title: Brodifacoum induces early hemoglobinuria and late hematuria in rats: novel rapid biomarkers of poisoning.
abstract: BACKGROUND
  Brodifacoum (BDF) is a superwarfarin that is used primarily as a rodenticide. There have been increasing numbers of reports of human cases of accidental or intentional BDF ingestion with high mortality rate. Its broad availability and high lethality suggest that BDF should be considered a potential chemical threat. Currently, there is no biomarker for early detection of BDF ingestion in humans; patients typically present with severe coagulopathy. Since we demonstrated earlier that warfarin can induce acute kidney injury with hematuria, we tested whether BDF would also lead to change in urinary biomarkers.
  
  
  METHODS
  BDF was administered to Sprague Dawley rats via oral gavage. N-acetylcysteine (NAC) was given per os in drinking water 24 h prior to BDF. Urinalysis was performed at different times after BDF administration. Anticoagulation and serum creatinine levels were analyzed in the blood.
  
  
  RESULTS
  We observed that within a few hours the animals developed BDF-dose-dependent transient hemoglobinuria, which ceased within 24 h. This was accompanied by a transient decrease in hematocrit, gross hemolysis and an increase in free hemoglobin in the serum. At later times, animals developed true hematuria with red blood cells in the urine, which was associated with BDF anticoagulation. NAC prevented early hemoglobinuria, but not late hematuria associated with BDF.
  
  
  CONCLUSIONS
  We propose that transient early hemoglobinuria (associated with oxidative stress) with consecutive late hematuria (associated with anticoagulation) are novel biomarkers of BDF poisoning, and they can be used in clinical setting or in mass casualty with BDF to identify poisoned patients.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Ware
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
authors.forename: Israel
authors.initials: I
authors.lastname: Rubinstein
authors.forename: Guy
authors.initials: G
authors.lastname: Weinberg
authors.forename: Brad H
authors.initials: BH
authors.lastname: Rovin
authors.forename: Lee
authors.initials: L
authors.lastname: Hebert
authors.forename: Navin
authors.initials: N
authors.lastname: Muni
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Cianciolo
authors.forename: Anjali A
authors.initials: AA
authors.lastname: Satoskar
authors.forename: Tibor
authors.initials: T
authors.lastname: Nadasdy
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Brodsky
mesh_terms: D015110:4-Hydroxycoumarins / Q000506:poisoning*; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers / Q000652:urine; D018450:Disease Progression; D016166:Free Radical Scavengers / Q000494:pharmacology; D006417:Hematuria / Q000139:chemically induced*; D006454:Hemoglobins / Q000187:drug effects; D006456:Hemoglobinuria / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012378:Rodenticides / Q000506:poisoning*
chemical_list: D015110:4-Hydroxycoumarins; D015415:Biomarkers; D016166:Free Radical Scavengers; D006454:Hemoglobins; D012378:Rodenticides; C013418:bromfenacoum; D000111:Acetylcysteine