Alternative titles; symbols
HGNC Approved Gene Symbol: F3
Cytogenetic location: 1p21.3 Genomic coordinates (GRCh38): 1:94,529,173-94,541,759 (from NCBI)
The extrinsic pathway of blood coagulation is initiated by contact of plasma factor VII (F7; 613878) with tissue factor (F3), a cellular membrane glycoprotein that normally is segregated from the bloodstream but can be exposed after tissue injury or newly synthesized in endothelial cells or leukocytes after stimulation by endotoxin and cytokines. Once formed, the tissue factor/factor VII complex converts to a complex of tissue factor and enzymatically active factor VII (F7a); this conversion leads to activation of factors X (F10; 613872) and IX (300746) and prothrombin (176930), and ultimately to formation of fibrin (134570/134580). These processes are regulated by plasma protease inhibitors and by the thrombomodulin (188040)-protein C (612283) pathway. A further regulatory mechanism in the extrinsic pathway is called tissue factor pathway inhibitor (TFPI; 152310). For a review, see Davie et al. (1991).
Spicer et al. (1987) isolated cDNA clones for tissue factor. The amino acid sequence deduced from the nucleotide sequence of the cDNAs indicates that tissue factor is synthesized as a higher molecular weight precursor with a leader sequence of 32 amino acids, while the sequence of the mature protein suggests that there are 3 distinct domains: extracellular (residues 1-219), hydrophobic (residues 220-242), and cytoplasmic (residues 243-263). Scarpati et al. (1987) screened a human placenta cDNA library in lambda-gt11 for expression of tissue factor antigens. Among 4 million recombinant clones screened, one that was positive expressed a protein that shares epitopes with authentic human brain tissue factor. The 1.1-kb cDNA insert encodes a peptide containing the N-terminal protein sequence of brain tissue factor.
Mackman et al. (1989) presented the complete sequence of the F3 gene. It is 12.4 kb long and has 6 exons. Mackman et al. (1990) concluded that the tissue factor promoter is relatively complex.
Bogdanov et al. (2003) identified an alternatively spliced form of human tissue factor that contains most of the extracellular domain but lacks a transmembrane domain and terminates with a unique peptide sequence. This sequence includes all of exons 1 through 4. Exon 5 is absent and exon 4 is spliced directly to exon 6. Because exon 6 begins with an incomplete codon and exon 4 terminates with a complete codon, such a fusion creates an open reading frame (ORF) frameshift. The new ORF encodes alternatively spliced human tissue factor (asHTF), whose mature peptide comprises 206 amino acids. Residues 1-166 are identical to the extracellular domain of TF, and residues 167-206 correspond to a unique C terminus. Bogdanov et al. (2003) noted that the 165-166 lysine doublet involved in F7a binding is maintained in asHTF. RT-PCR demonstrated asHTF expression in human lung, placenta, and pancreas, as well as in CD14+ monocytes. Levels of asHTF were much lower in placenta and pancreas than in lung tissue.
Carson et al. (1985) mapped the F3 gene to 1pter-p21 by study of somatic cell hybrids with a species-specific sensitive chromogenic assay.
Using the tissue factor clone in hybridization to flow-sorted human chromosomes, Scarpati et al. (1987) showed that the tissue factor gene is located on chromosome 1. Scarpati et al. (1987) used a RFLP to map factor III to proximal 1p by multipoint linkage analysis with probes known to span that region. Judging by the location arrived at by somatic cell hybridization, the location of F3 may be in the region 1p22-p21. By in situ hybridization, Kao et al. (1988) likewise mapped F3 to 1p22-p21.
Drake et al. (1989) found that the expression of tissue factor by adventitial fibroblasts and vascular smooth muscle cells surrounding blood vessels provides a hemostatic barrier that activates coagulation when vascular integrity is disrupted. They also found that TF is expressed by cardiac muscle but not by skeletal muscle.
The coagulation protease cascades are composed of the extrinsic (TF/FVIIa) and intrinsic (FVIIIa/FIXa) pathways, which together maintain hemostasis (Davie et al., 1991).
Bogdanov et al. (2003) found that asHTF is soluble, circulates in blood, exhibits procoagulant activity when exposed to phospholipids, and is incorporated into thrombi. The authors proposed that binding of asHTF to the edge of thrombi contributes to thrombus growth by creating a surface that both initiates and propagates coagulation.
Associations Pending Confirmation
For discussion of a possible association between variation in the F3 gene and a mild bleeding disorder, see 134390.0001.
In contrast to findings of earlier studies showing that TF-null mouse embryos did not survive beyond midgestation, Toomey et al. (1997) found that 14% of TF-deficient embryos from a hybrid background escaped this early mortality and survived to birth. On gross and microscopic inspection, these late gestation, TF-deficient embryos appeared normal. Furthermore, the growth and vascularity of TF +/+, TF +/-, and TF -/- teratomas and teratocarcinomas were indistinguishable. Toomey et al. (1997) concluded that tumor-derived TF is not required for tumor growth and angiogenesis and that the combined data do not support an essential role for TF in embryonic vascular development.
Erlich et al. (1999) generated mice with low levels of tissue factor and found that they had impaired uterine hemostasis. A similar phenotype was observed in low-FVII mice.
Pawlinski et al. (2002) performed a detailed characterization of low-TF mice. The mice exhibited shorter life spans than wildtype mice. Histologic analysis of various tissues of low-TF mice showed hemosiderin deposition and fibrosis selectively in their hearts. The findings suggested that cardiac fibrosis in low-TF mice is caused by hemorrhage from cardiac vessels due to impaired hemostasis. Mice exhibiting low levels of murine FVII exhibited a similar pattern of hemosiderin deposition and fibrosis in their hearts. In contrast, F9 -/- mice, a model of hemophilia B, had normal hearts. Pawlinski et al. (2002) proposed that TF expression by cardiac myocytes provides a secondary hemostatic barrier to protect the heart from hemorrhage.
