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
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15333-8. doi: 10.1073/pnas.242501899. Epub 2002 Nov 8.
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.
血液暴露于组织因子（TF）会激活凝血的外源性（TF:FVIIa）和内源性（FVIIIa:FIXa）途径。在本研究中，我们发现，在mTF(-/-)背景下表达低水平人TF（约为野生型水平的1%）的小鼠寿命明显短于野生型小鼠，部分原因是自发性致命出血。所有低TF小鼠均表现出一种选择性心脏缺陷，包括含铁血黄素沉积和纤维化。直接心内测量显示，与年龄匹配的野生型小鼠相比，8月龄低TF小鼠的左心室功能降低了30%（P < 0.001）。表达低水平鼠FVII（约为野生型水平的1%）的小鼠心脏中也表现出类似的含铁血黄素沉积和纤维化模式。相比之下，B型血友病模型FIX(-/-)小鼠的心脏正常。低TF和低FVII小鼠的心脏纤维化似乎是由于止血功能受损导致心脏血管出血所致。我们提出，心肌细胞表达的TF提供了一种继发性止血屏障，以保护心脏免受出血。
