Role of the factor V Leiden mutation in septic peritonitis assessed in factor V Leiden transgenic mice

Crit Care Med. 2006 Aug;34(8):2201-6. doi: 10.1097/01.CCM.0000228918.30931.E8.

Abstract

Objective: The factor V Leiden (FVL) mutation (Arg506Glu) results in the production of an FV protein that when activated is relatively resistant to inactivation by activated protein C and thereby leads to predisposition to thrombosis. The rather high prevalence of the FVL mutation in the general population prompted speculation about a potential survival benefit for individuals carrying the FVL allele. Indeed, both clinical and experimental animal data suggest that a heterozygous FVL genotype might protect against the lethal consequences of sepsis. We sought to confirm the survival advantage of heterozygous FVL mice in septic disease.

Design: Controlled animal experiment.

Setting: Academic research laboratory.

Subjects: Wild-type, heterozygous, and homozygous FVL mice subjected to 1 x 10 live bacteria as model for septic peritonitis.

Interventions: None.

Measurements and main results: The intraperitoneal injection of E. coli led to growth and dissemination of bacteria and provoked an inflammatory response as evident from elevated cytokine levels (interleukin-6, interleukin-10, and tumor necrosis factor-alpha), induced thrombin-antithrombin complex levels, increased granulocyte influx into the peritoneal cavity, liver necrosis, and adhesion of leukocytes to the vessel wall, resulting in approximately 50% mortality after 72 hrs. The FVL genotype had no significant effect on bacterial outgrowth, markers of inflammation (i.e., tumor necrosis factor-alpha levels of 152 [96.2-200], 152 [99.7-1745], and 110 [99.7-177] pg/mL in peritoneal lavage fluid at t = 20 hrs for wild-type, heterozygous, and homozygous FVL mice, respectively), thrombin generation (i.e., thrombin-antithrombin complex levels of 19.9 [9.31-37.4], 10.4 [6.55-15.8], and 12.6 [8.24-29.0] ng/mL in peritoneal lavage fluid at t = 6 hrs for wild-type, heterozygous, and homozygous FVL mice, respectively), and/or survival (50%, 36%, and 50% for wild-type, heterozygous, and homozygous FVL mice, respectively).

Conclusions: The FVL allele has no beneficial effect in mouse septic peritonitis, and the general protective effect of FVL in sepsis needs further investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antithrombin III / metabolism
  • Ascitic Fluid / metabolism
  • Cell Adhesion
  • Cytokines / blood
  • Disease Models, Animal
  • Escherichia coli
  • Factor V / genetics*
  • Fibrin / metabolism
  • Genotype
  • Granulocytes / metabolism
  • Heterozygote
  • Homozygote
  • Kidney / metabolism
  • Leukocytes / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Lung / metabolism
  • Mice
  • Mice, Transgenic
  • Necrosis
  • Peptide Hydrolases / metabolism
  • Peritoneal Lavage
  • Peritonitis / genetics*
  • Peritonitis / microbiology
  • Point Mutation*
  • Sepsis / genetics*
  • Sepsis / microbiology
  • Thrombosis / pathology

Substances

  • Cytokines
  • antithrombin III-protease complex
  • factor V Leiden
  • Antithrombin III
  • Factor V
  • Fibrin
  • Peptide Hydrolases