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

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.

SUBMITTER: Mehic D

PROVIDER: S-EPMC7839354 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Thrombomodulin in patients with mild to moderate bleeding tendency.

Project description:IntroductionA massive increase of soluble thrombomodulin (sTM) due to variants in the thrombomodulin gene (THBD) has recently been identified as a novel bleeding disorder.AimTo investigate sTM levels and underlying genetic variants as a cause for haemostatic impairment and bleeding in a large number of patients with a mild to moderate bleeding disorder (MBD), including patients with bleeding of unknown cause (BUC).Patients and methodsIn 507 MBD patients, sTM levels, thrombin generation and plasma clot formation were measured and compared to 90 age- and sex-matched healthy controls. In patients, genetic analysis of the THBD gene was performed.ResultsNo difference in sTM levels between patients and controls was found overall (median ([IQR] 5.0 [3.8-6.3] vs. 5.1 [3.7-6.4] ng/ml, p = .762), and according to specific diagnoses of MBD or BUC, and high sTM levels (≥95th percentile of healthy controls) were not overrepresented in patients. Soluble TM levels had no impact on bleeding severity or global tests of haemostasis, including thrombin generation or plasma clot formation. In the THBD gene, no known pathogenic or novel disease-causing variants affecting sTM plasma levels were identified in our patient cohort.ConclusionTM-associated coagulopathy appears to be rare, as it was not identified in our large cohort of patients with MBD. Soluble TM did not arise as a risk factor for bleeding or altered haemostasis in these patients.

| S-EPMC9293080 | biostudies-literature

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

Project description:BackgroundFactor (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.ObjectivesTo determine the potential of TFPI in modifying the bleeding risk in FXI-deficient individuals.MethodsThe 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.ResultsIn 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.ConclusionCoagulation 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.

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Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency.

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| S-EPMC2572790 | biostudies-literature

Tissue factor pathway inhibitor: structure-function.

Project description:TFPI is a multivalent, Kunitz-type proteinase inhibitor, which, due to alternative mRNA splicing, is transcribed in three isoforms: TFPIalpha, TFPIdelta, and glycosyl phosphatidyl inositol (GPI)-anchored TFPIbeta. The microvascular endothelium is thought to be the principal source of TFPI and TFPIalpha is the predominant isoform expressed in humans. TFPIalpha, apparently attached to the surface of the endothelium in an indirect GPI-anchor-dependent fashion, represents the greatest in vivo reservoir of TFPI. The Kunitz-2 domain of TFPI is responsible for factor Xa inhibition and the Kunitz-1 domain is responsible for factor Xa-dependent inhibition of the factor VIIa/tissue factor catalytic complex. The anticoagulant activity of TFPI in one-stage coagulation assays is due mainly to its inhibition of factor Xa through a process that is enhanced by protein S and dependent upon the Kunitz-3 and carboxyterminal domains of full-length TFPIalpha. Carboxyterminal truncated forms of TFPI as well as TFPIalpha in plasma, however, inhibit factor VIIa/tissue factor in two-stage assay systems. Studies in gene-disrupted mice demonstrate the physiological importance of TFPI.

| S-EPMC3692300 | biostudies-literature

Elevated pontine and putamenal GABA levels in mild-moderate Parkinson disease detected by 7 tesla proton MRS.

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| S-EPMC3266292 | biostudies-literature

Alternatively spliced isoforms of tissue factor pathway inhibitor.

Project description:Tissue factor pathway inhibitor (TFPI) is the major regulator of tissue factor (TF)-induced coagulation. It down regulates coagulation by binding to the TF/fVIIa complex in a fXa dependent manner. It is predominantly produced by microvascular endothelial cells, though it is also found in platelets, monocytes, smooth muscle cells, and plasma. Its physiological importance is demonstrated by the embryonic lethality observed in TFPI knockout mice and by the increase in thrombotic burden that occurs when heterozygous TFPI mice are bred with mice carrying genetic risk factors for thrombotic disease, such as factor V Leiden. Multiple TFPI isoforms, termed TFPIalpha, TFPIbeta, and TFPIdelta in humans and TFPIalpha, TFPIbeta, and TFPIgamma in mice, have been described, which differ in their domain structure and method for cell surface attachment. A significant functional difference between these isoforms has yet to be described in vivo. Both human and mouse tissues produce, on average, approximately 10 times more TFPIalpha message when compared to that of TFPIbeta. Consistent with this finding, several lines of evidence suggest that TFPIalpha is the predominant protein isoform in humans. In contrast, recent work from our laboratory demonstrates that TFPIbeta is the major protein isoform produced in adult mice, suggesting that TFPI isoform production is translationally regulated.

| S-EPMC2839007 | biostudies-literature

Protein S is a cofactor for platelet and endothelial tissue factor pathway inhibitor-? but not for cell surface-associated tissue factor pathway inhibitor.