To examine the role of the cytosolic domain of TF, Melis et al. (2001) developed mice with a targeted deletion of the 18 C-terminal amino acids. These mice displayed normal embryonic development, survival, fertility, and blood coagulation. Factor VIIa or factor Xa (613872) stimulation of mutant fibroblasts induced p44 (601795)/p42 (176948) Mapk activation, similar to that found in wildtype fibroblasts. Melis et al. (2001) concluded that the cytosolic domain of TF is not essential for signal transduction in embryogenesis and in physiologic postnatal processes.
Isermann et al. (2003) showed that the abortion of thrombomodulin (188040)-deficient mouse embryos is caused by TF-initiated activation of the blood coagulation cascade at the fetomaternal interface. Activated coagulation factors induced cell death and growth inhibition of placental trophoblast cells by 2 distinct mechanisms. The death of giant trophoblast cells was caused by the conversion of fibrinogen to fibrin (see 134820) and subsequent formation of fibrin degradation products. In contrast, the growth arrest of trophoblast cells is not mediated by fibrin, but is a likely result of engagement of the protease-activated receptors PAR2 (600933) and PAR4 (602779) by coagulation factors. Isermann et al. (2003) concluded that their findings show a novel function for the thrombomodulin-protein C system in controlling the growth and survival of trophoblast cells in the placenta. This function is essential for the maintenance of pregnancy.
Badeanlou et al. (2011) found that Tf activity was upregulated in plasma and epididymal visceral adipose tissue extracts in mice fed a high-fat diet. Mutant mice lacking the cytoplasmic domain of Tf (Tf-delta-CT mice) or deficient in Par2 expression (Par2 -/- mice) gained less weight than wildtype mice when fed a high-fat diet. Tf-delta-CT or Par2 -/- mice also had lower plasma concentrations of free fatty acids and fasting insulin and glucose, with improved insulin sensitivity and glucose tolerance, compared with wildtype mice fed a high-fat diet. Tf-delta-CT Par2 -/- double-mutant mice showed no additive effects. In hematopoietic cells, ablation of Tf/Par2 signaling reduced adipose tissue macrophage inflammation, and specific inhibition of macrophage Tf signaling ameliorated insulin resistance. In nonhematopoietic cells, Tf/F7a/Par2 signaling promoted obesity.
Reinhardt et al. (2012) showed that the gut microbiota promotes TF glycosylation associated with localization of tissue factor on the cell surface, the activation of coagulation proteases, and phosphorylation of the TF cytoplasmic domain in the small intestine. Anti-Tf treatment of colonized germ-free mice decreased microbiota-induced vascular remodeling and expression of the proangiogenic factor angiopoietin-1 (ANG1; 601667) in the small intestine. Mice with a genetic deletion of the Tf cytoplasmic domain or with hypomorphic Tf alleles had a decreased intestinal vessel density. Coagulation proteases downstream of Tf activate protease-activated receptor (PAR) signaling implicated in angiogenesis. Vessel density and phosphorylation of the cytoplasmic domain of Tf were decreased in small intestine from Par1 (187930)-deficient but not Par2-deficient mice, and inhibition of thrombin (176930) showed that thrombin-Par1 signaling was upstream of Tf phosphorylation. Reinhardt et al. (2012) concluded that the microbiota-induced extravascular TF-PAR1 signaling loop is a novel pathway in vascular remodeling in the small intestine.
Schulman et al. (2020) found that heterozygous F3 +/- mice demonstrated prolonged bleeding and impaired survival due to exsanguination compared to wildtype mice after aggressive tail amputation at 2 mm diameter. Mutant mice also had impaired thrombus formation following large vascular injury compared to wildtype; no difference was observed for small injuries. The mice did not show spontaneous bleeding, suggesting that F3 deficiency may be unmasked by injury.
This variant is classified as a variant of unknown significance because its contribution to a mild bleeding disorder has not been confirmed.
In a woman with a history of mild bleeding tendency, Schulman et al. (2020) identified a heterozygous 2-bp deletion (c.249delAG) in exon 3 of the F3 gene, predicted to result in a frameshift and premature termination (Ser117HisfsTer10). The variant, which was found by whole-genome sequencing, was paternally inherited. However, the father was estranged and clinical and medical history was not available. The patient's mother and maternal aunt had similar bleeding symptoms as the proband, but neither carried the F3 variant; their bleeding remained unexplained. The variant was not present in the gnomAD database. Cells and tissue from the patient or family members were not available for study. However, in vitro studies indicated that the variant is a null allele degraded by nonsense-mediated mRNA decay. CRISPR/Cas9-mediated engineering of the variant in human iPSC cells differentiated towards vascular smooth muscle cells and endothelial cells showed that the heterozygous variant yielded about 50% activity to support F3-dependent coagulation initiation compared to wildtype, consistent with haploinsufficiency. Studies of a recombinant F3 protein expressing the deletion (referred to as 'TF short') indicated that it did not impair coagulation through a dominant-negative manner. The patient had menorrhagia, epistaxis, easy bleeding, and bleeding following a dental extraction. Routine laboratory assessment for a bleeding disorder was normal. She was part of a cohort of 973 probands with unexplained bleeding who underwent whole-genome sequencing. Schulman et al. (2020) noted that the history of bleeding on the maternal side could also suggest a polygenic inheritance pattern. The authors concluded that F3 haploinsufficiency is a modifier of coagulation initiation that is not captured by routine clinical laboratory testing.
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