title: Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction.
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.
authors.affiliation: Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pawlinski
authors.forename: A
authors.initials: A
authors.lastname: Fernandes
authors.forename: B
authors.initials: B
authors.lastname: Kehrle
authors.forename: B
authors.initials: B
authors.lastname: Pedersen
authors.forename: G
authors.initials: G
authors.lastname: Parry
authors.forename: J
authors.initials: J
authors.lastname: Erlich
authors.forename: R
authors.initials: R
authors.lastname: Pyo
authors.forename: D
authors.initials: D
authors.lastname: Gutstein
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: F
authors.initials: F
authors.lastname: Castellino
authors.forename: E
authors.initials: E
authors.lastname: Melis
authors.forename: P
authors.initials: P
authors.lastname: Carmeliet
authors.forename: G
authors.initials: G
authors.lastname: Baretton
authors.forename: T
authors.initials: T
authors.lastname: Luther
authors.forename: M
authors.initials: M
authors.lastname: Taubman
authors.forename: E
authors.initials: E
authors.lastname: Rosen
authors.forename: N
authors.initials: N
authors.lastname: Mackman
mesh_terms: D000818:Animals; D004719:Endomyocardial Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005167:Factor VII / Q000009:adverse effects; D005340:Fibrinogen / Q000235:genetics; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D002836:Hemophilia B / Q000235:genetics / Q000473:pathology; D006474:Hemorrhagic Disorders / Q000235:genetics*; D006485:Hemosiderin / Q000032:analysis; D006487:Hemostasis / Q000502:physiology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000502:physiology; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000502:physiology; D013925:Thromboplastin / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000235:genetics* / Q000378:metabolism
chemical_list: D011993:Recombinant Fusion Proteins; D005167:Factor VII; D005340:Fibrinogen; D006485:Hemosiderin; D013925:Thromboplastin