Tissue Factor Pathway Inhibitor is a Potent Inhibitor of Plasmin

1998 ◽  
Vol 4 (2) ◽  
pp. 114-117 ◽  
Author(s):  
Rainer J. Klauser ◽  
Debra Hoppensteadt ◽  
Jawed Fareed
Keyword(s):  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Potent Inhibitor ◽  
Plasma Kallikrein ◽  
Amidolytic Activity ◽  
Lysis Time ◽  
Tissue Plasminogen ◽  
Factor Xiia ◽  
Euglobulin Lysis Time ◽  
Tissue Factor Pathway

Recombinant tissue factor pathway inhibitor (TFPI) was found to be a potent inhibitor of plasmin. In an amidolytic assay the inhibition constant K i was found to be 2.86 x 10-8 M. TFPI in the same concentration range also inhibited the activation of plasminogen by tissue plasminogen activator (tPA). The amidolytic activity of tPA was not inhib ited by TFPI. Other proteinases relevant to fibrinolysis such as urokinase, α-factor XIIa, and β-factor XIIa were not inhibited by TFPI. Plasma kallikrein was weakly inhibited by TFPI. When added to plasma, TFPI also prolonged the euglobulin lysis time. The interaction of TFPI with heparin and a muco polysaccharide polysulfuric ester, a heparin-like glycosamino glycan, was studied. Heparin augmented plasmin inhibition by TFPI, while mucopolysaccharide polysulfuric ester had no ef fect. Key Words: Tissue factor pathway inhibitor (TFPI)— Plasmin—Inhibition—Fibrinolysis.

Imbalance of Plasminogen Activator Inhibitor-I/ Tissue Plasminogen Activator and Tissue Factor/Tissue Factor Pathway Inhibitor in Young Japanese Men with Myocardial Infarction

2001 ◽  
Vol 86 (11) ◽  
pp. 1197-1203 ◽  
Author(s):  
Masahiko Saigo ◽  
Masakazu Ogawa ◽  
Tsuminori Yamashita ◽  
Sadatoshi Biro ◽  
Shinichi Minagoe ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Plasminogen Activator ◽  
Protein C ◽  
Tissue Factor Pathway Inhibitor ◽  
Antithrombin Iii ◽  
Plasminogen Activator Inhibitor ◽  
Lipoprotein A ◽  
Tissue Plasminogen ◽  
Tissue Factor Pathway ◽  
Activator Inhibitor

SummaryTo evaluate the association between haemostatic parameters and increased risk of myocardial infarction (MI) at a young age, we measured fibrinogen, factor VII, antithrombin III, protein C, protein S, tissue factor (TF), free form tissue factor pathway inhibitor (TFPI), plasminogen, 2-antiplasmin, tissue plasminogen activator (tPA), plasminogen activator inhibitor-I (PAI-I), and lipoprotein (a) in 140 young men with MI before age 45 and 150 age-matched healthy men. TF, TF/TFPI ratio, PAI-I, PAI-I/tPA ratio, plasminogen, and lipoprotein (a) in young MI patients were all significantly higher than controls, while TFPI, antithrombin III, and tPA were significantly lower (P <0.001 of each). Significant determinants of MI risk were PAI-I/tPA ratio (R2 = 0.300, P <0.001), TF/TFPI ratio (R2 = 0.049, P <0.001), antithrombin III (R2 = 0.034, P <0.001), hyperlipidaemia (R2 = 0.019, P = 0.004), diabetes (R2 = 0.014, P = 0.015), lipoprotein (a) (R2 = 0.012, P = 0.023), 2-antiplasmin (R2 = 0.014, P = 0.012), and protein C (R2 = 0.012, P = 0.018). We conclude that the imbalances of PAI-I/tPA and TF/TFPI are significantly associated with MI at a young age, perhaps mediated via impaired fibrinolytic activity.