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| S-EPMC4030531 | biostudies-literature

Tissue factor pathway inhibitor-gamma is an active alternatively spliced form of tissue factor pathway inhibitor present in mice but not in humans.

Project description:Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of tissue factor procoagulant activity produced as two alternatively spliced isoforms, TFPIalpha and TFPIbeta, which differ in domain structure and mechanism for cell surface association. 3' Rapid amplification of cDNA ends was used to search for new TFPI isoforms. TFPIgamma, a new alternatively spliced form of TFPI, was identified and characterized.The tissue expression, cell surface association and anticoagulant activity of TFPIgamma were characterized and compared to those of TFPIalpha and TFPIbeta through studies of mouse and human tissues and expression of recombinant proteins in Chinese hamster ovary (CHO) cells.TFPIgamma is produced by alternative splicing using the same 5'-splice donor site as TFPIbeta and a 3'-splice acceptor site 276 nucleotides beyond the stop codon of TFPIbeta in exon 8. The resulting protein has the first two Kunitz domains connected to an 18 amino acid C-terminal region specific to TFPIgamma. TFPIgamma mRNA is differentially produced in mouse tissues but is not encoded within the human TFPI gene. When expressed in CHO cells, TFPIgamma is secreted into conditioned media and effectively inhibits tissue factor procoagulant activity.TFPIgamma is a third alternatively spliced form of TFPI that is widely expressed in mouse tissues but not made by human tissues. It contains the first two Kunitz domains and is a secreted, rather than a cell surface-associated, protein. It is a functional anticoagulant and may partially explain the resistance of mice to coagulopathy in tissue factor-mediated models of disease.

| S-EPMC3549614 | biostudies-literature

Small peptides blocking inhibition of factor Xa and tissue factor-factor VIIa by tissue factor pathway inhibitor (TFPI).

Project description:Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that inhibits activated factor X (FXa) via a slow-tight binding mechanism and tissue factor-activated FVII (TF-FVIIa) via formation of a quaternary FXa-TFPI-TF-FVIIa complex. Inhibition of TFPI enhances coagulation in hemophilia models. Using a library approach, we selected and subsequently optimized peptides that bind TFPI and block its anticoagulant activity. One peptide (termed compound 3), bound with high affinity to the Kunitz-1 (K1) domain of TFPI (Kd ?1 nM). We solved the crystal structure of this peptide in complex with the K1 of TFPI at 2.55-? resolution. The structure of compound 3 can be segmented into a N-terminal anchor; an ?-shaped loop; an intermediate segment; a tight glycine-loop; and a C-terminal ?-helix that is anchored to K1 at its reactive center loop and two-stranded ?-sheet. The contact surface has an overall hydrophobic character with some charged hot spots. In a model system, compound 3 blocked FXa inhibition by TFPI (EC50 = 11 nM) and inhibition of TF-FVIIa-catalyzed FX activation by TFPI (EC50 = 2 nM). The peptide prevented transition from the loose to the tight FXa-TFPI complex, but did not affect formation of the loose FXa-TFPI complex. The K1 domain of TFPI binds and inhibits FVIIa and the K2 domain similarly inhibits FXa. Because compound 3 binds to K1, our data show that K1 is not only important for FVIIa inhibition but also for FXa inhibition, i.e. for the transition of the loose to the tight FXa-TFPI complex. This mode of action translates into normalization of coagulation of hemophilia plasmas. Compound 3 thus bears potential to prevent bleeding in hemophilia patients.

| S-EPMC3894350 | biostudies-literature

p21-activated kinase-1 signaling regulates transcription of tissue factor and tissue factor pathway inhibitor.

Project description:Tissue factor (TF) is a cell-surface glycoprotein responsible for initiating the coagulation cascade. Besides its role in homeostasis, studies have shown the implication of TF in embryonic development, cancer-related events, and inflammation via coagulation-dependent and -independent (signaling) mechanisms. Tissue factor pathway inhibitor (TFPI) plays an important role in regulating TF-initiated blood coagulation. Therefore, transcriptional regulation of TF expression and its physiological inhibitor TFPI would allow us to understand the critical step that controls many different processes. From a gene profiling study aimed at identifying differentially regulated genes between wild-type (WT) and p21-activated kinase 1-null (PAK1-KO) mouse embryonic fibroblasts (MEFs), we found TF and TFPI are differentially expressed in the PAK1-KO MEFs in comparison with wild-type MEFs. Based on these findings, we further investigated in this study the transcriptional regulation of TF and TFPI by PAK1, a serine/threonine kinase. We found that the PAK1·c-Jun complex stimulates the transcription of TF and consequently its procoagulant activity. Moreover, PAK1 negatively regulates the expression of TFPI and additionally contributes to increased TF activity. For the first time, this study implicates PAK1 in coagulation processes, through its dual transcriptional regulation of TF and its inhibitor.

| S-EPMC3501013 | biostudies-literature

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