Faculty Collaboration Database

Age-dependent vulnerability to endotoxemia is associated with reduction of anticoagulant factors activated protein C and thrombomodulin. Blood 2010 Jun 10;115(23):4886-93

Date

03/30/2010

Pubmed ID

20348393

Pubmed Central ID

PMC2890181

DOI

10.1182/blood-2009-10-246678

Scopus ID

2-s2.0-77954738683 (requires institutional sign-in at Scopus site)   64 Citations

Abstract

The protein C (PC) pathway is an important anticoagulant mechanism that prevents thrombosis during the systemic inflammatory response. Thrombomodulin (TM), an endothelial cell membrane receptor, accelerates the conversion of PC to activated protein C (APC), which leads to the down-regulation of thrombin production and fibrin formation. Induction of acute endotoxemia in young and aged mice with a low dose of bacterial endotoxin lipopolysaccharide (LPS, 2.5 mg/kg) caused a high mortality rate in aged (80%) but not young (0%) mice. After injection with this dose of LPS, fibrin formation was significantly elevated only in aged mice, plasma APC levels were increased only in young mice, and TM expression was profoundly depressed in the aged. The increased thrombosis, suppressed APC level, and decreased TM expression were not observed in young mice receiving a higher dose of LPS (20 mg/kg), which resulted in a mortality rate (78%) equivalent to that seen in aged mice with the low-dose LPS. Mutant mice with reduced TM showed significantly less plasma APC and increased fibrin formation compared with wild-type mice after LPS. These results demonstrate that PC pathway activation is suppressed with aging and is partly responsible for age-associated thrombosis and high mortality during endotoxemia.

Author List

Starr ME, Ueda J, Takahashi H, Weiler H, Esmon CT, Evers BM, Saito H

MESH terms used to index this publication - Major topics in bold

Aging
Animals
Endotoxemia
Fibrin
Gene Expression Regulation
Lipopolysaccharides
Mice
Mice, Mutant Strains
Mice, Transgenic
Protein C
Thrombomodulin
Thrombosis