Daily Sepsis Research Analysis

Sepsis disrupts the physiological balance between coagulation and fibrinolysis, resulting in a state in which fibrin formation exceeds fibrin removal and drives microvascular thrombosis, organ failure, and mortality. Although an early burst of endothelial tissue-type plasminogen activator (t-PA) may transiently increase plasmin generation, this phase is rapidly eclipsed by sustained upregulation of plasminogen activator inhibitor-1 (PAI-1), dysregulated activation of thrombin-activatable fibrinolysis inhibitor, depletion of endogenous anticoagulants, and progressive endotheliopathy. Beyond inhibitor excess, emerging evidence indicates that a quantitative defect in plasminogen is a central contributor to fibrinolytic insufficiency. Neutrophil extracellular traps (NETs) contain elastase, which cleaves plasminogen into inactive fragments, reducing functional plasminogen availability and impairing fibrin-bound plasmin generation. When functional plasminogen falls below rate-limiting levels, fibrin surfaces cannot efficiently support plasmin formation, resulting in persistent microvascular fibrin deposition despite elevated D-dimer concentrations. This NET-plasminogen axis links immunothrombosis to the "fibrinolytic insufficiency phenotype observed in sepsis-induced coagulopathy and overt disseminated intravascular coagulation (DIC)." Clinically, hypofibrinolysis is characterized by high D-dimers, elevated PAI-1, reduced plasmin generation, and low fibrinolytic activity on viscoelastic testing. Multimodal assessment integrating biomarker panels and viscoelastic assays, including t-PA- or urokinase-challenged protocols, may improve risk stratification. Therapeutic strategies largely targeted coagulation; however, persistent hypofibrinolysis limits their effectiveness. Translational data demonstrate that plasminogen supplementation restores functional plasminogen levels and normalizes plasmin generation in septic patients and in experimental DIC, providing proof of concept for fibrinolysis-directed therapy. Future progress requires standardized definitions, functional fibrinolytic phenotyping, and phenotype-guided clinical trials to restore the coagulo-fibrinolytic balance in sepsis.

INTRODUCTION: Sepsis remains difficult to treat, resulting in persistently high mortality, creating a significant clinical need for novel therapeutic approaches that provide precise immune modulation. A highly customizable telodendrimer nanotrap (TDNT) platform was developed to selectively remove inflammatory cytokines based on cytokine charge disparity and demonstrated improved survival in experimental murine sepsis. In this study, plasma from patients with abdominal sepsis was characterized for cytokine profiles and used to optimize the engineered TDNT resins for selective attenuation by targeting cytokine charge disparity. METHODS: TDNT resins were screened against a spiked mixture of patient plasma, and three lead formulations were identified with different cytokine binding profiles. The correlation between individual patient cytokine profiles and clinical diagnosis was studied. The cytokine removal efficacy of the lead candidates was subsequently validated using 20 individual sepsis patient plasma samples for comparison with a commercial macroporous hemoperfusion resin. RESULTS: After screening patient plasma, we optimized three lead nanotrap resins to selectively absorb either positively charged or negatively charged cytokines or to target universal cytokine removal. Upon validation in individual sepsis patient plasma, the selective cytokine binding profiles of the lead selective nanotrap resins were confirmed; however, overall cytokine clearance efficacy was moderate. The pan-affinitive TDNT resin effectively removes cytokines from patient plasma with comparable efficiency to the commercial MG250 CONCLUSION: Targeting cytokine charge disparity and total cytokine burden using TDNT resins with different cytokine binding profiles is promising for effectively addressing the dysregulated immune response in sepsis and reducing mortality, which warrants further testing in a large cohort of patients.

The blood urea nitrogen to serum albumin ratio (BAR) has shown promise as a prognostic marker in sepsis, yet its specific role in sepsis-induced coagulopathy (SIC) remains unclear. We aimed to clarify whether BAR informs mortality risk in critically ill intensive care unit (ICU) patients with SIC. Using the Medical Information Mart for Intensive Care IV database, we identified consecutive ICU patients admitted between 2008 and 2022 who fulfilled Sepsis-3 criteria and had an SIC score ≥4. BAR was calculated from the 1st available laboratory values. Multivariable Cox regression and restricted cubic splines were used to estimate mortality associations after adjustment for demographics, comorbidities, interventions, severity scores (Sequential Organ Failure Assessment, Simplified Acute Physiology Score II), and laboratory parameters. The primary end-point was 30-day mortality; 90- and 365-day mortality were secondary. Among 4244 patients, higher admission BAR independently predicted increased mortality at 30, 90, and 365 days. Each 10-unit rise in BAR conferred a 30% higher hazard of death within 30 days (unadjusted hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.25-1.35; P < .001). After full adjustment, the association persisted (HR 1.18, 95% CI 1.12-1.24; P < .001). Similar patterns were seen for longer-term outcomes. A clear dose-response relationship was observed across BAR tertiles; patients in the highest tertile (BAR ≥ 10 mg/g) had markedly higher mortality risk (adjusted HR 1.69, 95% CI 1.43-2.00; P < .001) than those in the lowest. Nonlinear analysis revealed a curvilinear BAR-mortality relationship, and subgroup analyses showed consistent findings, with significant effect modification by age. In critically ill patients with SIC, an elevated admission BAR independently predicts short- and long-term mortality and may aid risk stratification and early intervention planning.