Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice.

Abstract

In the pathogenesis of sepsis and disseminated intravascular coagulation (DIC), dysfunctional anticoagulant pathways are important. The function of the protein C system in DIC is impaired because of low levels of protein C and down-regulation of thrombomodulin. The administration of (activated) protein C results in an improved outcome in experimental and clinical studies of DIC. It is unknown whether congenital deficiencies in the protein C system are associated with more severe DIC. The aim of the present study was to investigate the effect of a heterozygous deficiency of protein C on experimental DIC in mice. Mice with single-allele targeted disruption of the protein C gene (PC+/-) mice and wild-type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg) intraperitoneally. PC+/-mice had more severe DIC, as evidenced by a greater decrease in fibrinogen level and a larger drop in platelet count. Histologic examination showed more fibrin deposition in lungs, kidneys, and liver in mice with a heterozygous deficiency of protein C. Interestingly, PC+/- mice had significantly higher levels of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, indicating an interaction between the protein C system and the inflammatory response. Survival was lower at 12 and 24 hours after endotoxin in the PC+/- mice. These results confirm the important role of the protein C system in the coagulative-inflammatory response on endotoxemia and may suggest that congenital deficiencies in the protein C system are associated with more severe DIC and adverse outcome in sepsis.

• Authors: Marcel Levi, Janine Dörffler-Melly, Pieter Reitsma, Harry Buller, Sandrine Florquin, Tom van der Poll, Peter Carmeliet
• Journal: Blood (Blood) Vol. 101 Issue 12 Pg. 4823-7 (Jun 15 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12609841 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Endotoxins
• Interleukin-1
• Interleukin-6
• Protein C
• Tumor Necrosis Factor-alpha
• Fibrin
• Fibrinogen

Topics

• Animals
• Cytokines (blood)
• Disseminated Intravascular Coagulation (etiology, genetics)
• Endotoxins
• Escherichia coli
• Fibrin (analysis)
• Fibrinogen (analysis)
• Heterozygote
• Interleukin-1 (blood)
• Interleukin-6 (blood)
• Kidney (chemistry)
• Liver (chemistry)
• Lung (chemistry)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Platelet Count
• Protein C (genetics, physiology)
• Protein C Deficiency (genetics)
• Tumor Necrosis Factor-alpha (analysis)