These processes significantly increase the risk of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. VTE is a well-recognized complication following severe trauma and orthopedic injury and is typically studied in relation to acute morbidity and mortality.

However, the potential relationship between thromboembolic events and long-term pain outcomes has not been systematically investigated. Several biological mechanisms suggest a possible link between VTE and persistent post-traumatic pain. These mechanisms may include microvascular dysfunction and tissue hypoperfusion, persistent inflammatory activation, impaired rehabilitation due to thromboembolic complications, and amplification of peripheral and central sensitization pathways. These processes may contribute to prolonged nociceptive and neuropathic pain after trauma.

Patients with major limb trauma are also at risk for long-term functional impairment and chronic pain syndromes. Persistent post-traumatic pain may significantly affect rehabilitation, quality of life, and return to daily activities. Identifying early predictors of pain chronicity is therefore essential for improving long-term outcomes in trauma populations.

This prospective observational cohort study will investigate whether objectively confirmed VTE is independently associated with the development of persistent clinically significant pain following major limb trauma. Adult patients with severe upper or lower limb injuries requiring surgical treatment or prolonged immobilization will be enrolled within 72 hours of hospital admission.

VTE will be defined as objectively confirmed deep vein thrombosis diagnosed by compression ultrasonography or pulmonary embolism confirmed by CT pulmonary angiography or ventilation-perfusion imaging. VTE events occurring during hospitalization or within 30 days after injury will be included in the exposure assessment.

Baseline VTE risk will be assessed using the Trauma Embolic Scoring System (TESS), which incorporates patient age, injury severity score, obesity status, ventilator days, and presence of lower extremity fracture. This will allow evaluation of whether baseline thromboembolic risk is associated with long-term pain outcomes.

Participants will be followed prospectively for six months after injury. Pain intensity will be measured using the Numeric Rating Scale (NRS), while neuropathic pain symptoms will be assessed using the DN4 questionnaire. Pain interference with daily activities will be evaluated using the Brief Pain Inventory (BPI), and health-related quality of life will be measured using the EQ-5D-5L instrument. Additional outcomes will include opioid consumption and markers of functional recovery, including time to independent mobilization.

Statistical analyses will include descriptive statistics for baseline characteristics and comparisons between patients with and without VTE. Multivariable logistic regression models will be used to identify independent predictors of persistent pain at 3 and 6 months, adjusting for potential confounders such as injury severity, surgical interventions, baseline pain intensity, and suspected nerve injury.

By clarifying the relationship between thromboembolic complications and persistent post-traumatic pain, this study may contribute to improved risk stratification and guide integrated clinical strategies for thromboprophylaxis, pain prevention, and rehabilitation in patients with major limb trauma.

• Neuropathic Pain [Time frame: 6 weeks, 3 months, and 6 months after injury.]
• Opioid Consumption [Time frame: Time Frame: up to 6 months after injury.]