Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4387-4392 ◽  
Author(s):  
Anders Dahm ◽  
Astrid van Hylckama Vlieg ◽  
Bjorn Bendz ◽  
Frits Rosendaal ◽  
Rogier M. Bertina ◽  
...  
Keyword(s):  
Risk Factor ◽  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Large Population ◽  
Population Based ◽  
Vein Thrombosis ◽  
Tissue Factor Pathway ◽  
Low Levels ◽  
Free Antigen

Abstract There is now strong experimental evidence that tissue factor pathway inhibitor (TFPI) is a critical inhibitor to modulate tissue factor–induced coagulation, but the role of TFPI as a risk factor for thrombosis is yet to be to be determined. This study investigated the role of low TFPI levels for the development of deep-vein thrombosis (DVT). We determined TFPI activity and TFPI-free and total antigen levels in the subjects enrolled in the Leiden Thrombophilia Study, which is a large population-based case-control study of 474 patients and 474 controls. The odds ratio (OR) for DVT in subjects who had TFPI-free antigen levels below the 10th percentile, as compared with those who had TFPI-free antigen levels above this cutoff, was 1.7 (95% confidence interval [CI], 1.1-2.6). The ORs for low TFPI activity and low total antigen were also mildly increased. When the 5th percentile was used as a cutoff, the ORs were 2.1 (95% CI, 1.1-4.1) for both TFPI-free antigen and TFPI total antigen. Exogenous female hormones had a profound lowering effect on TFPI levels, with lower levels in oral contraceptive users than in premenopausal nonusers, who had lower levels than men and postmenopausal women. These results indicate that low levels of TFPI, especially low TFPI-free and total antigen in plasma, constitute a risk factor for DVT.

scholarly journals Lipid-Mediated Relation between Tissue Factor Pathway Inhibitor Activity and Cardiovascular Risk Factors and Diseases in a Large Population Sample

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1169-1169
Author(s):  
Pauline van Paridon ◽  
Marina Panova-Noeva ◽  
Rene van Oerle ◽  
Andreas Schulz ◽  
Jürgen Prochaska ◽  
...  
Keyword(s):  
Risk Factors ◽  
Tissue Factor ◽  
Regression Models ◽  
Tissue Factor Pathway Inhibitor ◽  
Cox Regression ◽  
Large Population ◽  
Total Mortality ◽  
Population Based ◽  
Activity Levels ◽  
Tissue Factor Pathway

Abstract Background: Tissue factor pathway inhibitor (TFPI), a Kunitz-type serine protease, is a potent anticoagulant protein in the extrinsic coagulation pathway and acts by inhibiting both the FXa and the Tissue Factor-FVIIa complex. In contrast to total and free TFPI antigen levels, the reference values and clinical determinants of total TFPI activity have not yet been studied in detail in the general population. In the present study, we aim to identify the cardiovascular determinants for total TFPI activity and investigate its association with cardiovascular disease (CVD) and total mortality, in a population at large. Methods: For this study, the first 4779 subjects of the population-based Gutenberg Health Study were examined in a highly standardized setting. Total TFPI activity was assessed in platelet poor plasma by the Actichrome TFPI activity assay (American Diagnostica, Stamford, CT, USA). Sex-specific nomograms were developed to demonstrate the relation of total TFPI activity with age. Multivariable regression analysis was performed to assess the determinants of total TFPI activity and to evaluate the association with CVD. Cox-regression models, adjusted for age, sex, cardiovascular risk factors (CVRFs) and CVD, were calculated to investigate the association between total TFPI activity and total mortality. Results: The multivariable linear regression analysis identified smoking (β, 0.0952 [0.0541 to 0.136],) as a positive determinant for total TFPI activity, while diabetes (β, -0.0716 [-0.134 to -0.00905],), obesity (β, -0.0627 [-0.101 to -0.024],) and history of coronary artery disease (CAD) were negatively associated with TFPI activity, independent of age, sex and the remaining CVRFs. After adjustment for high-density lipoprotein levels (HDL), low-density lipoproteins (LDL) and triglycerides, the association between TFPI activity levels and obesity and CAD was lost. The analysis additionally reveals a strong positive association between TFPI activity levels and LDL (β, 0.221 [0.204 to 0.237],). The Cox regression models revealed that a higher TFPI activity, above 97.5th percentile of the reference group, was associated with an increased mortality risk (HR = 2.58, [95% CI: 1.49/4.47], p=0.00074) independent of age, sex, CVRFs, CVD, oral contraceptives and hormonal replacement therapy. After additional adjustment for LDL levels, this relation became stronger. Conclusion: To the best of our knowledge, this is the first large, epidemiological study of the general population, revealing an increased mortality risk in individuals with higher TFPI activity, independent of CVRFs and CVD and emphasized by LDL-levels. Additionally, it demonstrates the negative association between total TFPI activity levels and CVD, particularly CAD. Furthermore, an association between TFPI activity and obesity, mediated through lipoprotein particles is explored. Lastly, it describes the age- and sex-related reference range of total TFPI activity levels in a large population-based data set. Disclosures No relevant conflicts of interest to declare.

