Association of Inflammatory and Hemostatic Biomarkers with Inflammasomes in Septic Patients at Risk for Development of Coagulopathy

Abstract

Sepsis is a catastrophic complication of infection that results in systemic inflammatory responses. Inflammasomes initiate the inflammatory cascade that results in the activation of caspase 1, leading to the upregulation of inflammatory cytokines such as interleukins B and 18. The NRLP-3 inflammasome contributes to the innate immune response identification of pattern recognition receptors on pathogens including bacteria and viruses. Whereas the role of inflammasome in the inflammatory response is known, it is not clear how inflammasome contributes to the hemostatic dysregulation observed in sepsis-associated coagulopathy. The purpose of this study was to quantitate inflammasome levels in defined sepsis-associated patients and to determine its potential relevance to various biomarkers of hemostatic dysregulation. Plasma samples from 52 adults with sepsis and suspected coagulopathy were analyzed. Samples were collected from intensive care unit patients on day 0, under an Institution Review Board-approved protocol. Samples were stored at −80°C before analysis. Platelet count was determined as part of standard clinical practice. Healthy control samples were purchased from George King Bio-Medical (Overland, Kan). Prothrombin time and international normalized ratio were measured using recombiplastin reagent. Fibrinogen was measured using a clot-based method on ACL ELITE (Instrumentation Laboratory, Bedford, Mass) coagulation analyzer. Cortisol, D-dimer, plasminogen activator inhibitor 1 (PAI-1), NLRP-3 inflammasomes, microparticle-associated tissue factor, fibronectin, and CD40L were measured using commercially available enzyme-linked immunosorbent assays. In comparing patients with sepsis and suspected disseminated intravascular coagulation (DIC) with the normal plasma samples, there was a significant elevation in NLRP-3 inflammasome levels in the sepsis cohort (P < .0001). The Fig shows that the NLRP-3 inflammasome concentration in the sepsis cohort did not correlate with other biomarkers. An elevated level of NLRP-3 inflammasomes was significantly associated with increased levels of PAI-1 (P < .0004). No other inflammatory or hemostatic markers were significantly correlated with NLRP-3 inflammasomes. This is depicted in the Table. The study shows a significant relationship between inflammasomes and PAI-1 levels in patients with sepsis-associated coagulopathy. The positive correlation between NLRP-3 inflammasomes and PAI-1 shows that the activation of inflammasomes may have a role in the upregulation of PAI-1 and the observed hemostatic dysregulation. The strong association between NLRP-3 inflammasome and PAI-1 in baseline samples of patients with sepsis and DIC also suggests that NLRP-3 inflammasome may contribute to the fibrinolytic dysregulation in sepsis and DIC.TableInflammatory and hemostatic biomarkers correlated with NLRP-3 inflammasome levels in patients with sepsis and suspected disseminated intravascular coagulation (DIC)NLRP-3 inflammasome correlationP (Mann-Whitney)Spearman rCD40L.5716−0.08028PAI-1.00410.3915MP-TF.14910.2528Fibrinogen.76850.04314Fibronectin.8291−0.03067Cortisol.07580.2484D-Dimer.32720.1495MP-TF, Microparticle-associated tissue factor; PAI-1, plasminogen activator inhibitor 1. Open table in a new tab