Antithrombin (AT) is a natural anticoagulant that interacts with activated proteases of the coagulation system and with heparan sulfate proteoglycans (HSPG) on the surface of cells. The protein, which is synthesized in the liver, is also essential to confer the effects of therapeutic heparin. However, AT levels drop in systemic inflammatory diseases. The reason for this decline is consumption by the coagulation system but also by immunological processes. Aside from the primarily known anticoagulant effects, AT elicits distinct anti-inflammatory signaling responses. It binds to structures of the glycocalyx (syndecan-4) and further modulates the inflammatory response of endothelial cells and leukocytes by interacting with surface receptors. Additionally, AT exerts direct antimicrobial effects: depending on AT glycosylation it can bind to and perforate bacterial cell walls. Peptide fragments derived from proteolytic degradation of AT exert antibacterial properties. Despite these promising characteristics, therapeutic supplementation in inflammatory conditions has not proven to be effective in randomized control trials. Nevertheless, new insights provided by subgroup analyses and retrospective trials suggest that a recommendation be made to identify the patient population that would benefit most from AT substitution. Recent experiment findings place the role of various AT isoforms in the spotlight. This review provides an overview of new insights into a supposedly well-known molecule.

Background/Objectives: Early fluid resuscitation is a cornerstone of trauma care, but the relationship between resuscitation strategies and acute kidney injury (AKI) remains insufficiently characterized. This study aimed to evaluate whether administration of 4% succinylated gelatin is associated with the development of AKI in critically ill trauma patients during the first seven days of intensive care unit (ICU) treatment. Methods: We conducted an observational retrospective single-center cohort study including 215 adult trauma patients admitted to the ICU at a tertiary care center between 2015 and 2020. Gelatin exposure, kidney function, and clinical outcomes were assessed from the pre-ICU phase through the first ICU week. The primary outcome was the development of AKI, at stage ≥ 2 of the Kidney Disease: Improving Global Outcomes (KDIGO) staging. We used mixed-effects models, competing-risk analyses, correlation analyses and exploratory unsupervised clustering to explore associations between gelatin use and renal outcomes. Results: AKI occurred in 17% of patients and was associated with older age, higher Simplified Acute Physiology Score 3 (SAPS3), pre-existing comorbidities, and early signs of hemodynamic and metabolic compromise. Gelatin doses of ≥10 mL/kg/day were not associated with a consistent rise in serum creatinine or progression of AKI over time. Multivariable regression models revealed no independent association between gelatin and worsening AKI. Instead, KDIGO stage worsening was primarily associated with AKI present at ICU admission and with crystalloid volume. Clustering analysis identified a high-risk phenotype with increased gelatin exposure, but this cluster also showed pronounced shock and inflammation, suggesting confounding by indication. In a competing-risk analysis, gelatin was not associated with new-onset AKI, whereas higher gelatin doses were associated with a lower rate of ICU discharge. Conclusions: In this retrospective cohort of critically ill trauma patients, succinylated gelatin administration showed no statistically significant association with KDIGO-defined AKI progression across unadjusted and adjusted models. Gelatin doses of ≥10 mL/kg/day were more frequently administered in patients with greater hemodynamic instability, suggesting that gelatin use primarily reflected underlying illness severity rather than acting as a direct nephrotoxic agent. These findings provide no evidence of an independent nephrotoxic effect of gelatin when used as part of balanced trauma resuscitation strategies.