title: Exacerbated venous thromboembolism in mice carrying a protein S K196E mutation.
abstract: Protein S (PS) acts as an anticoagulant cofactor for activated protein C in regulation of blood coagulation. The K196E mutation in PS is a race-specific genetic risk factor for venous thromboembolism with a prevalence of ∼2% within the Japanese population. To evaluate the thrombosis risk of the PS-K196E mutation, we generated PS-K196E knockin mice and heterozygous PS-deficient mice. We analyzed their thrombotic states, comparing with mice carrying the factor V Leiden mutation (FV-R504Q), a race-specific genetic risk for venous thrombosis in whites. PS-K196E mice grew normally but had decreased activated protein C cofactor activity in plasma. Purified recombinant murine PS-K196E showed the same decreased activated protein C cofactor activity. A deep vein thrombosis model of electrolytic inferior vena cava injury and pulmonary embolism models induced by infusion of tissue factor or polyphosphates revealed that PS-K196E mice, heterozygous PS-deficient mice, and FV-R504Q mice were much more susceptible to venous thrombosis compared with wild-type mice. Transient middle cerebral artery ischemia-reperfusion injury model studies demonstrated that both PS-K196E mice and heterozygous PS-deficient mice had cerebral infarction similar to wild-type mice, consistent with human observations. Our in vitro and in vivo results support a causal relationship between the PS-K196E mutation and venous thrombosis and indicate that PS-K196E mice can provide an in vivo evaluation system to help uncovering racial differences in thrombotic diseases.
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan;
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Banno
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan;
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kita
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; and.
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández
authors.affiliation: Laboratory of Neurology and Neurosurgery and.
authors.forename: Hiroji
authors.initials: H
authors.lastname: Yanamoto
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan;
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tashima
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Kokame
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; and.
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan; Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D004195:Disease Models, Animal; D005165:Factor V / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D011486:Protein C / Q000235:genetics / Q000378:metabolism; D017293:Protein S / Q000235:genetics / Q000378:metabolism; D054556:Venous Thromboembolism / Q000097:blood / Q000235:genetics
chemical_list: D011486:Protein C; D017293:Protein S; C095381:factor V Leiden; D005165:Factor V