Coagulation inhibitors in inflammation

2005 ◽  
Vol 33 (2) ◽  
pp. 401-405 ◽  
Author(s):  
C.T. Esmon
Keyword(s):  
Tissue Factor ◽  
Inflammatory Mediators ◽  
Protein C ◽  
Tissue Factor Pathway Inhibitor ◽  
Clot Formation ◽  
Coagulation Inhibitors ◽  
Tissue Factor Pathway ◽  
Anti Inflammatory

Coagulation is triggered by inflammatory mediators in a number of ways. However, to prevent unwanted clot formation, several natural anticoagulant mechanisms exist, such as the antithrombin–heparin mechanism, the tissue factor pathway inhibitor mechanism and the protein C anticoagulant pathway. This review examines the ways in which these pathways are down-regulated by inflammation, thus limiting clot formation and decreasing the natural anti-inflammatory mechanisms that these pathways possess.

The 536C→T Transition in the Human Tissue Factor Pathway Inhibitor (TFPI) Gene Is Statistically Associated with a Higher Risk for Venous Thrombosis

1999 ◽  
Vol 82 (07) ◽  
pp. 1-5 ◽  
Author(s):  
Michael Schmidt ◽  
Christian Götting ◽  
Britt Schwenz ◽  
Stefan Lange ◽  
Gert Müller-Berghaus ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Blood Donors ◽  
Amino Acid Position ◽  
Immunological Methods ◽  
Venous Thromboembolic ◽  
Coagulation Inhibitors ◽  
Tissue Factor Pathway

SummaryTissue factor pathway inhibitor (TFPI) is an important regulator in the extrinsic blood coagulation pathway. Although the regulatory biochemical role of TFPI is evident, the clinical significance of this proteinase inhibitor remains to be elucidated. The definition of a clinical TFPI deficiency seems to be more complex than that of other coagulation inhibitors because the activity and concentration of circulating TFPI can not be considered a true measure of in vivo levels. Its determination in plasma samples by immunological methods or functional assays has been shown to be inadequate in the detection of a clinical deficiency.Therefore, we screened genomic DNA samples of blood donors and thrombotic patients for alterations in the TFPI gene to assess the influence of a modified TFPI in venous thromboembolic diseases. We detected a single nucleotide substitution in exon 7 (536C→T) leading to a proline to leucine exchange at amino acid position 151 of the protein ([P151L]TFPI) and found the prevalence of heterozygous carriers in German unrelated blood donors to be 0.2% (n = 5120).Four unrelated persons out of 14 probands carrying the genetic variation could be linked to venous thrombosis. For calculation of a potential risk for venous thrombosis for carriers of the mutation we investigated healthy blood donors about thrombotic events. 7 out of 308 blood donors were found to have a history of venous thrombosis, one of them carried the TFPI mutation. Statistical calculation showed a significant relative risk for venous thrombosis for individuals with the trait (odds ratio, 9.3; confidence interval, 1.8-48.6; p <0.01).

scholarly journals Elevated levels of tissue factor pathway inhibitor in patients with mild to moderate bleeding tendency

2021 ◽  
Vol 5 (2) ◽  
pp. 391-398
Author(s):  
Dino Mehic ◽  
Alexander Tolios ◽  
Stefanie Hofer ◽  
Cihan Ay ◽  
Helmuth Haslacher ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Genetic Alterations ◽  
Factor V ◽  
Bleeding Tendency ◽  
Healthy Controls ◽  
Single Nucleotide ◽  
Time To Peak ◽  
Coagulation Inhibitors ◽  
Tissue Factor Pathway

Abstract High levels of tissue factor pathway inhibitor (TFPI), caused by a longer TFPIα half-life after binding to a factor V splice variant and variants in the F5 gene, were recently identified in 2 families with an as-yet-unexplained bleeding tendency. This study aimed to investigate free TFPIα in a well-characterized cohort of 620 patients with mild to moderate bleeding tendencies and its association to genetic alterations in the F5 gene. TFPIα levels were higher in patients with bleeding compared with healthy controls (median [interquartile range], 8.2 [5.5-11.7] vs 7.8 [4.3-11.1]; P = .026). A higher proportion of patients had free TFPIα levels more than or equal to the 95th percentile compared with healthy controls (odds ratio [OR] [95% confidence interval (CI)], 2.82 [0.98-8.13]). This was pronounced in the subgroup of patients in whom no bleeding disorder could be identified (bleeding of unknown cause [BUC; n = 420]; OR [95% CI], 3.03 [1.02-8.98]) and in platelet function defects (PFDs) (n = 121; OR [95% CI], 3.47 [1.09-11.08]). An increase in free TFPIα was associated with a mild delay in thrombin generation (prolonged lag time and time to peak), but not with alterations in routinely used global clotting tests. We could neither identify new or known genetic variations in the F5 gene that are associated with free TFPIα levels, nor an influence of the single-nucleotide variant rs10800453 on free TFPIα levels in our patient cohort. An imbalance of natural coagulation inhibitors such as TFPIα could be an underlying cause or contributor for unexplained bleeding, which is most probably multifactorial in a majority of patients.

scholarly journals Expression of tissue factor pathway inhibitor by cultured endothelial cells in response to inflammatory mediators

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3219-3226 ◽  
Author(s):  
A Ameri ◽  
MN Kuppuswamy ◽  
S Basu ◽  
SP Bajaj
Keyword(s):  
Endothelial Cells ◽  
Blood Serum ◽  
Tissue Factor ◽  
Inflammatory Mediators ◽  
Whole Blood ◽  
Tissue Factor Pathway Inhibitor ◽  
Binding Motif ◽  
Cultured Endothelial Cells ◽  
The Media ◽  
Tissue Factor Pathway

