Author:

Keywords:

Animals, Cell Membrane, Cytosol, Gene Silencing, Genetic Predisposition to Disease, Mice, Mice, Transgenic, Mutagenesis, Site-Directed, Phenotype, Protein Structure, Tertiary, Survival Rate, Thrombophilia, Thromboplastin, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Biophysics, coagulation, gene targeting, thrombophilia, tissue factor, FACTOR PATHWAY, COAGULATION, THROMBOSIS, MODEL, MONOCYTES, FIBRIN, 0304 Medicinal and Biomolecular Chemistry, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3404 Medicinal and biomolecular chemistry

Abstract:

Mice with a targeted truncation in the gene encoding tissue factor of blood coagulation (TF) to eliminate the cytosolic domain and carrying a neo(R) cassette in intron 5 unexpectedly displayed severe spontaneous thrombosis in various vascular beds. Thrombosis was observed in heterozygous TF(+/neo) mice, causing death of over 50% of adults within 36 weeks of birth, and fulminantly exacerbating in pregnant females. Homozygous TF(neo/neo) mice were more severely affected and died within 7 weeks after birth. These TF(neo) mice primarily synthesized a mutant mRNA aberrantly spliced from exon 5 to neo(R), encoding an apparently non-vesicle-binding soluble TF lacking both the transmembrane and cytosolic domain, but still capable of blood coagulation induction. This severe thrombotic phenotype associated with the presence of a non-anchored soluble TF variant underscores the recently recognized significance of circulating TF for thrombus formation and development.