Delving into the Latest Updates on Tifacogin with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

LACI, TFPI, Tifacogin (USAN/INN)

+ [3]

Target

F10 x TFPI x factor VII

Mechanism

F10 inhibitors(Coagulation factor X inhibitors), TFPI inhibitors(Tissue factor pathway inhibitor inhibitors), factor VII inhibitors(Coagulation factor VII inhibitors)

Therapeutic Areas

Infectious DiseasesOther Diseases

Active Indication

Shock, Septic

Inactive Indication

Community Acquired PneumoniaThromboembolism

Originator Organization

Chiron Corp.

Active Organization

Chiron Corp.

Inactive Organization

Novartis Pharmaceuticals Corp.G.D. Searle & Co., Inc.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Gene Sequence

Sequence Code 37096

Source: *****

Acute lung injury (ALI) resulting from bacterial infection poses a significant risk, and its etiology involves the complex interplay of harmful immune responses and blood coagulation. Despite this understanding, the roles and mechanisms of tissue factor pathway inhibitor (TFPI) in LPS-induced ALI remain insufficiently elucidated. In this study, we aimed to explore the effects of TFPI in LPS-induced ALI. Our investigations revealed that TFPI exerts multiple beneficial effects in LPS-induced ALI. Specifically, TFPI reduces microvascular permeability, Myeloperoxidase (MPO) activity, and cytokine production while inhibiting blood coagulation. Moreover, TFPI demonstrates the capacity to promote proliferation and suppress apoptosis in Human microvascular endothelial cells (HMEC-1) and Human umbilical vein endothelial cells (HUVEC) through the inhibition of the caspase pathway and mitochondrial apoptosis pathway. Furthermore, our findings indicate a correlation between tissue factor (TF) and TFPI expression, with TFPI regulation observed in HMEC-1 cells following LPS treatment. This novel insight suggests that TFPI plays a regulatory role in TF expression. Overall, the protective effect of TFPI on LPS-induced ALI is unveiled by its ability to enhance endothelial cell proliferation and inhibit apoptosis through the modulation of caspase and Bcl-2/Bax pathways. These results underscore the potential of TFPI as a promising therapeutic target for ALI treatment.

01 Dec 2024·BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Tissue factor pathway inhibitor-2 inhibits integrin β1 activation and focal adhesion formation and suppresses peritoneal ovarian cancer dissemination in mice

Article

Author: Uomoto, Mari ; Miyagi, Yohei ; Sato, Shinya ; Hoshino, Daisuke ; Koizume, Shiro ; Yoshihara, Mitsuyo ; Nakamura, Yoshiyasu ; Tadokoro, Hiroko ; Ohtake, Norihisa ; Ota, Yukihide ; Myoba, Shohei ; Miyagi, Etsuko

Tissue factor pathway inhibitor-2 (TFPI2) is a Kunitz-type serine protease inhibitor and an ovarian clear cell carcinoma (CCC) biomarker. TFPI2 is expressed in several cancers and exerts tumor-suppressive effects; however, the role of TFPI2 in the CCC cell phenotype remains unclear. Therefore, in this study, we investigated the function of TFPI2 by establishing a gene knockout (KO) in ES-2 CCC cells and observed the change in phenotypes in vitro and in vivo. TFPI2 KO inhibited ES-2 cell proliferation, increased extracellular matrix protein adhesion, enhanced focal adhesion formation and activated integrin β1 cell surface clustering in vitro, and markedly increased ES-2 tumor growth and dissemination in the peritoneal cavity of a mouse xenograft model. These findings suggest a novel function of TFPI2 expression in suppressing the formation of focal adhesions in CCC cells, potentially by activating integrin β1. This function plays a role in the peritoneal growth characteristics of CCC cells.

01 Mar 2023·Journal of thrombosis and haemostasis : JTH

Tissue factor pathway inhibitor is a potential modifier of bleeding risk in factor XI deficiency

Article

Author: Mast, Alan E ; Wolberg, Alisa S ; Bolton-Maggs, Paula H B ; Reitsma, Stéphanie E ; Gidley, Gillian N ; Bouck, Emma G ; Burthem, John ; Monroe, Dougald M ; Holle, Lori A

BACKGROUND:

Factor (F) XI deficiency is associated with increased bleeding risk in some individuals. Neither FXI levels nor clinical clotting assays predict the bleeding risk. Compared with controls, FXI-deficient bleeders have reduced clot formation, decreased fibrin network density, and increased susceptibility to fibrinolysis. Tissue factor pathway inhibitor (TFPI) was recently implicated as a modifying factor in individuals with bleeding of unknown cause.

OBJECTIVES:

To determine the potential of TFPI in modifying the bleeding risk in FXI-deficient individuals.

METHODS:

The effects of TFPI on thrombin generation and clot formation, structure, and fibrinolysis in FXI-deficient plasma were measured in vitro in the absence or presence of inhibitory anti-TFPI antibody or exogenous recombinant TFPIα. Total plasma TFPI concentration was measured in 2 independent cohorts of controls and FXI-deficient individuals classified as bleeders or nonbleeders (cohort 1: 10 controls and 16 FXI-deficient individuals; cohort 2: 48 controls and 57 FXI-deficient individuals) and correlated with ex vivo plasma clot formation and fibrinolysis parameters associated with bleeding risk.

RESULTS:

In an in vitro FXI deficiency model, inhibition of TFPI enhanced thrombin generation and clot formation, increased the network density, and decreased fibrinolysis, whereas an increase in TFPI had the opposite effects. Compared with controls, plasma from FXI-deficient bleeders had higher TFPI concentration. Total plasma TFPI concentrations correlated with parameters from ex vivo clotting and fibrinolysis assays that differentiate FXI-deficient bleeders and nonbleeders.

CONCLUSION:

Coagulation and fibrinolysis parameters that differentiate FXI-deficient nonbleeders and bleeders were altered by plasma TFPIα. Total plasma TFPI was increased in FXI-deficient bleeders. TFPI may modify the bleeding risk in FXI-deficient individuals.

100 Deals associated with Tifacogin

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External Link

KEGG	Wiki	ATC	Drug Bank
D06142	-	-	DB06437

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Community Acquired Pneumonia	Phase 3	US	Novartis Pharmaceuticals Corp.	01 May 2004
Community Acquired Pneumonia	Phase 3	AR	Novartis Pharmaceuticals Corp.	01 May 2004
Community Acquired Pneumonia	Phase 3	AU	Novartis Pharmaceuticals Corp.	01 May 2004
Community Acquired Pneumonia	Phase 3	BE	Novartis Pharmaceuticals Corp.	01 May 2004
Community Acquired Pneumonia	Phase 3	BR	Novartis Pharmaceuticals Corp.	01 May 2004
Community Acquired Pneumonia	Phase 3	CA	Novartis Pharmaceuticals Corp.	01 May 2004
Community Acquired Pneumonia	Phase 3	CL	Novartis Pharmaceuticals Corp.	01 May 2004
Community Acquired Pneumonia	Phase 3	FR	Novartis Pharmaceuticals Corp.	01 May 2004
Community Acquired Pneumonia	Phase 3	DE	Novartis Pharmaceuticals Corp.	01 May 2004
Community Acquired Pneumonia	Phase 3	MY	Novartis Pharmaceuticals Corp.	01 May 2004