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

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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 × 104 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-α), 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-α 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.