Abstract We recently proposed that endothelium may represent the primary physiologic site of synthesis of the tissue factor pathway inhibitor (TFPI). In support of this conclusion, we have now found that the poly(A)+ RNAs obtained from rabbit and bovine lung tissues contain abundant amounts of TFPI messenger RNAs (mRNAs), whereas the poly(A)+ RNAs obtained from the liver of these animals contain less than 5% of that found in the lung tissues. Because inflammatory mediators are known to upregulate tissue factor (TF) expression by the endothelium, we have examined the effect of these agents on the TFPI expression by the cultured endothelial cells. When cultured human umbilical vein endothelial cells were stimulated (in 10% fetal bovine serum) with phorbol myristate acetate (PMA), endotoxin, interleukin-1, or tumor necrosis factor-alpha, the TF mRNA increased approximately 7- to 10- fold within 2 to 4 hours. Unstimulated cells constitutively expressed TFPI mRNA and its levels either did not change or increased slightly (up to 1.5-fold) upon stimulation with these inflammatory agents. TF mRNA abruptly declined to a negligible level and the TFPI mRNA returned essentially to the basal level at approximately 24 hours. The membrane- bound TF clotting activity of induced cells peaked between 4 and 8 hours, and finally declined. The cumulative TFPI activity secreted into the media was either unchanged or slightly higher in the induced cell cultures as compared with that present in the noninduced cultures. Endothelial cells were also cultured in 10% heat-inactivated human serum derived from plasma or whole blood. TFPI secreted into the media containing whole blood serum was consistently higher (approximately 1.5- fold at 8 hours) than that secreted into the media supplemented with serum obtained from plasma lacking the formed elements; these cells also expressed similarly increased levels of TFPI mRNA. Moreover, PMA- stimulated cells cultured in whole blood serum expressed modestly increased levels of TFPI mRNA (approximately 1.5-fold); supernatants from these cells also contained similarly increased TFPI activity. Cumulatively, our data indicate that, unlike thrombomodulin and fibrinolytic enzymes synthesized by the endothelial cells, TFPI synthesis is not downregulated and may be slightly upregulated during an inflammatory response. Inspection of the 5′ flanking region of the TFPI gene showed a conserved GATA-binding motif located approximately 400 bp upstream of the proposed transcription initiation site(s). This motif by binding to the GATA-2 transcriptional factor may keep the endothelium in an ‘on’ state for constitutive expression of TFPI.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Expression of tissue factor pathway inhibitor by cultured endothelial cells in response to inflammatory mediators

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3219-3226
Author(s):  
A Ameri ◽  
MN Kuppuswamy ◽  
S Basu ◽  
SP Bajaj
Keyword(s):  
Endothelial Cells ◽  
Blood Serum ◽  
Tissue Factor ◽  
Inflammatory Mediators ◽  
Whole Blood ◽  
Tissue Factor Pathway Inhibitor ◽  
Binding Motif ◽  
Cultured Endothelial Cells ◽  
The Media ◽  
Tissue Factor Pathway

We recently proposed that endothelium may represent the primary physiologic site of synthesis of the tissue factor pathway inhibitor (TFPI). In support of this conclusion, we have now found that the poly(A)+ RNAs obtained from rabbit and bovine lung tissues contain abundant amounts of TFPI messenger RNAs (mRNAs), whereas the poly(A)+ RNAs obtained from the liver of these animals contain less than 5% of that found in the lung tissues. Because inflammatory mediators are known to upregulate tissue factor (TF) expression by the endothelium, we have examined the effect of these agents on the TFPI expression by the cultured endothelial cells. When cultured human umbilical vein endothelial cells were stimulated (in 10% fetal bovine serum) with phorbol myristate acetate (PMA), endotoxin, interleukin-1, or tumor necrosis factor-alpha, the TF mRNA increased approximately 7- to 10- fold within 2 to 4 hours. Unstimulated cells constitutively expressed TFPI mRNA and its levels either did not change or increased slightly (up to 1.5-fold) upon stimulation with these inflammatory agents. TF mRNA abruptly declined to a negligible level and the TFPI mRNA returned essentially to the basal level at approximately 24 hours. The membrane- bound TF clotting activity of induced cells peaked between 4 and 8 hours, and finally declined. The cumulative TFPI activity secreted into the media was either unchanged or slightly higher in the induced cell cultures as compared with that present in the noninduced cultures. Endothelial cells were also cultured in 10% heat-inactivated human serum derived from plasma or whole blood. TFPI secreted into the media containing whole blood serum was consistently higher (approximately 1.5- fold at 8 hours) than that secreted into the media supplemented with serum obtained from plasma lacking the formed elements; these cells also expressed similarly increased levels of TFPI mRNA. Moreover, PMA- stimulated cells cultured in whole blood serum expressed modestly increased levels of TFPI mRNA (approximately 1.5-fold); supernatants from these cells also contained similarly increased TFPI activity. Cumulatively, our data indicate that, unlike thrombomodulin and fibrinolytic enzymes synthesized by the endothelial cells, TFPI synthesis is not downregulated and may be slightly upregulated during an inflammatory response. Inspection of the 5′ flanking region of the TFPI gene showed a conserved GATA-binding motif located approximately 400 bp upstream of the proposed transcription initiation site(s). This motif by binding to the GATA-2 transcriptional factor may keep the endothelium in an ‘on’ state for constitutive expression of TFPI.(ABSTRACT TRUNCATED AT 400 WORDS)

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