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Blood, 1 November 2003, Vol. 102, No. 9, pp. 3085-3092.
Prepublished online as a Blood First Edition Paper on July 17, 2003; DOI 10.1182/blood-2003-06-1789.
 Previous Article | Table of Contents | Next Article 
PLENARY PAPERS
Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia
Bryce A. Kerlin,
S. Betty Yan,
Berend H. Isermann,
John T. Brandt,
Rashmi Sood,
Bruce R. Basson,
David E. Joyce,
Hartmut Weiler, and
Jean-Francois Dhainaut
From the Blood Research Institute, Blood Center of Southeast Wisconsin and Medical College of Wisconsin, Milwaukee; Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN; and Department of Intensive Care, Cochin Hospital, AP-HP, Cochin Institute, Cochin Port-Royal Medical School, Paris V University, Paris, France.
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.
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