Faculty Collaboration Database

Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood 2003 Nov 01;102(9):3085-92

Date

07/19/2003

Pubmed ID

12869495

DOI

10.1182/blood-2003-06-1789

Scopus ID

2-s2.0-0142245617 (requires institutional sign-in at Scopus site)   140 Citations

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.

Author List

Kerlin BA, Yan SB, Isermann BH, Brandt JT, Sood R, Basson BR, Joyce DE, Weiler H, Dhainaut JF

Authors

Rashmi Sood PhD Associate Professor in the Pathology department at Medical College of Wisconsin
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Animals
Biomarkers
Blood Coagulation
Endotoxemia
Factor V
Female
Heterozygote
Humans
Inflammation
Male
Mice
Mice, Mutant Strains
Middle Aged
Point Mutation
Protein C
Recombinant Proteins
Retrospective Studies
Sepsis
Survival Rate
Treatment Outcome