title: Survival advantage of heterozygous factor V Leiden carriers in murine sepsis.
abstract: BACKGROUND
  The high allelic frequency of the prothrombotic Leiden polymorphism in human blood coagulation factor V (FV) has been speculated to reflect positive selection during evolution. Heterozygous Leiden carriers enrolled in the placebo arm of the PROWESS sepsis trial and heterozygous Leiden mice challenged with endotoxin both showed reduced mortality, whereas homozygous Leiden mice were not protected from lethal endotoxemia. Follow-up analyses of clinical outcomes and of mouse models of infection with various pathogens remained inconclusive.
  
  
  OBJECTIVE
  To establish whether activated protein C resistance of FV Leiden modifies the outcome of bacterial infection in murine sepsis models.
  
  
  METHODS
  Homozygous and heterozygous FV Leiden mice were subjected to gram-positive (S. aureus) or gram-negative (Y. pestis; E. coli) septic peritonitis or polymicrobial, focal septic peritonitis induced by cecal ligation and puncture. The effect of FV Leiden on 7-day survival and bacterial dissemination was assessed. Outcomes were compared with the sepsis survival of mice with genetically impaired hemostasis (hemophilia A, thrombocytopenia, thrombin receptor PAR4 [protease activated receptor 4] deficiency, endothelial protein C receptor [ProcR/EPCR] deficiency).
  
  
  RESULTS
  Heterozygous, but not homozygous, Leiden mice were protected from lethal infection with highly virulent S. aureus and Y. pestis strains. FV Leiden did not affect the outcome of sepsis induced by cecal ligation and puncture, staphylokinase-deficient S. aureus, Pla-deficient Y. pestis, or E. coli. Thrombocytopenia, deficiency of PAR1 or PAR4 did not affect S. aureus sepsis survival, whereas hemophilia A increased mortality. ProcR deficiency selectively abolished the survival advantage of heterozygous Leiden mice.
  
  
  CONCLUSIONS
  In mice, heterozygous FV Leiden carriers are protected from sepsis mortality after infection with clinically relevant human bacterial pathogens.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kerschen
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.
authors.forename: I
authors.initials: I
authors.lastname: Hernandez
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zogg
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Maas
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Weiler
mesh_terms: D020016:Activated Protein C Resistance / Q000097:blood / Q000235:genetics*; D000818:Animals; D018988:Bacterial Translocation; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism / Q000382:microbiology; D004195:Disease Models, Animal; D000074283:Endothelial Protein C Receptor; D004926:Escherichia coli / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000097:blood / Q000382:microbiology; D005165:Factor V / Q000235:genetics / Q000378:metabolism*; D005342:Fibrinolysis; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010538:Peritonitis / Q000097:blood / Q000382:microbiology; D010641:Phenotype; D010930:Plague / Q000097:blood / Q000382:microbiology; D065840:Protective Factors; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D018805:Sepsis / Q000097:blood / Q000235:genetics* / Q000382:microbiology; D013203:Staphylococcal Infections / Q000097:blood / Q000382:microbiology; D013211:Staphylococcus aureus / Q000472:pathogenicity; D013997:Time Factors; D015010:Yersinia pestis / Q000472:pathogenicity
chemical_list: D000074283:Endothelial Protein C Receptor; C080248:Procr protein, mouse; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; C095381:factor V Leiden; D005165:Factor V; C112908:protease-activated receptor 4
keywords: APC resistance; EPCR protein, human; blood coagulation; factor V Leiden; sepsis