title: Extracellular histone H3 levels are inversely correlated with antithrombin levels and platelet counts and are associated with mortality in sepsis patients.
abstract: OBJECTIVE
  Sepsis is a leading cause of death worldwide. Extracellular histones are cytotoxic compounds mediating death in murine sepsis and circulating nucleosome levels predict mortality in human inflammation and sepsis. Whether or not circulating extracellular histone H3 correlates with other plasma parameters and/or ICU scoring systems has not been completely established, nor if levels of circulating extracellular histones can be used as predictive markers for clinical outcome in sepsis.
  
  
  METHODS
  We measured plasma histone H3 (H3) levels in the plasma of 43 sepsis patients who were admitted to the Intensive Care Unit and determined their correlation with disease severity, organ failure, mortality and coagulation- and tissue homeostasis parameters including LDH levels, thrombin potential (ETP), prothrombin levels, antithrombin levels and platelet counts.
  
  
  RESULTS
  Median H3 levels of sepsis patients at the ICU were significantly increased in non-survivors as compared to survivors with levels found being 3.15μg/ml versus 0.57μg/ml respectively, P=0.04. H3 levels are positively correlated with lactate dehydrogenase (LDH) activity (Spearman's rho=0.49, P<0.001), and negatively correlated with antithrombin levels (rho=-0.34, P=0.027) and platelet counts (rho=-0.33, P=0.031).
  
  
  CONCLUSIONS
  We conclude that circulating H3 levels correlate with mortality in sepsis patients and inversely correlate with antithrombin levels and platelet counts.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
authors.forename: Karin C A A
authors.initials: KC
authors.lastname: Wildhagen
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Maryse A
authors.initials: MA
authors.lastname: Wiewel
authors.affiliation: Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.affiliation: Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Janneke
authors.initials: J
authors.lastname: Horn
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
authors.forename: Roy
authors.initials: R
authors.lastname: Schrijver
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
authors.forename: Chris P M
authors.initials: CP
authors.lastname: Reutelingsperger
authors.affiliation: Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands. Electronic address: g.nicolaes@maastrichtuniversity.nl.
authors.forename: Gerry A F
authors.initials: GA
authors.lastname: Nicolaes
mesh_terms: D000991:Antithrombins / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D005260:Female; D006657:Histones / Q000097:blood*; D006801:Humans; D006836:Hydro-Lyases / Q000097:blood*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D010976:Platelet Count / Q000706:statistics & numerical data*; D011379:Prognosis; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity; D018805:Sepsis / Q000097:blood* / Q000175:diagnosis / Q000401:mortality*; D015996:Survival Rate
chemical_list: D000991:Antithrombins; D015415:Biomarkers; D006657:Histones; D006836:Hydro-Lyases; C045581:lactate dehydratase
keywords: Antithrombin; Histones; Mortality; NETosis; Sepsis; Thrombin generation