Activated FXI-antithrombin and thrombin-antithrombin complexes in the prediction of venous thromboembolism and mortality in non-small cell lung cancer patients

BACKGROUND: Non-small cell lung cancer (NSCLC) patients are at high risk of venous thromboembolism (VTE), especially during chemotherapy. Even though the contact system is implicated in the pathogenesis of thrombosis, limited data are available on the role of contact system activation in NSCLC-associated VTE. AIM: In a prospective cohort of NSCLC patients starting chemotherapy, contact system activation and thrombin generation biomarkers were assessed in relation to 6-month VTE occurrence and mortality. METHODS: Prechemotherapy plasma samples of 719 newly diagnosed NSCLC patients were tested for in vivo biomarkers of contact system activation (i.e., kallikrein: antithrombin [PKa:AT], activated FXI:AT [FXIa:AT], FXIa: C1-esterase inhibitor C1Inh [FXIa:c1Inh], activated factor IX:AT [FIXa:AT]), and thrombin generation (i.e., prothrombin fragment 1+2 [F1+2], thrombin-antithrombin complex [TAT]). Clinical data, VTE, and mortality were recorded prospectively. RESULTS: The 6-month VTE and mortality cumulative incidences were 11% and 27%, respectively. Basal levels of FXIa:AT complexes, F1+2, and TAT levels were higher in patients who developed VTE than VTE-free patients. Differently, PKa:AT, FIXa:AT, and TAT were lower in survivors compared to non-survivors. The multivariable analysis identified FXIa:AT (HR 1.17, 95%CI 1.00-1.37) and TAT (HR 1.28, 1.10-1.50) as VTE-independent risk factors during chemotherapy. A score based on these biomarkers was generated, able to discriminate patients at significantly higher rates of VTE and mortality. CONCLUSIONS: Elevated in vivo contact pathway activation and thrombin generation were observed in NSCLC patients who developed VTE. Furthermore, a score based on both FXIa:AT and TAT levels was developed to identify those patients at higher risk of VTE and mortality.