Ixolaris, a novel recombinant tissue factor pathway inhibitor (TFPI) from the salivary gland of the tick, Ixodes scapularis: identification of factor X and factor Xa as scaffolds for the inhibition of factor VIIa/tissue factor complex

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3602-3612 ◽  
Author(s):  
Ivo M. B. Francischetti ◽  
Jesus G. Valenzuela ◽  
John F. Andersen ◽  
Thomas N. Mather ◽  
José M. C. Ribeiro
Keyword(s):  
Salivary Gland ◽  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Factor Viia ◽  
Ixodes Scapularis ◽  
Factor Ix ◽  
Hard Tick ◽  
Factor X ◽  
Amidolytic Activity ◽  
Tissue Factor Pathway

Saliva of the hard tick and Lyme disease vector, Ixodes scapularis, has a repertoire of compounds that counteract host defenses. Following sequencing of an I scapularis salivary gland complementary DNA (cDNA) library, a clone with sequence homology to tissue factor pathway inhibitor (TFPI) was identified. This cDNA codes for a mature protein, herein called Ixolaris, with 140 amino acids containing 10 cysteines and 2 Kunitz-like domains. Recombinant Ixolaris was expressed in insect cells and shown to inhibit factor VIIa (FVIIa)/tissue factor (TF)–induced factor X (FX) activation with an inhibitory concentration of 50% (IC50) in the picomolar range. In nondenaturing gel, Ixolaris interacted stoichiometrically with FX and FXa but not FVIIa. Ixolaris behaves as a fast-and-tight ligand of the exosites of FXa and γ-carboxyglutamic acid domainless FXa (des-Gla-FXa), increasing its amidolytic activity. At high concentration, Ixolaris attenuates the amidolytic activity of FVIIa/TF; however, in the presence of DEGR-FX or DEGR-FXa (but not des-Gla-DEGR-FXa), Ixolaris becomes a tight inhibitor of FVIIa/TF as assessed by recombinant factor IX (BeneFIX) activation assays. This indicates that FX and FXa are scaffolds for Ixolaris in the inhibition of FVIIa/TF and implies that the Gla domain is necessary for FVIIa/TF/Ixolaris/FX(a) complex formation. Additionally, we show that Ixolaris blocks FXa generation by endothelial cells expressing TF. Ixolaris may be a useful tool to study the structural features of FVIIa, FX, and FXa, and an alternative anticoagulant in cardiovascular diseases.

Tissue factor pathway inhibitor 2 is a potent kallikrein-related protease 12 inhibitor

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Marion Lavergne ◽  
Audrey Guillon-Munos ◽  
Woodys Lenga Ma Bonda ◽  
Sylvie Attucci ◽  
Thomas Kryza ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Tissue Factor ◽  
Cancer Progression ◽  
Serine Proteases ◽  
Tissue Factor Pathway Inhibitor ◽  
Potent Inhibitor ◽  
Matrix Metalloproteases ◽  
Lung Tumour ◽  
Matrix Remodeling ◽  
Tissue Factor Pathway

Abstract The protease activities are tightly regulated by inhibitors and dysregulation contribute to pathological processes such as cancer and inflammatory disorders. Tissue factor pathway inhibitor 2 (TFPI-2) is a serine proteases inhibitor, that mainly inhibits plasmin. This protease activated matrix metalloproteases (MMPs) and degraded extracellular matrix. Other serine proteases are implicated in these mechanisms like kallikreins (KLKs). In this study, we identified for the first time that TFPI-2 is a potent inhibitor of KLK5 and 12. Computer modeling showed that the first Kunitz domain of TFPI-2 could interact with residues of KLK12 near the catalytic triad. Furthermore, like plasmin, KLK12 was able to activate proMMP-1 and -3, with no effect on proMMP-9. Thus, the inhibition of KLK12 by TFPI-2 greatly reduced the cascade activation of these MMPs and the cleavage of cysteine-rich 61, a matrix signaling protein. Moreover, when TFPI-2 bound to extracellular matrix, its classical localisation, the KLK12 inhibition was retained. Finally, TFPI-2 was downregulated in human non-small-cell lung tumour tissue as compared with non-affected lung tissue. These data suggest that TFPI-2 is a potent inhibitor of KLK12 and could regulate matrix remodeling and cancer progression mediated by KLK12.

Elevated Tissue Factor and Tissue Factor Pathway Inhibitor Circulating Levels in Ischaemic Heart Disease Patients

1998 ◽  
Vol 79 (03) ◽  
pp. 495-499 ◽  
Author(s):  
Anna Maria Gori ◽  
Sandra Fedi ◽  
Ludia Chiarugi ◽  
Ignazio Simonetti ◽  
Roberto Piero Dabizzi ◽  
...  
Keyword(s):  
Heart Disease ◽  
Ischaemic Heart Disease ◽  
Tissue Factor ◽  
Plasma Levels ◽  
Tissue Factor Pathway Inhibitor ◽  
Common Source ◽  
Previous Myocardial Infarction ◽  
Control Subjects ◽  
Tissue Factor Pathway ◽  
Circulating Levels

