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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Starr, ME; Takahashi, H; Okamura, D; Zwischenberger, BA; Mrazek, AA; Ueda, J; Stromberg, AJ; Evers, BM; Esmon, CT; Saito, H

Published Date

  • January 15, 2015

Published In

Volume / Issue

  • 308 / 2

Start / End Page

  • H83 - H91

PubMed ID

  • 25380813

Pubmed Central ID

  • 25380813

Electronic International Standard Serial Number (EISSN)

  • 1522-1539

Digital Object Identifier (DOI)

  • 10.1152/ajpheart.00289.2014

Language

  • eng

Conference Location

  • United States