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Am J Physiol Heart Circ Physiol. 2015 Jan 15;308(2):H83-91. doi: 10.1152/ajpheart.00289.2014. Epub 2014 Nov 7.

Increased coagulation and suppressed generation of activated protein C in aged mice during intra-abdominal sepsis.

Author information

1
Department of Surgery, University of Kentucky, Lexington, Kentucky;
2
Department of Surgery, University of Texas Medical Branch, Galveston, Texas;
3
Department of Statistics, University of Kentucky, Lexington, Kentucky;
4
Department of Surgery, University of Kentucky, Lexington, Kentucky; Markey Cancer Center, University of Kentucky, Lexington, Kentucky;
5
Oklahoma Medical Research Foundation, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma.
6
Department of Surgery, University of Kentucky, Lexington, Kentucky; Department of Physiology, University of Kentucky, Lexington, Kentucky; Markey Cancer Center, University of Kentucky, Lexington, Kentucky; hiroshi.saito@uky.edu.

Abstract

Sepsis is a life-threatening clinical condition that is particularly serious among the elderly who experience considerably higher mortality rates compared with younger patients. Using a sterile endotoxemia model, we previously reported age-dependent mortality in conjunction with enhanced coagulation and insufficient levels of anti-coagulant factor activated protein C (aPC). The purpose of the present study was to further investigate the mechanisms for age-dependent coagulation and aPC insufficiency during experimental sepsis. Intra-abdominal sepsis was induced by cecal ligation and puncture (CLP) using 21 or 16 gauge (G) needles (double-puncture) on young (4 to 6 mo old) and aged (20 to 25 mo old) male C57BL/6 mice. When compared with young mice, aged mice showed significantly increased mortality (92% vs. 28%), systemic inflammation, and coagulation in the lung and kidney after 21G CLP. Young mice with more severe CLP (16G) showed a mortality rate and inflammation equivalent to aged mice with 21G CLP; however, enhanced coagulation and kidney dysfunction were significant only in the aged. In young mice, increased levels of aPC after CLP were coupled with reduced levels of protein C (PC), suggesting the conversion of PC to aPC; however, PC and aPC levels remained unchanged in aged mice, indicating a lack of PC to aPC conversion. Activation of fibrinolysis, determined by plasma d-dimer levels, was similar regardless of age or CLP severity, and plasminogen activator inhibitor-1, an inhibitor of fibrinolysis, showed severity-dependent induction independent of age. These results suggest that enhanced coagulation in aged mice during sepsis is due to dysfunction of the PC activation mechanism.

KEYWORDS:

aging; cecal ligation and puncture; coagulation; protein C; renal dysfunction; sepsis

PMID:
25380813
PMCID:
PMC4338937
DOI:
10.1152/ajpheart.00289.2014
[Indexed for MEDLINE]
Free PMC Article

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