title: Generation and phenotypic analysis of protein S-deficient mice.
abstract: Protein S (PS) is an important natural anticoagulant with potentially multiple biologic functions. To investigate further the role of PS in vivo, we generated Pros(+/-) heterozygous mice. In the null (-) allele, the Pros exons 3 to 7 have been excised through conditional gene targeting. Pros(+/-) mice did not present any signs of spontaneous thrombosis and had reduced PS plasma levels and activated protein C cofactor activity in plasma coagulation and thrombin generation assays. Tissue factor pathway inhibitor cofactor activity of PS could not be demonstrated. Heterozygous Pros(+/-) mice exhibited a notable thrombotic phenotype in vivo when challenged in a tissue factor-induced thromboembolism model. No viable Pros(-/-) mice were obtained through mating of Pros(+/-) parents. Most E17.5 Pros(-/-) embryos were found dead with severe intracranial hemorrhages and most likely presented consumptive coagulopathy, as demonstrated by intravascular and interstitial fibrin deposition and an increased number of megakaryocytes in the liver, suggesting peripheral thrombocytopenia. A few E17.5 Pros(-/-) embryos had less severe phenotype, indicating that life-threatening manifestations might occur between E17.5 and the full term. Thus, similar to human phenotypes, mild heterozygous PS deficiency in mice was associated with a thrombotic phenotype, whereas total homozygous deficiency in PS was incompatible with life.
authors: Service and Central Laboratory of Hematology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors: François
authors: F
authors: Saller
authors: Anne C
authors: AC
authors: Brisset
authors: Svetlana N
authors: SN
authors: Tchaikovski
authors: Monica
authors: M
authors: Azevedo
authors: Roman
authors: R
authors: Chrast
authors: José A
authors: JA
authors: Fernández
authors: Marc
authors: M
authors: Schapira
authors: Tilman M
authors: TM
authors: Hackeng
authors: John H
authors: JH
authors: Griffin
authors: Anne
authors: A
authors: Angelillo-Scherrer
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005313:Fetal Death / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D020300:Intracranial Hemorrhages / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008074:Lipoproteins; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011486:Protein C / Q000235:genetics / Q000378:metabolism; D017293:Protein S; D018455:Protein S Deficiency / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013917:Thrombin / Q000235:genetics / Q000378:metabolism; D013923:Thromboembolism / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D008074:Lipoproteins; D011486:Protein C; D017293:Protein S; C051928:lipoprotein-associated coagulation inhibitor; D013917:Thrombin