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.
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 mouseseptic peritonitis, and the general protective effect of FVL in sepsis needs further investigation.
Authors: Thomas Benfield; Karen Ejrnaes; Klaus Juul; Christian Østergaard; Jannik Helweg-Larsen; Nina Weis; Lea Munthe-Fog; Gitte Kronborg; Marianne Ring Andersen; Anne Tybjaerg-Hansen; Børge G Nordestgaard; Peter Garred Journal: Crit Care Date: 2010-03-05 Impact factor: 9.097
Authors: Marcel Schouten; Cornelis van't Veer; Joris J T H Roelofs; Marcel Levi; Tom van der Poll Journal: Crit Care Date: 2010-08-03 Impact factor: 9.097
Authors: Maiara Marx Luz Fiusa; Marco Antonio Carvalho-Filho; Joyce M Annichino-Bizzacchi; Erich V De Paula Journal: BMC Med Date: 2015-05-06 Impact factor: 8.775
Authors: Lois W Brüggemann; Henri H Versteeg; Tatjana M Niers; Pieter H Reitsma; C Arnold Spek Journal: J Cell Mol Med Date: 2008-03-20 Impact factor: 5.310