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 (≈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 (≈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.

Original languageEnglish (US)
Pages (from-to)15333-15338
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number24
DOIs
StatePublished - Nov 26 2002

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Pawlinski, R., Fernandes, A., Kehrle, B., Pedersen, B., Parry, G., Erlich, J., Pyo, R., Gutstein, D., Zhang, J., Castellino, F., Melis, E., Carmeliet, P., Baretton, G., Luther, T., Taubman, M., Rosen, E., & Mackman, N. (2002). Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction. Proceedings of the National Academy of Sciences of the United States of America, 99(24), 15333-15338. https://doi.org/10.1073/pnas.242501899