Disease relevance of Tfpi

• Factor VII deficiency rescues the intrauterine lethality in mice associated with a tissue factor pathway inhibitor deficit [1].
• Tissue factor pathway inhibitor reduces experimental lung metastasis of B16 melanoma [2].
• B16 murine melanoma cells stably transfected with a TFPI expression vector exhibited reduced lung seeding following intravenous injection by 81% (P < 0.001) compared with controls [2].
• Deficiency of tissue factor pathway inhibitor promotes atherosclerosis and thrombosis in mice [3].
• The role of local vascular TFPI in thrombosis and the development of vascular disease is unknown [4].

High impact information on Tfpi

• A genetically engineered hybrid protein consisting of the light chain of factor Xa and the first Kunitz-type inhibitor domain of LACI is shown to directly inhibit the activity of the factor VIIa-TF catalytic complex [5].
• Thus, the rescue of TFPIdelta/delta embryos, either by an accompanying homozygous or heterozygous FVII deficiency, suggests that diminishment of FVII activity precludes the need for TFPI-mediated inhibition of the FVIIa/tissue factor coagulation pathway during embryogenesis [1].
• A balance between tissue factor and tissue factor pathway inhibitor is required for embryonic development and hemostasis in adult mice [6].
• Conversely, a decrease in TFPI levels dose-dependently prolonged the survival of low-TF mice and rescued the hemorrhagic defects in the lung and placenta but not in the heart or uterus [6].
• Identification and characterization of a very low density lipoprotein receptor-binding peptide from tissue factor pathway inhibitor that has antitumor and antiangiogenic activity [7].

Chemical compound and disease context of Tfpi

• Taken together, these data indicated that local VSMC-specific TFPI overexpression attenuated ferric chloride-induced thrombosis without systemic or hemostatic effects [4].

Biological context of Tfpi

• Since many animal studies have shown that anticoagulant therapy can reduce experimental metastasis, we studied whether the natural inhibitor of TF-mediated blood coagulation, Tissue Factor Pathway Inhibitor (TFPI), might be similarly effective [2].
• Gene targeting in hemostasis. tissue factor pathway inhibitor [8].
• Compared with mice with a normal TFPI genotype (TFPI(+/+)/apoE(-/-)), mice with a TFPI deficiency exhibited a greater atherosclerotic burden involving the carotid and common iliac arteries [3].
• METHODS AND RESULTS: Mice with a combined heterozygous TFPI deficiency and homozygous apolipoprotein E deficiency (TFPI(+/-)/apoE(-/-)) were generated by crossbreeding, and they were analyzed for atherosclerosis throughout the vascular tree [3].
• Daily and circadian rhythms of tissue factor pathway inhibitor and factor VII activity [9].

Anatomical context of Tfpi

• Activated factor X and thrombin formation triggered by tissue factor on endothelial cell matrix in a flow model: effect of the tissue factor pathway inhibitor [10].
• To study the effect of TFPI deficiency on neointimal formation, age matched TFPI(K1)+/- and wildtype littermates underwent unilateral common carotid artery ligation [11].
• Recombinant mouse TFPI was expressed in the human kidney cell line 293 and purified for functional assays [12].
• TFPI is expressed by both endothelial and smooth muscle cells in the vasculature and circulates at low levels [4].
• The effect of vascular smooth muscle cell-targeted expression of tissue factor pathway inhibitor in a murine model of arterial thrombosis [4].

Associations of Tfpi with chemical compounds

• Prolongation of the PT occurred only moderately and linearly with increasing concentrations of heparin in LACI-depleted plasma [13].
• Placental protein 5 (PP5)/tissue factor pathway inhibitor-2 (TFPI-2) is a new homologue of TFPI, which contains three tandemly repeated Kunitz-type proteinase inhibitory (KPI) domains and potently inhibits the extrinsic blood coagulation cascade [14].
• Overexpression of TFPI inhibited neointimal formation (P=0.038), resulting in enhanced luminal area (P=0.001) 4 weeks after flow cessation [15].
• Phosphoamino acid analysis of the purified 32P-LACI established that the phosphorylation occurred on (a) serine residue(s) [16].
• LACI isolated from the conditioned media of HepG2 cells grown in the presence of [32P]orthophosphate was observed to be covalently phosphorylated [16].

Regulatory relationships of Tfpi

• Tissue factor pathway inhibitor (TFPI) is the protease inhibitor that regulates the extrinsic coagulation pathway initiated by the factor VIIa/TF complex [17].

Other interactions of Tfpi

• Down-regulation of murine tissue factor pathway inhibitor mRNA by endotoxin and tumor necrosis factor-alpha in vitro and in vivo [17].
• The low density lipoprotein receptor-related protein can function independently from heparan sulfate proteoglycans in tissue factor pathway inhibitor endocytosis [18].

Analytical, diagnostic and therapeutic context of Tfpi

• To establish an experimental animal model to directly modulate smooth muscle cell-derived TFPI on the development of arterial thrombosis, transgenic mice in which a cDNA encoding murine TFPI is expressed from the murine SM22alpha promoter were generated [4].
• Northern blot analyses show that the tissues for mouse TFPIbeta synthesis are heart and lung; in contrast, TFPI appears in Northern blots of heart and spleen [19].
• By using site-directed mutagenesis, an altered form of LACI was produced in which the serine-2 residue had been changed to alanine [16].
• Genetic manipulation of, for example, endothelial cells leading to the stable expression of TFPI may inhibit the development of coronary artery heart disease following cardiac allotransplantation, and may inhibit thrombosis in the context of xenotransplantation [20].
• Cross-linking/immunoprecipitation analyses on bend cells also revealed that HSPGs were specifically associated with TFPI and fXa [21].

References