The extrinsic pathway of blood coagulation is initiated by contact of plasma factor VII with tissue factor (FIII), 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 (FVIIa); this conversion leads to activation of factors X and IX and prothrombin, and ultimately to formation of fibrin. These processes are regulated by plasma protease inhibitors and by the thrombomodulin-protein C pathway. A further regulatory mechanism in the extrinsic pathway is called tissue factor pathway inhibitor (TFPI).
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.
Carson et al. (1985) mapped the FIII 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 FIII may be in the region 1p22-p21. By in situ hybridization, Kao et al. (1988) likewise mapped FIII to 1p22-p21.
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.
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 comprised 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.
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 stimulation of mutant fibroblasts induced p44/p42 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-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 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 and PAR4 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.
Sources: DiaPharma, Wikipedia, PubMed