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.
MeSH terms
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Acute Disease
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Animals
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Biomarkers / blood
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Blood Coagulation / drug effects
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Blood Platelets / metabolism
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Disease Models, Animal
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Endothelial Cells / metabolism
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Extracellular Vesicles / metabolism
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Fibrin Fibrinogen Degradation Products / metabolism
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Intercellular Adhesion Molecule-1 / metabolism
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Leukopenia / chemically induced
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Lipopolysaccharides*
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Male
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MicroRNAs / blood
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Neutrophils / metabolism
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Neutrophils / pathology
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Plasminogen Activator Inhibitor 1 / metabolism
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Rats
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Rats, Wistar
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Thrombophilia / chemically induced*
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Thrombophilia / immunology
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Thrombophilia / physiopathology*
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Time Factors
Substances
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Biomarkers
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Fibrin Fibrinogen Degradation Products
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Lipopolysaccharides
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MicroRNAs
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Plasminogen Activator Inhibitor 1
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fibrin fragment D
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Intercellular Adhesion Molecule-1
Grants and funding
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. 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. Amgen Inc., Merck Research Laboratories, GlaxoSmithKline, Bayer Pharma AG, Lilly Research Laboratories and Covance Laboratories provided either direct, in-direct or in-kind resources to this study and had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.