title: A combined deficiency of tissue factor and PAR-4 is associated with fatal pulmonary hemorrhage in mice.
abstract: BACKGROUND
  Mice with a complete absence of tissue factor (TF) die during embryonic development whereas mice with low levels of TF (Low-TF mice) survive to adulthood. Low-TF mice exhibit spontaneous hemorrhage in various organs, including the lung. In contrast, mice can survive without protease-activated receptor (PAR)-4, which is the major thrombin receptor on mouse platelets. We determined the effect of combining a deficiency PAR-4 (primary hemostasis) with a deficiency in TF (secondary hemostasis) on embryonic development and survival of adult mice.
  
  
  METHODS
  Low-TF mice (mTF-/-, hTF+/+) were crossed with PAR-4-/-mice to generate heterozygous mice (mTF+/-, hTF+/-, PAR-4+/-). These mice were intercrossed to generate Low-TF mice lacking PAR-4. Mice surviving to wean were genotyped and survival was monitored for 6months.
  
  
  RESULTS
  We observed the expected number of Low-TF,PAR-4-/-mice at wean indicating survival in utero and after birth. However, an absence of PAR-4 was associated with premature death of all Low-TF,PAR-4-/-mice in the 6month observational period. This compares with 40% death of the Low-TF,PAR-4+/+mice (p=0.003). Low-TF,PAR-4+/-mice had an intermediate phenotype with 55% of the mice dying within 6months. The primary cause of mortality of Low-TF,PAR-4-/-mice was pulmonary hemorrhage.
  
  
  CONCLUSIONS
  Low-TF,PAR-4-/-mice survive into adulthood, but combining a deficiency of primary hemostasis (PAR-4 deficiency) with secondary hemostasis (low levels of TF) leads to premature death primarily due to pulmonary hemorrhage.
authors: University of North Carolina, Division of Cardiology, Department of Medicine; 160 Dental Circle, CB #7075, 6025 Burnett-Womack-Bldg., Chapel Hill, NC 27514-7075, USA. Electronic address: michael_bode@med.unc.edu.
authors: Michael F
authors: MF
authors: Bode
authors: University of North Carolina, Division of Hematology and Oncology, Department of Medicine; McAllister Heart Institute, 111 Mason Farm Road, 2312C Medical Biomolecular Research Bldg., CB #7126, Chapel Hill, NC 27599-7126, USA. Electronic address: nigel_mackman@med.unc.edu.
authors: Nigel
authors: N
authors: Mackman
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000378:metabolism*; D006801:Humans; D008171:Lung Diseases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D044462:Receptors, Proteinase-Activated / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: D044462:Receptors, Proteinase-Activated; C481942:protease-activated receptor 4, mouse; D013925:Thromboplastin
keywords: Hemostasis; Platelet; Pulmonary hemorrhage; Transgenic mice