Submitted March 9, 2009
Accepted June 23, 2009
Generation and phenotypic analysis of protein S-deficient mice
Francois Saller, Anne C. Brisset, Svetlana N. Tchaikovski, Monica Azevedo, Roman Chrast, Jose A. Fernandez, Marc Schapira, Tilman M. Hackeng, John H. Griffin, and Anne Angelillo-Scherrer*
Service and Central Laboratory of Hematology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, United States
* Corresponding author; email: anne.angelillo-scherrer{at}chuv.ch.
Protein S (PS) is an important natural anticoagulant with potentially multiple biological 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 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 while total homozygous deficiency in PS was incompatible with life.
