Chest
Clinical Investigations in Critical CareLow Levels of Protein C Are Associated With Poor Outcome in Severe Sepsis
Section snippets
Materials and Methods
The ISS was a randomized, double-blind, placebo-controlled multicenter study of IV ibuprofen in 455 patients with severe sepsis. The study was approved by the institutional review board at each of the seven centers in the United States and Canada, and consent was obtained from each patient or their next of kin. Patient characteristics and the main study results have been reported elsewhere.16 Patients were enrolled into the study from October 1989 to March 1995.
Patients with a known or
Results
Table 2 displays baseline characteristics and results of the coagulation marker levels (ie, D-dimer, fibrinogen, protein C antigen, and platelets) of the seven subgroups of patients selected from the ISS trial as defined in the “Material and Methods” section. A total of 58 of the 70 patients (83%) included in this study received placebo, and the other 12 patients received ibuprofen in the ISS study. There were no statistically significant (ie, p≤ 0.05) differences between the two treatment
Discussion
Activated protein C is a serine protease that inhibits coagulation factors Va and VIIIa, subsequently blocking the generation of thrombin. Both plasminogen activator inhibitor (PAI)-1 and activated thrombin-activatable fibrinolysis inhibitor (TAFI) are inhibitors of the endogenous fibrinolytic system. TAFI is activated by thrombin. Activated protein C also exhibits profibrinolytic activity by neutralizing PAI-1 or by limiting the activation of TAFI by limiting thrombin generation.1920 Protein C
References (44)
- et al.
Time course of hemostatic abnormalities in sepsis and its relation to outcome
Chest
(1993) - et al.
Septic shock, multiple organ failure and disseminated intravascular coagulation: compare patterns of antithrombin III, protein C and protein S deficiencies
Chest
(1992) - et al.
Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients
Blood
(1996) - et al.
Antithrombotic and anti-inflammatory agents of the protein C anticoagulant pathway
Ann Rep Med Chem
(1994) - et al.
A trial of antioxidants N-acetylcysteine and procysteine in ARDS
Chest
(1997) - et al.
The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent
Blood
(1996) - et al.
The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide A in systemic meningococcal disease
Thromb Res
(1989) - et al.
Direct detection of activated protein C in blood from human subjects
Blood
(1992) Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin?
Blood
(2000)- et al.
Immunobiology and therapeutic applications of protein C/protein S/thrombomodulin in human and experimental allotransplantation and xenotransplantation
Trends Cardiovasc Med
(1997)
New therapies for severe meningococcal disease but better outcome?
Lancet
Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture
Blood
Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects
N Engl J Med
Coagulation, fibrinolysis, and kallikrein systems in sepsis: relation to outcome
Crit Care Med
Plasminogen activator inhibitor 1: a new prognostic marker in septic shock
Thromb Haemost
Fibrinolysis and coagulation in patients with infectious disease and sepsis
Thromb Haemost
How coagulation defects alter outcome in sepsis: survival may depend on reversing procoagulant conditions
J Crit Illness
Modulators of coagulation: a critical appraisal of their role in sepsis
Arch Intern Med
Pathogenesis of disseminated intravascular coagulation in sepsis
JAMA
Complement activation and endotoxin levels in systemic meningococcal disease
J Infect Dis
Protein C, protein S, and C4b-binding protein in severe infection and septic shock
Thromb Haemost
Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality
Thromb Haemost
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Drs. Yan, Helterbrand, and Wright are employees of Eli Lilly and Company. Dr. Hartman was an employee of Lilly during the collaboration of this study. This study is a scientific collaboration between Lilly and Dr. Bernard.
Funds needed for conducting the coagulation assays at the University of Vermont were provided by Eli Lilly and Co. The ibuprofen clinical trial was supported by grant HL43167 from National Heart, Lung, and Blood Institute of the National Institutes of Health.