The Procoagulant and Fibrinolytic Balance of Extracellular Vesicles Predicts Mortality in Septic Shock Patients

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.