title: Increase in activated protein C mediates acute traumatic coagulopathy in mice.
abstract: In severely injured and hypoperfused trauma patients, endogenous acute coagulopathy (EAC) is associated with an increased morbidity and mortality. Recent human data correlate this coagulopathy with activation of the protein C pathway. To examine the mechanistic role of protein C in the development of EAC, we used a mouse model of trauma and hemorrhagic shock, characterized by the combination of tissue injury and severe metabolic acidosis. Mice were subjected to one of four treatment groups: 1) C, control; 2) T, trauma (laparotomy); 3) H, hemorrhage (MAP, 35 mmHg x 60 min); 4) TH, trauma + hemorrhage. After 60 min, blood was drawn for analysis. Compared with C mice, the TH mice had a significantly elevated activated partial thromboplastin time (23.3 vs. 34.5 s) and significantly increased levels of activated protein C (aPC; 2.30 vs. 13.58 ng/mL). In contrast, T and H mice did not develop an elevated activated partial thromboplastin time or increased aPC. Selective inhibition of the anticoagulant property of aPC prevented the coagulopathy seen in response to trauma/hemorrhage (23.5 vs. 38.6 s [inhibitory vs. control monoclonal antibody]) with no impact on survival during the shock period. However, complete blockade of both the anticoagulant and cytoprotective functions of aPC caused 100% mortality within 45 min of shock, with histopathology evidence of pulmonary thrombosis and perivascular hemorrhage. These results indicate that our unique mouse model of T/H shock mimics our previous observations in trauma patients and demonstrates that EAC is mediated by the activation of the protein C pathway. In addition, the cytoprotective effect of protein C activation seems to be necessary for survival of the initial shock injury.
authors.affiliation: The Department of Surgery, University of California, San Francisco, California, USA. hermanodequeso@yahoo.com
authors.forename: Brian B
authors.initials: BB
authors.lastname: Chesebro
authors.forename: Pamela
authors.initials: P
authors.lastname: Rahn
authors.forename: Michel
authors.initials: M
authors.lastname: Carles
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Karim
authors.initials: K
authors.lastname: Brohi
authors.forename: Daniel
authors.initials: D
authors.lastname: Frith
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Pittet
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Cohen