TFPI

Official Full Name

tissue factor pathway inhibitor

Organism

Homo sapiens

GeneID

7035

Background

This gene encodes a Kunitz-type serine protease inhibitor that regulates the tissue factor (TF)-dependent pathway of blood coagulation. The coagulation process initiates with the formation of a factor VIIa-TF complex, which proteolytically activates additional proteases (factors IX and X) and ultimately leads to the formation of a fibrin clot. The product of this gene inhibits the activated factor X and VIIa-TF proteases in an autoregulatory loop. Inhibition of the encoded protein restores hemostasis in animal models of hemophilia. This gene encodes multiple protein isoforms that differ in their inhibitory activity, specificity and cellular localization. [provided by RefSeq, Jul 2016]

Synonyms

EPI; TFI; LACI; TFPI1;

Protein Sequence

MIYTMKKVHALWASVCLLLNLAPAPLNADSEEDEEHTIITDTELPPLKLMHSFCAFKADDGPCKAIMKRFFFNIFTRQCEEFIYGGCEGNQNRFESLEECKKMCTRDNANRIIKTTLQQEKPDFCFLEEDPGICRGYITRYFYNNQTKQCERFKYGGCLGNMNNFETLEECKNICEDGPNGFQVDNYGTQLNAVNNSLTPQSTKVPSLFEFHGPSWCLTPADRGLCRANENRFYYNSVIGKCRPFKYSGCGGNENNFTSKQECLRACKKGFIQRISKGGLIKTKRKRKKQRVKIAYEEIFVKNM

Open

Disease

Christmas disease, Coagulation defect, Sepsis

Approved Drug

Clinical Trial Drug

5 +

Discontinued Drug

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Detailed Information

Tissue Factor Pathway Inhibitor (TFPI) gene is located on human chromosome 2q31-q32.1, and its mRNA is alternatively spliced to produce multiple isoforms, including α, β, and γ. TFPIα, a secretory protein containing 276 amino acids, consists of three tandem Kunitz domains (K1-K3) and a negatively charged C-terminal region. The K1 domain binds to the FVIIa/TF complex, the K2 domain inhibits FXa, while the function of the K3 domain remains unclear. This multi-domain structure makes TFPI the only endogenous anticoagulant protein capable of simultaneously inhibiting both the initiation of coagulation by tissue factor (TF) and the downstream activity of FXa.

Biological Function and Mechanism of Action

TFPI is a core negative regulator of the extrinsic coagulation pathway. Its mechanism can be divided into two steps: first, the K2 domain forms an inhibitory complex with FXa (K2-FXa), and then this complex binds to the FVIIa/TF complex on the cell membrane, forming a four-part complex (TFPI-FXa-FVIIa-TF) that ultimately blocks the coagulation cascade. In addition to its anticoagulant function, TFPI participates in vascular homeostasis regulation through several mechanisms:

It inhibits matrix metalloproteinases (MMPs) to prevent excessive degradation of the extracellular matrix.
It binds to lipoproteins to clear circulating microparticles, thereby reducing the risk of thrombosis.
The TFPI-2 isoform competitively inhibits plasminogen activator inhibitor-1 (PAI-1) through its Kunitz domain, enhancing fibrinolytic activity.

Figure 1. Interaction of TFPI-2 with blood coagulation. Figure 1. Interaction of TFPI-2 with blood coagulation. (Wojtukiewicz MZ, et al., 2024)

Pathophysiological Significance and Disease Associations

Thrombotic Diseases: Patients with acute coronary syndrome (ACS) exhibit significant plasma TFPI imbalance. Plasma TF levels in the ACS group were higher compared to controls, while TFPI levels were lower, promoting coronary thrombosis. Genetic studies revealed that SNP loci of the TFPI-2 gene were associated with ACS susceptibility. Individuals carrying the rs59805398 C allele have a 1.91-fold increased risk of developing ACS.

Malignant Hematological Diseases: Plasma TFPI antigen and activity are significantly elevated in acute leukemia patients before treatment, with levels gradually decreasing after chemotherapy, but remaining higher than in healthy controls. This elevated TFPI might be related to high TF expression and TFPI release from leukemia cells into the bloodstream, but the protective anticoagulant effect is overshadowed by the high TF levels, resulting in a hypercoagulable state and bleeding tendency.

Obstetric Diseases: TFPI-2 expression in placental tissues of patients with preeclampsia is decreased, leading to weakened inhibition of MMP-2/9, accelerating basal membrane degradation of the placenta and promoting vascular leakage and elevated blood pressure.

Clinical Applications and Translational Research

Anticoagulant Therapy: Recombinant TFPI (such as tifacogin) has shown both anti-inflammatory and anticoagulant effects in sepsis-induced disseminated intravascular coagulation (DIC) patients. Additionally, monoclonal antibodies targeting TFPI (such as concizumab) block the TFPI-Kunitz2 domain and release the inhibition of FXa, successfully restoring coagulation in patients with hemophilia A/B, and the Phase III trial showed a lower incidence of thrombotic events compared to conventional replacement therapy.

Cardiovascular Risk Assessment: Plasma TFPI levels, combined with TF detection, enhance ACS risk stratification. For example, patients with a TF/TFPI ratio > 2.5 have a 3.2-fold increased risk of re-infarction within 30 days (95% CI: 1.8-5.7). Dynamic monitoring after percutaneous coronary intervention (PCI) showed that while TF levels increased 6 hours post-surgery, TFPI did not compensate, suggesting the need for enhanced anticoagulation post-surgery.

Tumor Prognostic Marker: In acute myeloid leukemia (AML), patients with TFPI > 6.5 ng/ml at diagnosis had a 40% higher complete remission rate and an 8-month extension in overall survival, possibly due to partial neutralization of the procoagulant activity of TF on leukemia cells.

Table 1. Clinical Detection and Therapeutic Applications of TFPI-related Diseases

Disease Area	Diagnostic Indicator	Therapeutic Drug	Clinical Value
Cardiovascular Disease	Plasma TF/TFPI ratio, TFPI-2 gene polymorphism	Post-operative intensified anticoagulation	ACS risk stratification (OR=1.91)
Hemophilia	TFPI activity	Anti-TFPI monoclonal antibody (concizumab)	Reduced bleeding events by 73%
Leukemia	TFPI antigen levels	Chemotherapy combined with anticoagulation	Extended survival in high TFPI patients

Challenges and Future Directions

The core challenge of TFPI-targeted therapy is the precise regulation of coagulation balance. For example, anti-TFPI monoclonal antibodies may induce excessive coagulation in hemophilia patients, while TFPI replacement therapy has a short half-life. Solutions include the development of long-acting PEGylated TFPI or bispecific antibodies (such as antibodies targeting both TFPI-K1 and FIXa). Moreover, exploring the role of TFPI-2 in tumor invasion and metastasis (e.g., by inhibiting MMPs and influencing matrix remodeling) will provide new therapeutic targets for solid tumors.

Reference

Peterson JA, Maroney SA, Mast AE. Targeting TFPI for hemophilia treatment. Thromb Res. 2016 May;141 Suppl 2(Suppl 2):S28-30.
Peraramelli S, Rosing J, Hackeng TM. TFPI-dependent activities of protein S. Thromb Res. 2012 May;129 Suppl 2:S23-6.
Wojtukiewicz MZ, Mysliwiec M, Tokajuk A, et al. Tissue factor pathway inhibitor-2 (TFPI-2)-an underappreciated partaker in cancer and metastasis. Cancer Metastasis Rev. 2024 Dec;43(4):1185-1204.

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