HYPERCOAGULABILITY AND SYSTEMIC INFLAMMATION ARE ASSOCIATED WITH VENOUS THROMBOEMBOLISM IN PATIENTS WITH SURGICALLY TREATED METASTATIC BONE DISEASE: A PILOT STUDY

Patients with metastatic bone disease (MBD) are at increased risk for potentially life-threatening venous thromboembolism (VTE) following orthopaedic surgery. The pathophysiology of VTE is poorly understood in patients with MBD; however, increasing evidence supports the interaction between hypercoagulability and inflammation during clot formation. Thrombelastography (TEG), a whole-blood viscoelastic haemostatic assay, can identify orthopaedic trauma patients at 4-fold increased risk for in-hospital VTE. Furthermore, some pro-inflammatory cytokines (e.g., interleukin (IL)6, IL9, and IL17A) are linked to thrombosis. This pilot study aimed to quantify serial hypercoagulability and inflammatory cytokine levels in patients with surgically treated MBD. We hypothesized that hypercoagulability and increased systemic inflammation would be associated with VTE. Adults with MBD who required orthopaedic surgery were enrolled in a single-centre, prospective cohort study. Exclusion criteria were primary bone cancer or current anticoagulation for an acute VTE. Serial TEG (TEG6s Hemostasis Analyzer) and plasma cytokine analyses for 17 relevant inflammatory cytokines (Meso Scale Discovery) were performed pre-operatively and at six timepoints over a 3-month post-operative period. Patients used pharmacological thromboprophylaxis for four weeks post-operatively and incidence of VTE was monitored throughout the study. Maximal amplitude (MA), which indicates clot strength, was evaluated using TEG, with hypercoagulability defined as MA ≥65mm. One-sample t-tests were performed to compare mean MA values with the 65mm threshold, and two-sample t-tests were used to evaluate changes in post-operative cytokine levels and compare values stratified by VTE incidence. Thirty-five patients (21 female, 60.0%) with a mean age of 68 (SD = 11) years participated in this study. Five patients (14.3%) developed VTE (four proximal DVT and one PE). Patients with VTE complications demonstrated significant hypercoagulability pre-operatively (p = 0.03), which increased until VTE incidence (Figure 1). Overall trends in inflammatory cytokine levels also indicated sustained elevation in patients with VTE (Figure 2). For example, patients who developed VTE demonstrated significantly elevated levels of interferon gamma-induced protein-10 (IP10) and IL17A pre-operatively compared to patients without VTE (p = 0.02 and p = 0.03, respectively). In patients without VTE, hypercoagulability began on post-operative day (POD)3 (p = 0.02) and MA remained elevated at 6-weeks post-operatively (Figure 1). Additionally, patients without VTE demonstrated post-operative elevation in inflammatory cytokine levels compared with pre-operative measurements (Figure 2). For example, IP10 concentration progressively increased from POD1 until three months post-operatively, while IL17A levels increased from POD5 until 3-months post-operatively. Patients with MBD who developed VTE complications demonstrated significant hypercoagulability and increased systemic inflammation compared to patients without VTE. Notably, hypercoagulability and elevated inflammatory cytokine levels persisted for six weeks post-operatively, suggesting that VTE risk may continue beyond the 4-week period during which thromboprophylaxis is commonly prescribed. Significantly elevated IP10 and IL17A, which have been linked to endothelial dysfunction and platelet activation, suggest that hypercoagulability may be, in part, inflammatory-mediated. Future investigation into the safety and efficacy of thromboprophylaxis agents with antiplatelet and anti-inflammatory effects (i.e., acetylsalicylic acid) is warranted. For any figures or tables, please contact the authors directly.

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