Factor Xa Enhances the Binding of Tissue Factor Pathway Inhibitor to Acidic Phospholipids

1996 ◽  
Vol 75 (05) ◽  
pp. 796-800 ◽  
Author(s):  
Sanne Valentin ◽  
Inger Schousboe
Keyword(s):  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Factor Xa ◽  
Microtitre Plate ◽  
C Terminus ◽  
Microtitre Plate Assay ◽  
Kunitz Domain ◽  
Tissue Factor Pathway ◽  
Acidic Phospholipids

SummaryIn the present study, the interaction between tissue factor pathway inhibitor (TFPI) and phospholipids has been characterized using a microtitre plate assay. TFPI was shown to bind calcium-independently to an acidic phospholipid surface composed of phosphatidylserine, but not a surface composed of the neutral phosphatidylcholine. The interaction was demonstrated to be dependent on the presence of the TFPI C-terminus. The presence of heparin (1 U/ml, unfractionated) was able to significantly reduce the binding of TFPI to phospholipid. The interaction of TFPI with phosphatidylserine was significantly decreased in the presence of calcium, but this was counteracted, and even enhanced, following complex formation of TFPI with factor Xa prior to incubation with the phospholipid surface. Moreover, a TFPI variant, not containing the third Kunitz domain and the C-terminus, was unable to bind to phospholipid. However, following the formation of a TFPI/factor Xa-complex this TFPI variant was capable of interacting with the phospholipid surface. This indicates that the role of factor Xa as a TFPI cofactor, at least in part, is to mediate the binding of TFPI to the phospholipid surface.

Role of GATA Motifs in Tissue Factor Pathway Inhibitor Gene Expression in Malignant Cells

2001 ◽  
Vol 101 (3) ◽  
pp. 203-211 ◽  
Author(s):  
Madhu S. Bajaj ◽  
Darren R. Tyson ◽  
Sarah A. Steer ◽  
Mohan N. Kuppuswamy
Keyword(s):  
Gene Expression ◽  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Malignant Cells ◽  
Tissue Factor Pathway ◽  
Inhibitor Gene

Tissue factor pathway inhibitor (TFPI) and its response to heparin in patients with spontaneous deep vein thrombosis

1993 ◽  
Vol 72 (5) ◽  
pp. 467-470 ◽  
Author(s):  
Jan Holst ◽  
Bengt Lindblad ◽  
Eva Wedeberg ◽  
David Bergqvist ◽  
Ole Nordfang ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Vein Thrombosis ◽  
Tissue Factor Pathway ◽  
Deep Vein

The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis

Blood Reviews ◽  
2013 ◽  
Vol 27 (3) ◽  
pp. 119-132 ◽  
Author(s):  
Kristien Winckers ◽  
Hugo ten Cate ◽  
Tilman M. Hackeng
Keyword(s):  
Tissue Factor ◽  
Arterial Thrombosis ◽  
Tissue Factor Pathway Inhibitor ◽  
Tissue Factor Pathway

scholarly journals Endogenous tissue factor pathway inhibitor has a limited effect on host defence in murine pneumococcal pneumonia

2015 ◽  
Vol 114 (07) ◽  
pp. 115-122 ◽  
Author(s):  
Cornelis van ’t Veer ◽  
Joris J. T. H. Roelofs ◽  
Joost C. M. Meijers ◽  
Marcus J. Schultz ◽  
George Broze Jr ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Bacterial Growth ◽  
Pneumococcal Pneumonia ◽  
Tissue Factor Pathway Inhibitor ◽  
Community Acquired Pneumonia ◽  
Lung Pathology ◽  
Kunitz Domain ◽  
Tissue Factor Pathway ◽  
Genetic Deletion ◽  
Low Levels

SummaryStreptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. Coagulation and inflammation interact in the host response to infection. Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant protein that inhibits tissue factor (TF), the main activator of inflammation-induced coagulation. It was the objective of this study to investigate the effect of endogenous TFPI levels on coagulation, inflammation and bacterial growth during S. pneumoniae pneumonia in mice. The effect of low endogenous TFPI levels was studied by administration of a neutralising anti-TFPI antibody to wild-type mice, and by using genetically modified mice expressing low levels of TFPI, due to a genetic deletion of the first Kunitz domain of TFPI (TFPIK1(-/-)) rescued with a human TFPI transgene. Pneumonia was induced by intranasal inoculation with S. pneumoniae and samples were obtained at 6, 24 and 48 hours after infection. Anti-TFPI reduced TFPI activity by ~50 %. Homozygous lowTFPI mice and heterozygous controls had ~10 % and ~50 % of normal TFPI activity, respectively. TFPI levels did not influence bacterial growth or dissemination. Whereas lung pathology was unaffected in all groups, mice with ~10 % (but not with ~50 %) of TFPI levels displayed elevated lung cytokine and chemokine concentrations 24 hours after infection. None of the groups with low TFPI levels showed an altered procoagulant response in lungs or plasma during pneumonia. These data argue against an important role for endogenous TFPI in the antibacterial, inflammatory and procoagulant response during pneumococcal pneumonia.

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