Increased coagulation and suppressed generation of activated protein C in aged mice during intra-abdominal sepsis.
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.
Department of Surgery, University of Kentucky, Lexington, Kentucky;
Marlene E
ME
Starr
Department of Surgery, University of Kentucky, Lexington, Kentucky;
Hitoshi
H
Takahashi
Department of Surgery, University of Kentucky, Lexington, Kentucky;
Daiki
D
Okamura
Department of Surgery, University of Kentucky, Lexington, Kentucky;
Brittany A
BA
Zwischenberger
Department of Surgery, University of Texas Medical Branch, Galveston, Texas;
Amy A
AA
Mrazek
Department of Surgery, University of Texas Medical Branch, Galveston, Texas;
Junji
J
Ueda
Department of Statistics, University of Kentucky, Lexington, Kentucky;
Arnold J
AJ
Stromberg
Department of Surgery, University of Kentucky, Lexington, Kentucky; Markey Cancer Center, University of Kentucky, Lexington, Kentucky;
B Mark
BM
Evers
Oklahoma Medical Research Foundation, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma.
Charles T
CT
Esmon
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.
Hiroshi
H
Saito
D000375:Aging / Q000097:blood*; D000818:Animals; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism*; D019446:Endotoxemia / Q000209:etiology / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D001779:Blood Coagulation Factors; D008070:Lipopolysaccharides; D002097:C-Reactive Protein
aging; cecal ligation and puncture; coagulation; protein C; renal dysfunction; sepsis