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Prepublished online as a Blood First Edition Paper on July 17, 2003; DOI 10.1182/blood-2003-06-1789.
Submitted June 3, 2003
Accepted July 7, 2003
Survival advantage associated with heterozygous Factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia
Bryce A Kerlin, Sau-Chi Betty Yan*, Berend H Isermann, John T Brandt, Rashmi Sood, Bruce R Basson, David E Joyce, Hartmut Weiler, and Jean-Francois Dhainaut
Blood Research Institute & Medical College of Wisconsin, Blood Center of SE Wisconsin, Milwaukee, WI, USA
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN, USA
Department of Intensive Care, Cochin Hospital, AP-HP, Cochin Institute, Cochin Port-Royal Medical School, Paris V University, Paris, France
Children's Specialists of San Diego, San Diego, CA, USA
* Corresponding author; email: s.betty_yan{at}lilly.com.
Sepsis is associated with systemic inflammation, coagulopathy, and disrupted protein C (PC) pathway function. The effect of prothrombotic polymorphism, factor V Leiden (R506Q) (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=0.013). 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=0.981). VL+/- status did not appear to influence baseline biomarkers of coagulopathy and inflammation or disease severity, with exception that vasopressor usage was less in VL+/- patients (46.2% vs 63.0 %; P=0.009). In an LD50 (40mg/kg) endotoxin mouse model, VL+/- mice had lower mortality than wild type mice (19% vs 57%; P=0.008), while mortality of homozygous (VL+/+) mice was almost identical to that of wild type mice (65% vs 57%; P=0.76). 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.
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