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 (Ϸ1% 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 (Ϸ1% 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. E xpression of tissue factor (TF) by adventitial fibroblasts and vascular smooth muscle cells surrounding blood vessels provides a hemostatic barrier that activates coagulation when vascular integrity is disrupted (1). TF is also expressed by cardiac muscle but not by skeletal muscle (1). TF functions as the high-affinity cellular receptor for FVII͞VIIa (2). The coagulation protease cascades are comprised of the extrinsic (TF:FVIIa) and intrinsic (FVIIIa:FIXa) pathways, which together maintain hemostasis (3).Many murine models of coagulation have been generated that provide new insights into the role of the various procoagulant and anticoagulant proteins in hemostasis (4). For instance, FV Leiden/Leiden mice, which express an FV variant that is resistant to inactivation by activated protein C, and TM Pro/Pro mice, which express a mutated version of thrombomodulin (TM) with reduced thrombin binding, both exhibit prothrombotic phenotypes with increased fibrin deposition in select tissues (5-7). Mice with prohemorrhage phenotypes include models of hemophilia A (FVIII Ϫ/Ϫ ) and B (FIX Ϫ/Ϫ ), as well as fibrinogen-deficient mice (Fbg Ϫ/Ϫ ) and thrombocytopenic mice (NF-E2 Ϫ/Ϫ ) (8-12). Mice with complete deficiencies in TF, FVII, FX, FV, and prothrombin die in utero or shortly after birth (4). We and others have generated mice expressing low levels (Ͻ0.1-1% of wild-type levels) of human TF, murine FVII, and murine FV (13-15). We have shown that low-TF mice have impaired uterine hemostasis (16). A similar phenotype is observed with low-FVII mice.In this study, we performed a detailed characterization of low-TF mice. These mice exhibited shorter lifespans than wildtype mice. Histological analysis of various tissues of low-TF mice revealed hemosiderin deposition and fibrosis selectively in their hearts. Our data suggest that cardiac fibrosis in low-TF mice is caused by hemorrhage from cardiac vessels due to impaired hemostasis. M...

Bleeding hearts

“…Support for this idea was first provided by the observation that mice engineered to express very low levels of tissue factor (ϳ1%) exhibited tissue-specific hemostatic defects, particularly in the heart. 4,5 Similar hemostatic defects were observed in mice expressing very low levels of fVII (ϳ1%) and low levels of fX (approximately 5.5%). 4,6 In contrast, mice lacking either fVIII or fIX survive to adulthood and have no hemostatic defects in their hearts.…”

“…4,5 Similar hemostatic defects were observed in mice expressing very low levels of fVII (ϳ1%) and low levels of fX (approximately 5.5%). 4,6 In contrast, mice lacking either fVIII or fIX survive to adulthood and have no hemostatic defects in their hearts. However, patients with hemophilia A (fVIII deficiency) or hemophilia B (fIX deficiency) often experience spontaneous hemorrhages in tissues with low levels of tissue factor expression (ie, joints and skeletal muscle) and have excessive hemorrhage after injury.…”

“…Assumptions that many of us have had for years about VWD2B and its diagnosis now need to be reexamined in light of this important study. While some might question whether the patients with normal VWF multimers, VWD New York 3 and VWD Malmo, 4 should be included in VWD2B, these investigators demonstrate much greater diversity in the laboratory studies, even in patients with abnormal multimers.…”

Mapping of angiogenic markers for targeting of vectors to tumor vascular endothelial cells

“…Other differences involve expression of the receptors tissue factor, a V b 3 and Tie-2 on the vascular endothelial cells of solid tumors but not of normal tissues. [9][10][11][12][13][14][15][16] The kinetics of solid tumor growth has three phases: an initial phase of slow growth, a second phase of more rapid growth and a third phase of slow growth. 7 This growth pattern was shown to fit a mathematical function 7 that was interpreted in terms of variable rates of 'birth' and 'death' of tumor cells between the interior and periphery of the tumor as growth progresses.…”

A balance between tissue factor and tissue factor pathway inhibitor is required for embryonic development and hemostasis in adult mice

“…Low-TF mice have shorter lifespans compared with wild-type mice, in part, due to fatal lung hemorrhages. 15 In addition, low-TF mice exhibit fatal postpartum hemorrhages, blood pools in the placenta, and cardiac fibrosis beyond 3 months of age. 6,15 These results suggest that low-TF mice have impaired hemostasis in the uterus, placenta, lung, and heart.…”