SummarySeveral studies have shown that thrombosis and inflammation play an important role in the pathogenesis of Ischaemic Heart Disease (IHD). In particular, Tissue Factor (TF) is responsible for the thrombogenicity of the atherosclerotic plaque and plays a key role in triggering thrombin generation. The aim of this study was to evaluate the TF/Tissue Factor Pathway Inhibitor (TFPI) system in patients with IHD.We have studied 55 patients with IHD and not on heparin [18 with unstable angina (UA), 24 with effort angina (EA) and 13 with previous myocardial infarction (MI)] and 48 sex- and age-matched healthy volunteers, by measuring plasma levels of TF, TFPI, Prothrombin Fragment 1-2 (F1+2), and Thrombin Antithrombin Complexes (TAT).TF plasma levels in IHD patients (median 215.4 pg/ml; range 72.6 to 834.3 pg/ml) were significantly (p<0.001) higher than those found in control subjects (median 142.5 pg/ml; range 28.0-255.3 pg/ml).Similarly, TFPI plasma levels in IHD patients were significantly higher (median 129.0 ng/ml; range 30.3-316.8 ng/ml; p <0.001) than those found in control subjects (median 60.4 ng/ml; range 20.8-151.3 ng/ml). UA patients showed higher amounts of TF and TFPI plasma levels (TF median 255.6 pg/ml; range 148.8-834.3 pg/ml; TFPI median 137.7 ng/ml; range 38.3-316.8 ng/ml) than patients with EA (TF median 182.0 pg/ml; range 72.6-380.0 pg/ml; TFPI median 115.2 ng/ml; range 47.0-196.8 ng/ml) and MI (TF median 213.9 pg/ml; range 125.0 to 341.9 pg/ml; TFPI median 130.5 ng/ml; range 94.0-207.8 ng/ml). Similar levels of TF and TFPI were found in patients with mono- or bivasal coronary lesions. A positive correlation was observed between TF and TFPI plasma levels (r = 0.57, p <0.001). Excess thrombin formation in patients with IHD was documented by TAT (median 5.2 μg/l; range 1.7-21.0 μg/l) and F1+2 levels (median 1.4 nmol/l; range 0.6 to 6.2 nmol/l) both significantly higher (p <0.001) than those found in control subjects (TAT median 2.3 μg/l; range 1.4-4.2 μg/l; F1+2 median 0.7 nmol/l; range 0.3-1.3 nmol/l).As in other conditions associated with cell-mediated clotting activation (cancer and DIC), also in IHD high levels of circulating TF are present. Endothelial cells and monocytes are the possible common source of TF and TFPI. The blood clotting activation observed in these patients may be related to elevated TF circulating levels not sufficiently inhibited by the elevated TFPI plasma levels present.

Behandlung der tiefen Venenthrombose

2000 ◽  
Vol 20 (01) ◽  
pp. 65-69 ◽  
Author(s):  
A. Loew ◽  
H. Riess
Keyword(s):  
Tissue Factor ◽  
Medikamentöse Therapie ◽  
Tissue Factor Pathway Inhibitor ◽  
Tissue Factor Pathway ◽  
Faktor Xa

ZusammenfassungVon den verschiedenen, zur Behandlung der tiefen Venenthrombose zur Verfügung stehenden Optionen, stellt die akute Antikoagulanzientherapie mit Heparinen, insbesondere niedermolekularen Heparinen, gefolgt von der frühzeitig überlappend eingeleiteten oralen Antikoagulation, das Standardvorgehen dar. Thrombolyse, Thrombektomie und Implantation von Kavaschirmfiltern kommen nur bei wenigen Patienten sinnvoll in Betracht. Während somit die medikamentöse Therapie mit Heparinen und Cumarinen die medikamentöse Standardbehandlung darstellt, sind begleitende Therapiemaßnahmen, wie die Notwendigkeit zur initialen Immobilisation der Patienten sowie zur Kompressionsbehandlung bei tiefen Venenthrombosen in ihrer Wertigkeit ungesichert und Gegenstand kontroverser Diskussionen. Darüber hinaus werden die optimale Dauer der oralen Antikoagulation, der Stellenwert einer prolongierten Therapie mit niedermolekularen Heparinen sowie der Stellenwert neuerer Antithrombotika wie Antithrombine, Faktor-Xa-Hemmstoffe und »Tissue factor pathway inhibitor« diskutiert.

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