Major limb trauma is associated with a high risk of venous thromboembolism (VTE) due to systemic inflammation, endothelial injury, immobilization, and hypercoagulability. While VTE is commonly studied as a short-term complication affecting morbidity and mortality, its potential relationship with long-term pain outcomes after trauma has not been well investigated.

This prospective observational cohort study aims to evaluate whether objectively confirmed VTE is associated with an increased risk of persistent clinically significant pain after 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 and followed for six months.

The study will assess whether patients who develop VTE have a higher likelihood of persistent pain compared with those without VTE. In addition, the study will explore the association between baseline VTE risk (using the Trauma Embolic Scoring System, TESS), thromboprophylaxis timing, and long-term pain outcomes. Secondary analyses will evaluate neuropathic pain symptoms, pain interference with daily activities, quality of life, opioid consumption, and functional recovery.

Understanding the relationship between thromboembolic complications and persistent pain may help improve risk stratification, optimize thromboprophylaxis strategies, and support early rehabilitation planning in patients with 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.

Inclusion Criteria:

• Age ≥18 years
• Major upper or lower limb trauma
• Surgical treatment and/or immobilization ≥72 hours
• Enrollment within 72 hours of admission
• Informed consent

Exclusion Criteria:

• Pre-existing chronic pain unrelated to trauma (investigator judgment)
• Therapeutic anticoagulation prior to trauma
• Cognitive inability to complete follow-up
• Expected survival <48 hours

The study population will include adult patients (≥18 years) with major upper or lower limb trauma requiring surgical treatment and/or prolonged immobilization (≥72 hours). Participants will be recruited from trauma centers managing severe civilian and combat-related injuries. Eligible patients will be enrolled within 72 hours of hospital admission. The cohort will include patients with various mechanisms of injury, including blast injuries, fragmentation injuries, gunshot wounds, and other high-energy trauma. Participants will be followed prospectively for up to 6 months to evaluate the association between venous thromboembolism (VTE) and the development of persistent post-traumatic pain.

Individual participant data (IPD) will not be publicly shared due to ethical, legal, and privacy considerations related to sensitive clinical data from trauma patients, including individuals with combat-related injuries. The dataset may contain potentially identifiable health information and operational details. De-identified aggregated data may be made available upon reasonable request to the study investigators and subject to approval by the institutional ethics committee and applicable data protection regulations.