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

Marlene E. Starr, Hitoshi Takahashi, Daiki Okamura, Brittany A. Zwischenberger, Amy A. Mrazek, Junji Ueda, Arnold J. Stromberg, B. Mark Evers, Charles T. Esmon, Hiroshi Saito

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)H83-H91
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume308
Issue number1
DOIs
StatePublished - 2015

Bibliographical note

Publisher Copyright:
© 2015 the American Physiological Society.

Keywords

  • Aging
  • Cecal ligation and puncture
  • Coagulation
  • Protein C
  • Renal dysfunction
  • Sepsis

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