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Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction.

R Pawlinski·A Fernandes·B Kehrle·B Pedersen·G Parry·J Erlich·R Pyo·D Gutstein·J Zhang·F Castellino·E Melis·P Carmeliet·G Baretton·T Luther·M Taubman·E Rosen·N Mackman
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Abstract

Exposure of blood to tissue factor (TF) activates the extrinsic (TF:FVIIa) and intrinsic (FVIIIa:FIXa) pathways of coagulation. In this study, we found that mice expressing low levels of human TF ( approximately 1% of wild-type levels) in an mTF(-/-) background had significantly shorter lifespans than wild-type mice, in part, because of spontaneous fatal hemorrhages. All low-TF mice exhibited a selective heart defect that consisted of hemosiderin deposition and fibrosis. Direct intracardiac measurement demonstrated a 30% reduction (P < 0.001) in left ventricular function in 8-month-old low-TF mice compared with age-matched wild-type mice. Mice expressing low levels of murine FVII ( approximately 1% of wild-type levels) exhibited a similar pattern of hemosiderin deposition and fibrosis in their hearts. In contrast, FIX(-/-) mice, a model of hemophilia B, had normal hearts. Cardiac fibrosis in low-TF and low-FVII mice appears to be caused by hemorrhage from cardiac vessels due to impaired hemostasis. We propose that TF expression by cardiac myocytes provides a secondary hemostatic barrier to protect the heart from hemorrhage.

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AnimalsEndomyocardial FibrosisFactor VIIFibrinogenGene ExpressionGenetic Predisposition to DiseaseHemophilia BHemorrhagic DisordersHemosiderinHemostasisHumansMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutMice, TransgenicModels, BiologicalMuscle, SkeletalMyocardiumOrgan SpecificityProtein Structure, TertiaryRecombinant Fusion ProteinsThromboplastinVentricular Dysfunction, LeftComparative StudyJournal ArticleResearch Support, U.S. Gov't, P.H.S.

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R Pawlinski, A Fernandes, B Kehrle, B Pedersen, G Parry, J Erlich, R Pyo, D Gutstein, J Zhang, F Castellino, E Melis, P Carmeliet, G Baretton, T Luther, M Taubman, E Rosen, N Mackman. 2002-11-08. Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction.. https://doi.org/10.1073/pnas.242501899

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