A Phase 3, Multicenter, Randomized, Placebo-Controlled, Double-Blind, Three-Arm Study to Evaluate the Safety andEfficacy of Tifacogin (Recombinant Tissue Factor Pathway Inhibitor) Administration in Subjects with Severe Community-Acquired Pneumonia

开始日期2004-07-01

申办/合作机构

Novartis Pharmaceuticals Corp.

[+1]

NCT00084071 / Completed临床3期

Tifacogin (Recombinant Tissue Factor Pathway Inhibitor) for the Treatment of Patients With Severe Community-Acquired Pneumonia

The purpose of this study is to determine whether tifacogin is effective and safe in the treatment of patients with severe community-acquired pneumonia.

开始日期2004-05-01

申办/合作机构

Novartis Pharmaceuticals Corp.

PER-047-04 / Completed临床3期

MULTI-CENTER RANDOMIZED STUDY CONTROLLED WITH DOUBLE-BLIND PLACEBO OF 3 ARMS OF PHASE 3 TO EVALUATE THE SAFETY AND EFFICACY OF THE ADMINISTRATION OF TIFACOGIN (RECOMBINANT INHIBITOR OF THE TISSUE FACTOR´S ROUTE) IN SUBJECTS WITH PNEUMONIA ACQUIRED IN THE SEVERE COMMUNITY

开始日期1900-01-01

申办/合作机构-

100 项与 factor VII x TFPI x F10 相关的临床结果

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100 项与 factor VII x TFPI x F10 相关的转化医学

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0 项与 factor VII x TFPI x F10 相关的专利（医药）

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项与 factor VII x TFPI x F10 相关的文献（医药）

2020-01-01·Clinical and Applied Thrombosis/Hemostasis4区 · 医学

Studies on Tissue Factor Pathway Inhibitor Antigen Release by Bovine, Ovine and Porcine Heparins Following Intravenous Administration to Non-Human Primates

4区 · 医学

Article

作者: Fareed, Jawed ; Cera, Lee ; Kouta, Ahmed ; Duff, Richard ; Hoppensteadt, Debra ; Bontekoe, Emily ; Jeske, Walter

Unfractionated heparin (UFH) is a sulfated glycosaminoglycan that consists of repeating disaccharides, containing iduronic acid (or glucuronic acid) and glucosamine, exhibiting variable degrees of sulfation. UFHs release tissue factor pathway inhibitor (TFPI) which inhibits the extrinsic pathway of coagulation by inactivating factor Xa and the factor VIIa/TF complex. Most heparins used clinically are derived from porcine intestinal mucosa however, heparins can also be derived from tissues of bovine and ovine origin. Currently there are some concerns about the shortage of the porcine heparins as they are widely used in the manufacturing of the low molecular weight heparins (LMWHs). Moreover, due to cultural and religious reasons in some countries, alternative sources of heparins are needed. Bovine mucosal heparins (BMH) are currently being developed for re-introduction to the US market for both medical and surgical indications. Compared to porcine mucosal heparin (PMH), BMH exhibits a somewhat weaker anti-coagulant activity. In this study, we determined the TFPI antigen level following administration of various dosages of UFHs from different origins. These studies demonstrated that IV administration of equigravemetric dosages of PMH and ovine mucosal heparin (OMH) to non-human primates resulted in comparable TFPI antigen release from endothelial cells. In addition, the levels of TFPI were significantly higher than TFPI antigen levels observed after BMH administration. Potency adjusted dosing resulted in comparable TFPI release profiles for all 3 heparins. Therefore, such dosing may provide uniform levels of anticoagulation for the parenteral indications for UFHs. These observations warrant further clinical validation in specific indications.

2020-01-01·International Journal of Hematology4区 · 医学

Anti-tissue factor pathway inhibitor (TFPI) therapy: a novel approach to the treatment of haemophilia

4区 · 医学

Review

作者: Chowdary, Pratima

Novel approaches to the treatment of haemophilia are needed due to the limitations of the current standard of care, factor replacement therapy. Aspirations include lessening the treatment burden and effectively preventing joint damage. Treating haemophilia by restoring thrombin generation may be an effective approach. A promising target for restoring thrombin generation is tissue factor pathway inhibitor (TFPI), a multivalent Kunitz-type serine protease inhibitor that regulates tissue factor-induced coagulation via factor Xa-dependent feedback inhibition of the tissue factor-factor VIIa complex. Inhibition of TFPI reverts the coagulation process to a more primitive state evolutionarily, whilst regulation by other natural inhibitors is preserved. An aptamer and three monoclonal antibodies directed against TFPI have been investigated in clinical trials. As well as improving thrombin generation in the range associated with mild haemophilia, anti-TFPI therapies have the advantage of subcutaneous administration. However, the therapeutic window needs to be defined along with the potential for complications due to the novel mechanism of action. This review provides an overview of TFPI, its role in normal coagulation, the rationale for TFPI inhibition, and a summary of anti-TFPI therapies, previously or currently in development.

2018-03-01·Thrombosis and Haemostasis2区 · 医学

Suppressive Role of Tissue Factor Pathway Inhibitor-α in Platelet-Dependent Fibrin Formation under Flow Is Restricted to Low Procoagulant Strength

2区 · 医学

Article

作者: Thomassen, Stella ; Maroney, Susan A ; Mast, Alan E ; Winckers, Kristien ; Schrijver, Roy ; Mastenbroek, Tom G ; Swieringa, Frauke ; Heemskerk, Johan W M ; Cosemans, Judith M E M ; Hackeng, Tilman M ; Feijge, Marion A H

AbstractTissue factor pathway inhibitor-alpha (TFPI-α) is a Kunitz-type serine protease inhibitor, which suppresses coagulation by inhibiting the tissue factor (TF)/factor VIIa complex as well as factor Xa. In static plasma-phospholipid systems, TFPI-α thus suppresses both factor Xa and thrombin generation. In this article, we used a microfluidics approach to investigate how TFPI-α regulates fibrin clot formation in platelet thrombi at low wall shear rate. We therefore hypothesized that the anticoagulant effect of TFPI-α in plasma is a function of the local procoagulant strength—defined as the magnitude of thrombin generation under flow, due to local activities of TF/factor VIIa and factor Xa. To test this hypothesis, we modulated local coagulation by microspot coating of flow channels with 0 to 100 pM TF/collagen, or by using blood from patients with haemophilia A or B. For blood or plasma from healthy subjects, blocking of TFPI-α enhanced fibrin formation, extending from a platelet thrombus, under flow only at <2 pM coated TF. This enhancement was paralleled by an increased thrombin generation. For mouse plasma, genetic deficiency in TFPI enhanced fibrin formation under flow also at 0 pM TF microspots. On the other hand, using blood from haemophilia A or B patients, TFPI-α antagonism markedly enhanced fibrin formation at microspots with up to 100 pM coated TF. We conclude that, under flow, TFPI-α is capable to antagonize fibrin formation in a manner dependent on and restricted by local TF/factor VIIa and factor Xa activities.