title: Non-Lethal Endotoxin Injection: A Rat Model of Hypercoagulability.
abstract: Systemic inflammation co-activates coagulation, which unchecked culminates in a lethal syndrome of multi-organ microvascular thrombosis known as disseminated intravascular coagulation (DIC). We studied an endotoxin-induced inflammatory state in rats to identify biomarkers of hemostatic imbalance favoring hypercoagulability. Intraperitoneal injection of LPS at 15 mg/kg body weight resulted in peripheral leukopenia and widespread neutrophilic sequestration characteristic of an acute systemic inflammatory response. Early indicators of hemostatic pathway activation developed within 4 hours, including increased circulating concentrations of procoagulant extracellular vesicles (EVs), EVs expressing endothelial cell and platelet membrane markers, and high concentration of soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor-1 (PAI-1), and D-dimers. Inflammation persisted throughout the 48-hour observation period; however, increases were found in a subset of serum microRNA (miRNA) that coincided with gradual resolution of hemostatic protein abnormalities and reduction in EV counts. Dose-adjusted LPS treatment in rats provides a time-course model to develop biomarker profiles reflecting procoagulant imbalance and rebalance under inflammatory conditions.
authors.affiliation: Comparative Coagulation Section, Department of Population Medicine and Diagnostic Sciences, Cornell University, Ithaca, NY, United States of America.
authors.forename: Marjory B
authors.initials: MB
authors.lastname: Brooks
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Turk
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, United States of America.
authors.forename: Abraham
authors.initials: A
authors.lastname: Guerrero
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, United States of America.
authors.forename: Padma K
authors.initials: PK
authors.lastname: Narayanan
authors.affiliation: Scintillon Institute, San Diego, CA, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Nolan
authors.affiliation: Department of Pathology, Safety Assessment and Laboratory Animal Resources, Merck Research Laboratories, West Point, PA, United States of America.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Besteman
authors.affiliation: Department of Pathology Microbiology and Immunology, School of Veterinary Medicine, University of California-Davis, Davis, CA, United States of America.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Wilson
authors.affiliation: GlaxoSmithKline, Research and Development, King of Prussia, Pennsylvania, United States of America.
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Thomas
authors.affiliation: GlaxoSmithKline, Research and Development, King of Prussia, Pennsylvania, United States of America.
authors.forename: Cindy E
authors.initials: CE
authors.lastname: Fishman
authors.affiliation: Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United States of America.
authors.forename: Karol L
authors.initials: KL
authors.lastname: Thompson
authors.affiliation: Bayer Pharma AG, Aprather Weg,Wuppertal, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Ellinger-Ziegelbauer
authors.affiliation: Health and Environmental Sciences Institute, Suite, Washington, DC, United States of America.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Pierson
authors.affiliation: Department of Pathology, Covance Laboratories, Greenfield, IN, United States of America.
authors.forename: April
authors.initials: A
authors.lastname: Paulman
authors.affiliation: Global Statistical Sciences, Lilly Research Laboratories, Indianapolis, IN, United States of America.
authors.forename: Alan Y
authors.initials: AY
authors.lastname: Chiang
authors.affiliation: Pathology Department, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, United States of America.
authors.forename: Albert E
authors.initials: AE
authors.lastname: Schultze
mesh_terms: D000208:Acute Disease; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D000067128:Extracellular Vesicles / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced; D008070:Lipopolysaccharides; D008297:Male; D035683:MicroRNAs / Q000097:blood; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019851:Thrombophilia / Q000139:chemically induced* / Q000276:immunology / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; D008070:Lipopolysaccharides; D035683:MicroRNAs; D017395:Plasminogen Activator Inhibitor 1; C036309:fibrin fragment D; D018799:Intercellular Adhesion Molecule-1