Plasma Nucleosomes Correlate with Markers of Inflammation and Thrombosis in Patients with Sepsis‐Associated Coagulopathy
Authors: Walborn Amanda Temple , Patel Priya , Hoppensteadt Debra , Mosier Michael , Statz Stephen , Rondina Matthew , Fareed Jawed 
Published: November 2023

Introduction

Inflammation is known to contribute to the development of a pro‐thrombotic state, a process which is exemplified in patients who develop coagulopathy secondary to the severe inflammatory state observed in sepsis. Sepsis‐associated coagulopathy (SAC) is a severe clinical condition characterized by uncontrolled and widespread activation of coagulation. This leads to fibrin deposition in the microvasculature and subsequent organ dysfunction, accompanied by an elevated risk of bleeding due to the consumption of platelets and coagulation factors. The presence of nuclear material including histones, DNA, and nucleosomes (histone‐DNA complexes) in blood has recently been identified as an additional potential link between inflammation and coagulation in patients with SAC. In response to infection, neutrophils can expel their nuclear contents, including DNA, histones, and bactericidal factors into the blood in order to trap and kill bacteria. As these nuclear components are known to be procoagulant, this process may also contribute to hemostatic disruption in patients with sepsis.

Materials and Methods

In order to test the hypothesis that extracellular nuclear material is associated with linking infection and inflammation with coagulopathies in patients with SAC, nucleosomes (histone‐DNA complexes) as well as biomarkers of infection and inflammation were measured. Plasma samples were obtained from 113 adult patients with sepsis and suspected coagulopathy at the time of ICU admission. Levels of extracellular nucleosomes, Procalcitonin (a marker of infection), and D‐Dimer (a marker of thrombosis) were measured using commercially available ELISA kits. Levels of the pro‐inflammatory cytokine IL‐8 were measured using a commercially available biochip system. Correlations were evaluated using Spearman correlation coefficients for non‐parametric data in GraphPad Prism software.

Results

Plasma levels of nucleosomes along with D‐dimer, procalcitonin and IL‐8 were markedly higher in SAC patients. Significant correlations were observed between nucleosomes and D‐Dimer (p=0.0004, r=0.3297), procalcitonin (p=0.0024, r=0.2834), and IL‐8 (p=0.0181, r=0.223).

Conclusions

Nucleosomes showed significant correlations with D‐Dimer, procalcitonin, and IL‐8 in the plasma of patients with sepsis‐associated coagulopathy. The correlation of nucleosomes with procalcitonin, a marker of bacterial infection in patients with sepsis, supports the hypothesis that extracellular nucleosomes occur due to an infection related process. The correlation of nucleosomes with IL‐8, a pro‐inflammatory cytokine and chemotactic factor for nucleosomes, supports the hypothesis that extracellular nucleosomes may be associated with neutrophil response. The correlation between nucleosomes and D‐Dimer, a clinically used thrombosis marker supports the hypothesis that extracellular nucleosomes and nuclear material links inflammation and thrombosis and may contribute to the pathogenesis of sepsis‐associated coagulopathy.