title: The characterization of mice with a targeted combined deficiency of protein c and factor XI.
abstract: Activated protein C functions directly as an anticoagulant and indirectly as a profibrinolytic enzyme. To determine whether the fibrin deposition previously observed in PC(-/-) murine embryos and neonates was mediated through the FXI pathway, PC(+/-)/FXI(-/-) mice were generated and crossbred to produce double-deficient progeny (PC(-/-)/FXI(-/-)). PC(-/-)/FXI(-/-) mice survived the early lethality observed in the PC(-/-)/FXI(+/+) neonates, with the oldest PC(-/-)/FXI(-/-) animal living to 3 months of age. However, the majority of these animals was sedentary and significantly growth-retarded. On sacrifice or natural death, all of these PC(-/-)/FXI(-/-) mice demonstrated massive systemic fibrin deposition with concomitant hemorrhage and fibrosis, as confirmed through histological analyses. Several of these animals also presented with enlarged lymph nodes and extensive lymphatic fluid in the thoracic cavity. Thus, although a number of the PC(-/-)/FXI(-/-) mice survived the lethal perinatal coagulopathy seen in the PC(-/-) neonates, they nonetheless succumbed to overwhelming thrombotic disease in later life. This combined deficiency state provided the first clear indication that the course of a severe thrombotic disorder could be manipulated by blocking the intrinsic pathway and provided the first opportunity to study a total protein C deficiency in an adult animal.
authors.affiliation: Department of Chemistry and Biochemistry, W. M. Keck Center for Transgene Research, and the Freimann Life Science Center, University of Notre Dame, Notre Dame, Indiana 46556, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Chan
authors.forename: J G
authors.initials: JG
authors.lastname: Ganopolsky
authors.forename: I
authors.initials: I
authors.lastname: Cornelissen
authors.forename: M A
authors.initials: MA
authors.lastname: Suckow
authors.forename: M J
authors.initials: MJ
authors.lastname: Sandoval-Cooper
authors.forename: E C
authors.initials: EC
authors.lastname: Brown
authors.forename: F
authors.initials: F
authors.lastname: Noria
authors.forename: D
authors.initials: D
authors.lastname: Gailani
authors.forename: E D
authors.initials: ED
authors.lastname: Rosen
authors.forename: V A
authors.initials: VA
authors.lastname: Ploplis
authors.forename: F J
authors.initials: FJ
authors.lastname: Castellino
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003433:Crosses, Genetic; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005314:Embryonic and Fetal Development / Q000235:genetics; D005172:Factor XI / Q000235:genetics / Q000378:metabolism; D005173:Factor XI Deficiency / Q000235:genetics*; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005838:Genotype; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011247:Pregnancy; D011486:Protein C / Q000235:genetics / Q000378:metabolism; D020151:Protein C Deficiency / Q000235:genetics*; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; D011486:Protein C; D014409:Tumor Necrosis Factor-alpha; D005337:Fibrin; D005172:Factor XI