Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction

R Pawlinski, A Fernandes, B Kehrle… - Proceedings of the …, 2002 - National Acad Sciences
R Pawlinski, A Fernandes, B Kehrle, B Pedersen, G Parry, J Erlich, R Pyo, D Gutstein…
Proceedings of the National Academy of Sciences, 2002National Acad Sciences
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 …
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.
National Acad Sciences