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

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(4) 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.