Lacroix Romaric, Judicone Coralie, Souab Karim Harti, Bonifay Amandine, Loundou Anderson, Bouriche Tarik, Cointe Sylvie, Vallier Loris, Abdili Evelyne, Arnaud Laurent, Robert Stéphane, Poncelet Philippe, Grosdidier Charlotte, Morange Pierre, Cochery-Nouvellon Eva, Bouvier Sylvie, Gris Jean-Christophe, Lefrant Jean-Yves, Leone Marc, Albanese Jacques, Dignat-George Françoise
C2VN, INSERM 1263, INRA 1260, Aix-Marseille University, Marseille, France.
Department of Hematology, Biogenopole, CHU La Timone, APHM, Marseille, France.
J Extracell Vesicles. 2025 Jun;14(6):e70073. doi: 10.1002/jev2.70073.
Septic shock is characterised by abnormal coagulation activation with defective fibrinolysis, leading to a high mortality rate. Cellular activation triggers the release of extracellular vesicles (EVs) conveying both procoagulant and fibrinolytic activities. We investigated whether the balance between these activities, termed EV-coagulolytic balance (EV-CLB), predicts day-90 mortality in 225 septic shock patients included in a multicentre prospective study. EV-CLB, quantified as a ratio of TF-dependent thrombin generation to uPA-dependent plasmin generation, was higher in non-survivors than in survivors at 24 h (2.78 [0.86-16.1] a.u. vs. 0.97 [0.34-2.18] a.u., p < 0.001). Moreover, survivors showed a significant decrease in EV-CLB from H0 to H48 in contrast to non-survivors. EV-CLB was a better predictor than EV-associated-procoagulant and -fibrinolytic activities taken individually and better correlated with sepsis severity markers such as SAPS II and lactate levels. Multivariate Cox regression models including severity markers and comorbidities confirmed EV-CLB as an independent predictor of mortality in septic shock patients. Interestingly, subgroup analysis revealed EV-CLB's strong prognostic value in peritonitis, biliary and urinary tract infections and Gram-negative sepsis. Despite challenges in EV measurement requiring technical advancement for clinical translation, EV-CLB represents a potential novel biomarker to guide individualised therapy targeting coagulation/fibrinolysis imbalance in septic shock. Trial Registration: This trial was registered at ClinicalTrials.gov identifier: NCT02062970.
脓毒性休克的特征是凝血活化异常且纤维蛋白溶解功能缺陷，导致死亡率很高。细胞活化触发细胞外囊泡（EVs）的释放，这些囊泡兼具促凝和纤溶活性。我们调查了在一项多中心前瞻性研究纳入的225例脓毒性休克患者中，这些活性之间的平衡（称为EV-凝溶平衡，EV-CLB）是否可预测90天死亡率。EV-CLB通过组织因子（TF）依赖性凝血酶生成与尿激酶型纤溶酶原激活物（uPA）依赖性纤溶酶生成的比率进行量化，在24小时时，非存活者的EV-CLB高于存活者（2.78 [0.86 - 16.1]任意单位vs. 0.97 [0.34 - 2.18]任意单位，p < 0.001）。此外，与非存活者相比，存活者从H0到H48的EV-CLB显著降低。与单独的EV相关促凝和纤溶活性相比，EV-CLB是更好的预测指标，并且与脓毒症严重程度标志物如简化急性生理学评分系统II（SAPS II）和乳酸水平具有更好的相关性。包含严重程度标志物和合并症的多变量Cox回归模型证实，EV-CLB是脓毒性休克患者死亡率的独立预测指标。有趣 的是，亚组分析显示EV-CLB在腹膜炎、胆道和尿路感染以及革兰氏阴性脓毒症中具有很强的预后价值。尽管EV测量存在挑战，需要技术进步以实现临床转化，但EV-CLB代表了一种潜在的新型生物标志物，可指导针对脓毒性休克中凝血/纤溶失衡的个体化治疗。试验注册：本试验已在ClinicalTrials.gov注册，标识符：NCT02062970。
