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.


METHODS
Controlled animal experiment.


METHODS
Academic research laboratory.


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


METHODS
None.


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.
Brüggemann
Lois W
LW
Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Schoenmakers
Saskia H H F
SH
Groot
Angelique P
AP
Reitsma
Pieter H
PH
Spek
C Arnold
CA
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D001202:Ascitic Fluid / Q000378:metabolism; D002448:Cell Adhesion; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004926:Escherichia coli; D005165:Factor V / Q000235:genetics*; D005337:Fibrin / Q000378:metabolism; D005838:Genotype; D006098:Granulocytes / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D007668:Kidney / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D010447:Peptide Hydrolases / Q000378:metabolism; D010533:Peritoneal Lavage; D010538:Peritonitis / Q000235:genetics* / Q000382:microbiology; D017354:Point Mutation; D018805:Sepsis / Q000235:genetics* / Q000382:microbiology; D013927:Thrombosis / Q000473:pathology
D016207:Cytokines; C046193:antithrombin III-protease complex; C095381:factor V Leiden; D000990:Antithrombin III; D005165:Factor V; D005337:Fibrin; D010447:Peptide Hydrolases