The reference OMIM entry for this protein is 152310

Tissue factor pathway inhibitor; tfpi
Extrinsic pathway inhibitor; epi
Lipoprotein-associated coagulation inhibitor; laci
Tfpi1

GENE FUNCTION

The extrinsic pathway of blood coagulation is initiated by contact of plasma factor VII (F7; 613878) with tissue factor (TF, or F3; 134390), 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) by an unknown mechanism; this conversion leads to production of activated factors X (FXa; see 613872) and IX (FIXa; see 300746) and prothrombin (176930), 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 was proposed following discovery of a novel protease inhibitor called tissue factor pathway inhibitor (TFPI) by Broze and Miletich (1987) and extrinsic pathway inhibitor (EPI) by Rao and Rapaport (1987). TFPI is otherwise known as lipoprotein-associated coagulation inhibitor (LACI) because it circulates in association with plasma lipoproteins VLDL, LDL, and HDL. It is a multivalent, Kunitz-type proteinase inhibitor. LACI directly inhibits factor Xa, and, in an Xa-dependent fashion, also inhibits the factor VIIa-tissue factor catalytic complex. Davie et al. (1991) reviewed the coagulation cascade including the role of LACI in its regulation. Using microarray analysis and a literature-based search, Lupu et al. (2011) found that TFPI was coexpressed with ADTRP (C6ORF105; 614348). Immunofluorescence analysis of human umbilical vein endothelial cells (HUVECs) and EA.hy926 human endothelial cells showed that ADTRP colocalized with TFPI on the cell surface and with both TFPI and the caveolae membrane protein Cav1 (601047) intracellularly. In baboon aorta, Adtrp colocalized with Cav1 in endothelium and with Tfpi in endothelium and smooth muscle cells. ELISA showed that silencing ADTRP via short hairpin RNA reduced the cell surface expression of TFPI, as well as ADTRP, in HUVECs and reduced colocalization of TFPI with CAV1. Knockdown of ADTRP also compromised the ability of TFPI to inhibit TF-FVIIa-dependent production of FXa by endothelial cells. In contrast, overexpression of ADTRP in HUVECs elevated the surface expression of both TFPI and ADTRP and increased the colocalization of TFPI, TF-FVIIa, and CAV1. Dihydrotestosterone increased TFPI and ADTRP mRNA in both HUVECs and EA.hy926 cells, and it increased TFPI-dependent FXa inhibition. Both overexpression of ADTRP and knockdown of ADTRP abrogated the effects of dihydrotestosterone. Lupu et al. (2011) concluded that ADTRP preserves the anticoagulant potential of TFPI on the endothelial cell surface.

GENE STRUCTURE

Girard et al. (1991) found that the TFPI gene contains 9 exons and identified alternative splicing resulting in the absence of exon 2 in the 5-prime untranslated region of some messages. Enjyoji et al. (1993) cloned a 125-kb genomic region containing the entire TFPI gene on 6 overlapping cosmids. More than half of the 85-kb gene is occupied with 5-prime noncoding elements; coding begins at exon 3.

MAPPING

By study of human-mouse somatic cell hybrids, Girard et al. (1991) mapped the LACI gene to chromosome 2. By in situ hybridization to metaphase chromosomes, they further localized the gene to 2q31-q32.1 ... More on the omim web site

Subscribe to this protein entry history

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 152310 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).