TY - JOUR
T1 - Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction
AU - Pawlinski, R.
AU - Fernandes, A.
AU - Kehrle, B.
AU - Pedersen, B.
AU - Parry, G.
AU - Erlich, J.
AU - Pyo, R.
AU - Gutstein, D.
AU - Zhang, J.
AU - Castellino, F.
AU - Melis, E.
AU - Carmeliet, P.
AU - Baretton, G.
AU - Luther, T.
AU - Taubman, M.
AU - Rosen, E.
AU - Mackman, N.
PY - 2002/11/26
Y1 - 2002/11/26
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/0037180549
U2 - 10.1073/pnas.242501899
DO - 10.1073/pnas.242501899
M3 - Article
C2 - 12426405
AN - SCOPUS:0037180549
SN - 0027-8424
VL - 99
SP - 15333
EP - 15338
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -