title: Impact of the factor V Leiden mutation on the outcome of pneumococcal pneumonia: a controlled laboratory study.
abstract: BACKGROUND
  Streptococcus (S.) pneumoniae is the most common cause of community-acquired pneumonia. The factor V Leiden (FVL) mutation results in resistance of activated FV to inactivation by activated protein C and thereby in a prothrombotic phenotype. Human heterozygous FVL carriers have been reported to be relatively protected against sepsis-related mortality. We here determined the effect of the FVL mutation on coagulation, inflammation, bacterial outgrowth and outcome in murine pneumococcal pneumonia.
  
  
  METHODS
  Wild-type mice and mice heterozygous or homozygous for the FVL mutation were infected intranasally with 2*106 colony forming units of viable S. pneumoniae. Mice were euthanized after 24 or 48 hours or observed in a survival study. In separate experiments mice were treated with ceftriaxone intraperitoneally 24 hours after infection and euthanized after 48 hours or observed in a survival study.
  
  
  RESULTS
  The FVL mutation had no consistent effect on activation of coagulation in either the presence or absence of ceftriaxone therapy, as reflected by comparable lung and plasma levels of thrombin-antithrombin complexes and fibrin degradation products. Moreover, the FVL mutation had no effect on lung histopathology, neutrophil influx, cytokine and chemokine levels or bacterial outgrowth. Remarkably, homozygous FVL mice were strongly protected against death due to pneumococcal pneumonia when treated with ceftriaxone, which was associated with more pronounced FXIII depletion; this protective effect was not observed in the absence of antibiotic therapy.
  
  
  CONCLUSIONS
  Homozygosity for the FVL mutation protects against lethality due to pneumococcal pneumonia in mice treated with antibiotics.
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, room G2-130, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. m.schouten@amc.uva.nl
authors.forename: Marcel
authors.initials: M
authors.lastname: Schouten
authors.forename: Cornelis
authors.initials: C
authors.lastname: van't Veer
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D020016:Activated Protein C Resistance / Q000150:complications / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001780:Blood Coagulation Tests; D002443:Ceftriaxone / Q000627:therapeutic use; D005165:Factor V / Q000235:genetics* / Q000502:physiology; D005260:Female; D006720:Homozygote; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D011018:Pneumonia, Pneumococcal / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation
chemical_list: D000900:Anti-Bacterial Agents; C095381:factor V Leiden; D002443:Ceftriaxone; D005165:Factor V