Gomez-Rosas Patricia, Nagy Magdolna, Spronk Henry M H, Russo Laura, Gamba Sara, Tartari Carmen Julia, Bolognini Silvia, Ticozzi Chiara, Schieppati Francesca, Sarmiento Roberta, De Braud Filippo, Masci Giovanna, Tondini Carlo, Petrelli Fausto, Giuliani Francesco, D'Alessio Andrea, Santoro Armando, Gasparini Giampietro, Labianca Roberto, Cate Hugo Ten, Falanga Anna, Marchetti Marina
Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands; Hospital de Oncologia, Unidad Medica de Alta Especialidad (UMAE), Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.
Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands.
J Thromb Haemost. 2025 Jun;23(6):1908-1919. doi: 10.1016/j.jtha.2025.02.029. Epub 2025 Mar 6.
Patients with non-small cell lung cancer (NSCLC) 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.
In a prospective cohort of patients with NSCLC starting chemotherapy, contact system activation and thrombin generation biomarkers were assessed in relation to 6-month VTE occurrence and mortality.
Prechemotherapy plasma samples of 719 newly diagnosed patients with NSCLC were tested for in vivo biomarkers of contact system activation (ie, kallikrein [pKa]:antithrombin [AT; PKa:AT], activated factor [F]XI:AT [FXIa:AT], FXIa:C1-esterase inhibitor C1Inh [FXIa:C1Inh], activated FIX:AT [FIXa:AT]), and thrombin generation (ie, prothrombin fragment 1+2 [F1+2] and thrombin-antithrombin complex [TAT]). Clinical data, VTE, and mortality were recorded prospectively.
The 6-month VTE and mortality cumulative incidences were 11% and 27%, respectively. Basal levels of FXIa:AT complexes, F1+2, and TAT were higher in patients who developed VTE than those in VTE-free patients. Differently, PKa:AT, FIXa:AT, and TAT were lower in survivors than those in nonsurvivors. The multivariable analysis identified FXIa:AT (subdistribution hazard ratio, 1.17; 95% CI, 1.00-1.37) and TAT (subdistribution hazard ratio, 1.28; 95% CI, 1.10-1.50) as VTE-independent risk factors during chemotherapy. A score based on these biomarkers was generated, which was able to discriminate patients at significantly higher rates of VTE and mortality.
Elevated in vivo contact pathway activation and thrombin generation were observed in patients with NSCLC 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.
非小细胞肺癌（NSCLC）患者发生静脉血栓栓塞症（VTE）的风险较高，尤其是在化疗期间。尽管接触系统与血栓形成的发病机制有关，但关于接触系统激活在NSCLC相关VTE中的作用的数据有限。
在一组开始化疗的NSCLC患者前瞻性队列中，评估接触系统激活和凝血酶生成生物标志物与6个月VTE发生和死亡率的关系。
对719例新诊断的NSCLC患者化疗前的血浆样本进行检测，以检测接触系统激活的体内生物标志物（即激肽释放酶[pKa]：抗凝血酶[AT；pKa：AT]、活化因子[F]XI：AT[FXIa：AT]、FXIa：C1酯酶抑制剂C1Inh[FXIa：C1Inh]、活化FIX：AT[FIXa：AT]）和凝血酶生成（即凝血酶原片段1+2[F1+2]和凝血酶-抗凝血酶复合物[TAT]）。前瞻性记录临床数据、VTE和死亡率。
6个月时VTE和死亡率的累积发生率分别为11%和27%。发生VTE的患者中FXIa：AT复合物、F1+2和TAT的基础水平高于未发生VTE的患者。不同的是，幸存者中的PKa：AT、FIXa：AT和TAT低于非幸存者。多变量分析确定FXIa：AT（亚分布风险比，1.17；95%CI，1.00-1.37）和TAT（亚分布风险比，1.28；95%CI，1.10-1.50）是化疗期间独立于VTE的风险因素。基于这些生物标志物生成了一个评分，该评分能够以显著更高的VTE和死亡率对患者进行区分。
在发生VTE的NSCLC患者中观察到体内接触途径激活和凝血酶生成升高。此外，基于FXIa：AT和TAT水平开发了一个评分，以识别那些VTE和死亡风险较高的患者。
