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PLoS One. 2017 Jan 12;12(1):e0169976. doi: 10.1371/journal.pone.0169976. eCollection 2017.

Non-Lethal Endotoxin Injection: A Rat Model of Hypercoagulability.

Author information

1
Comparative Coagulation Section, Department of Population Medicine and Diagnostic Sciences, Cornell University, Ithaca, NY, United States of America.
2
Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, CA, United States of America.
3
Scintillon Institute, San Diego, CA, United States of America.
4
Department of Pathology, Safety Assessment and Laboratory Animal Resources, Merck Research Laboratories, West Point, PA, United States of America.
5
Department of Pathology Microbiology and Immunology, School of Veterinary Medicine, University of California-Davis, Davis, CA, United States of America.
6
GlaxoSmithKline, Research and Development, King of Prussia, Pennsylvania, United States of America.
7
Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United States of America.
8
Bayer Pharma AG, Aprather Weg,Wuppertal, Germany.
9
Health and Environmental Sciences Institute, Suite, Washington, DC, United States of America.
10
Department of Pathology, Covance Laboratories, Greenfield, IN, United States of America.
11
Global Statistical Sciences, Lilly Research Laboratories, Indianapolis, IN, United States of America.
12
Pathology Department, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, United States of America.

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.

PMID:
28081568
PMCID:
PMC5233421
DOI:
10.1371/journal.pone.0169976
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Lilly supported the in-life phase of this study by contracting for laboratories services, animals and reagents at the Covance facility in Greenfield, IN. All other work was provided in-kind by the ILSI HESI Cardiac Safety Committee Cardiac Biomarkers Working Group, which is supported by sponsorships from member companies. HESI’s scientific initiatives are primarily supported by the in-kind contributions (from public and private sector participants) of time, expertise, and experimental effort. These contributions are supplemented by direct funding (that primarily supports program infrastructure and management) provided primarily by HESI’s corporate sponsors. All authors are members of the ILSI HESI Cardiac Safety Committee Cardiovascular Biomarkers Working Group, a global non-profit organization. James R. Turk, Abraham Guerrero and Padma K. Narayanan are employed by Amgen Inc. Elizabeth G. Besteman is employed by Merck Research Laboratories. Roberta A. Thomas and Cindy E. Fishman are employed by GlaxoSmithKline. Heidrun Ellinger-Ziegelbauer is employed by Bayer Pharma AG. April Paulman is employed by Covance Laboratories. Alan Y. Chiang and Albert E. Schultze are employed by Lilly Research Laboratories. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

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