title: Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia.
abstract: Sepsis is associated with systemic inflammation, coagulopathy, and disrupted protein C (PC) pathway function. The effect of prothrombotic polymorphism, factor V Leiden (Arg506Gln; FV Leiden), was examined in a large clinical trial (PROWESS) of severe sepsis and a mouse endotoxemia model. In PROWESS, 4.1% (n = 65) of patients were heterozygous FV Leiden (VL+/-) carriers. The 28-day mortality was lower in VL+/- (13.9%) than in non-FV Leiden (VL-/-; 27.9%) patients (P =.013). The mortality benefit of recombinant human activated PC (rhAPC) treatment was similar in VL+/- (placebo, 15.6%; rhAPC,12.1%) and VL-/- patients (placebo, 31.0%; rhAPC, 24.7%; interaction P =.981). VL+/- status did not appear to influence baseline biomarkers of coagulopathy and inflammation or disease severity, with the exception that vasopressor usage was less in VL+/- patients (46.2% versus 63.0%; P =.009). In a median lethal dose (40 mg/kg) endotoxin mouse model, VL+/- mice had lower mortality than wild-type mice (19% versus 57%; P =.008), whereas the mortality of homozygous (VL+/+) mice was almost identical to that of wild-type mice (65% versus 57%; P =.76). The findings suggest that FV Leiden constitutes a rare example of a balanced gene polymorphism that maintains the FV Leiden mutation in the general gene pool due to a survival advantage of VL+/- in severe sepsis.
authors.affiliation: Blood Research Institute, Blood Center of Southeast Wisconsin and Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Kerlin
authors.forename: S Betty
authors.initials: SB
authors.lastname: Yan
authors.forename: Berend H
authors.initials: BH
authors.lastname: Isermann
authors.forename: John T
authors.initials: JT
authors.lastname: Brandt
authors.forename: Rashmi
authors.initials: R
authors.lastname: Sood
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Basson
authors.forename: David E
authors.initials: DE
authors.lastname: Joyce
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Dhainaut
mesh_terms: D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation; D019446:Endotoxemia / Q000235:genetics* / Q000401:mortality; D005165:Factor V / Q000502:physiology*; D005260:Female; D006579:Heterozygote; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D017354:Point Mutation; D011486:Protein C / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D012189:Retrospective Studies; D018805:Sepsis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D011486:Protein C; D011994:Recombinant Proteins; C095381:factor V Leiden; D005165:Factor V