Venous thromboembolism (VTE) represents a significant cause of morbidity and mortality in patients with cancer, particularly those with non–small cell lung cancer (NSCLC). Despite advances in prophylaxis and treatment, the incidence of VTE remains high in this population, underscoring the limitations of existing clinical prediction tools [1].
Current models, such as the Khorana score, rely primarily on clinical and laboratory parameters but often fail to accurately identify patients at the highest risk [2].
In this context, there is growing interest in the role of novel hemostatic biomarkers that reflect the activation of specific coagulation pathways. A recent prospective study explored whether circulating complexes of in vivo contact system activation and thrombin generation could serve as predictors of VTE and mortality in patients with NSCLC [3].
Epidemiology of VTE and Challenges in Risk Stratification
Patients with NSCLC face a significantly higher risk of VTE compared to the general population, with estimates indicating an incidence of up to 20% within the first year after diagnosis [4]. This increased thrombotic tendency is multifactorial, including tumor-related procoagulant activity, systemic inflammation, endothelial dysfunction, and treatment-related factors such as chemotherapy and antiangiogenic therapies [5,6]. The prothrombotic state in NSCLC is partly mediated by the release of tissue factor–expressing microparticles from tumor cells, which trigger the extrinsic coagulation pathway [7].
Additionally, inflammatory cytokines may upregulate the expression of procoagulant proteins and downregulate endogenous anticoagulants, further shifting the balance toward thrombosis [8]. While risk assessment models, such as the Khorana score, are widely used, their ability to discriminate risk remains limited [2]. In particular, these models often categorize many patients as being in the intermediate risk category, which complicates decisions about prophylactic anticoagulation [6].
Moreover, biomarkers traditionally used in thrombosis prediction, such as D-dimer, lack specificity in the oncologic setting, as elevated levels may reflect tumor burden or systemic inflammation rather than imminent thrombotic events [9]. This diagnostic ambiguity underscores the need for more precise tools that can capture the coagulation dynamics contributing to VTE in cancer patients [3].
Activated Factor XI-antithrombin (FXIa:AT) and Thrombin-antithrombin (TAT) Complexes as Predictive Biomarkers
The prospective cohort study evaluated 719 patients with newly diagnosed, advanced-stage NSCLC, aiming to investigate the prognostic value of in vivo contact system activation (FXIa:AT, FXIa:C1Inh, FIXa:AT, PKa:AT) and thrombin generation (prothrombin fragment 1,2 and TAT) markers in pre-chemotherapy plasma samples [3]. The 6-month cumulative incidence of VTE was 10%, with PE and DVT being the most common events. VTE was associated with younger age, metastatic disease, and poor ECOG performance status. Competing risk analysis was used to identify predictors of VTE. Elevated levels of FXIa:AT (SHR 1.17) and TAT (SHR 1.28) complexes were identified as independent predictors of VTE within 6 months [3]. FXIa is generated through activation of factor XII, representing the contact activation pathway, and plays a central role in amplifying thrombin generation [10]. TAT complexes, in contrast, are direct indicators of active thrombin formation, which not only converts fibrinogen to fibrin but also activates platelets and other coagulation factors [11].
A risk assessment model based on FXIa:AT and TAT levels was developed, achieving moderate accuracy (AUC = 0.647). Patients were stratified into low-risk (8% VTE incidence) and high-risk (23% VTE incidence) groups, with a SHR of 3.12 (95% CI, 1.88-5.17), with a log-rank p-value <.001 [3]. These findings imply that measuring contact system activation and thrombin generation may offer incremental prognostic information beyond conventional parameters.
Impact on Mortality, Clinical Implications, and Future Perspectives
Beyond their association with thrombosis, FXIa:AT and TAT were also independent predictors of mortality. Therefore, the VTE risk score was applied to mortality prediction, stratifying patients into low-risk (26% mortality) and high-risk (41% mortality) groups HR of 1.45 (95% CI, 1.15-1.83; log-rank, P = .002) [3], suggesting that the biomarkers capture additional dimensions of disease biology [3,9].
The study highlights important implications for clinical care. First, identifying patients with concurrent elevations in FXIa:AT and TAT could facilitate targeted thromboprophylaxis in those most likely to benefit. Second, the observed association with mortality raises the possibility that coagulation activation is not merely a bystander but may contribute directly to cancer progression, consistent with experimental models demonstrating thrombin-mediated tumor growth and metastasis [12]. Finally, incorporation of these assays into routine workflows will require validation studies, cost-effectiveness analyses, and development of standardized thresholds for clinical decision-making [3].
Conclusion
The identification of FXIa:AT and TAT complexes as independent predictors of VTE and mortality in NSCLC patients represents a promising advance in the field of cancer-associated thrombosis [3]. By capturing in vivo activation of the coagulation cascade, these biomarkers may complement existing clinical models, enabling more accurate risk stratification and individualized prophylactic strategies [3]. However, further prospective studies are needed to confirm these findings in diverse cancer populations and to establish whether biomarker-guided interventions can effectively reduce VTE incidence and improve survival [3].
As research continues to elucidate the complex interplay between coagulation, inflammation, and tumor biology, biomarker-driven approaches are likely to play an increasingly central role in the management of thrombotic risk among patients with cancer [5,12]. Continued efforts in this direction will be essential to reduce the burden of VTE and enhance outcomes in this vulnerable population [3].
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