scholarly journals The effect of corn trypsin inhibitor, anti-tissue factor pathway inhibitor antibodies and phospholipids on microvesicle-associated thrombin generation in patients with pancreatic cancer and healthy controls

PLoS ONE ◽  
2017 ◽  
Vol 12 (9) ◽  
pp. e0184579 ◽  
Author(s):  
Marit Hellum ◽  
Isabel Franco-Lie ◽  
Reidun Øvstebø ◽  
Truls Hauge ◽  
Carola E. Henriksson
Keyword(s):  
Pancreatic Cancer ◽  
Tissue Factor ◽  
Trypsin Inhibitor ◽  
Thrombin Generation ◽  
Tissue Factor Pathway Inhibitor ◽  
Healthy Controls ◽  
Tissue Factor Pathway ◽  
Corn Trypsin Inhibitor

scholarly journals Children with Inflammatory Bowel Disease Exhibit Insensitivity to Tissue Factor Pathway Inhibitor

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2504-2504 ◽  
Author(s):  
Axel Schlagenhauf ◽  
Harald Haidl ◽  
Pohl Sina ◽  
Jahnel Jörg ◽  
Wolfgang Muntean ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Tissue Factor ◽  
Bowel Disease ◽  
Thrombin Generation ◽  
Tissue Factor Pathway Inhibitor ◽  
Conflicts Of Interest ◽  
Lag Time ◽  
Healthy Controls ◽  
Inflammatory Bowel ◽  
Tissue Factor Pathway

Abstract Background: Patients with inflammatory bowel diseases (IBD) exhibit chronic inflammation of the digestive tract associated with a prothrombotic shift in the plasmatic coagulation system as well as heightened platelet reactivity and preactivation. Recently, microbial and platelet-derived inorganic polyphosphate has been shown to inhibit tissue factor pathway inhibitor (TFPI), thus, influencing the hemostatic balance during inflammation. We hypothesized that polyphosphate plays a role in the pathophysiology of inflammatory bowel disease resulting in refractoriness to TFPI activity. Aims: We aimed to determine the hemostatic sensitivity to exogenous TFPI in IBD patients and healthy controls. Methods: Plasma from pediatric patients with active Crohn's disease (CD) (N=10) or ulcerative colitis (UC) (N=10) and age-matched healthy controls (N=20) was spiked with recombinant TFPI (150 ng/ml). Thrombin generation with/without exogenous TFPI was performed using Calibrated Automated Thrombography. Differences in lag time of thrombin generation with/without TFPI were calculated (∆lag time). Results: Without addition of exogenous TFPI, IBD patients exhibited a shorter lag time than controls (IBD: 2.65±0.41 min; Controls: 3.72±0.48 min, P<0.001) Addition of exogenous TFPI prolonged the lag time significantly in healthy controls (∆lag time= 4.69±0.61 min; P<0.001), while the lag time was just slightly prolonged in IBD patients (CD: ∆lag time=0.92±0.37 min; P<0.001; UC: ∆lag time=0.34±27 min; P<0.05). Conclusion: Plasma samples from pediatric IBD patients exhibit refractoriness towards the anticoagulant activity of exogenous TFPI. This hyposensitivity potentially extends to the action of endogenous TFPI which adds to the prothrombotic phenotype associated with IBD. Further studies are needed to determine potential associations with disease activity and the susceptibility to develop thrombosis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Procoagulant activity in patients with combined type 2 diabetes and coronary artery disease: No effects of long-term exercise training

2017 ◽  
Vol 14 (2) ◽  
pp. 144-151 ◽  
Author(s):  
Vibeke Bratseth ◽  
Rune Byrkjeland ◽  
Ida U Njerve ◽  
Svein Solheim ◽  
Harald Arnesen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Exercise Training ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Tissue Factor Pathway Inhibitor ◽  
Ex Vivo ◽  
Tissue Factor Pathway ◽  
Artery Disease ◽  
Total Tissue

We investigated the effects of 12-month exercise training on hypercoagulability in patients with combined type 2 diabetes mellitus and coronary artery disease. Associations with severity of disease were further explored. Patients ( n = 131) were randomized to exercise training or a control group. Blood was collected at inclusion and after 12 months. Tissue factor, free and total tissue factor pathway inhibitor, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer were determined by enzyme-linked immunosorbent assay and ex vivo thrombin generation by the calibrated automated thrombogram assay. Tissue factor and ex vivo thrombin generation increased from baseline to 12 months ( p < 0.01, all), with no significant differences in changes between groups. At baseline, free and total tissue factor pathway inhibitor significantly correlated to fasting glucose ( p < 0.01, both) and HbA1c ( p < 0.05, both). In patients with albuminuria ( n = 34), these correlations were strengthened, and elevated levels of D-dimer, free and total tissue factor pathway inhibitor ( p < 0.01, all) and decreased ex vivo thrombin generation ( p < 0.05, all) were observed. These results show no effects of exercise training on markers of hypercoagulability in our population with combined type 2 diabetes mellitus and coronary artery disease. The association between poor glycaemic control and tissue factor pathway inhibitor might indicate increased endothelial activation. More pronounced hypercoagulability and increased tissue factor pathway inhibitor were demonstrated in patients with albuminuria.

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.

Abstract 43: Prothrombinase Assembled with Factor V Leiden is Resistant to Inhibition by Tissue Factor Pathway Inhibitor α Lowering the Procoagulant Threshold for Initiation of Coagulation

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jeremy P Wood ◽  
Lisa M Baumann Kreuziger ◽  
Susan A Maroney ◽  
Rodney M Camire ◽  
Alan E Mast
Keyword(s):  
Tissue Factor ◽  
Thrombin Generation ◽  
Tissue Factor Pathway Inhibitor ◽  
Platelet Rich Plasma ◽  
Anticoagulant Activity ◽  
Factor V Leiden ◽  
Factor Xa ◽  
Factor V ◽  
Activation Threshold ◽  
Tissue Factor Pathway

Factor V (FV) assembles with factor Xa (FXa) into prothrombinase, the enzymatic complex that converts prothrombin to thrombin. Tissue factor pathway inhibitor α (TFPIα) inhibits prothrombinase by high affinity interactions with FXa-activated FV and the FXa active site, thereby blocking the initiation of coagulation. FV Leiden (FVL) is strongly linked to venous thrombosis through its resistance to degradation by activated protein C (aPC), which enhances the propagation of coagulation. FVL combined with a 50% reduction in TFPI causes severe thrombosis and perinatal lethality in mice, suggesting that FVL also promotes the initiation of coagulation. To examine this possibility, thrombin generation assays initiated with limiting FXa were performed with control or FVL plasma and platelet-rich plasma (PRP). The activation threshold for thrombin generation was 10 to 20 pM FXa in 10 control plasmas, but was 5 pM in 4 of 10 homozygous FVL plasmas. FVL PRP had a similar decrease in the activation threshold. The differences in activation threshold were totally normalized by an anti-TFPI antibody, while exogenous TFPIα and a FV-binding peptide that mimics TFPIα had reduced anticoagulant activity in FVL plasma, revealing that the procoagulant effects of FVL in these assays rely on TFPIα. Next, FVL plasmas were studied in fibrin clot formation assays, as they are sensitive to small amounts of thrombin. In reactions activated with 0.5 pM FXa, 1 of 8 control plasmas, compared to 7 of 8 homozygous FVL plasmas, clotted within 60 minutes, with differences again normalized by the anti-TFPI antibody. In prothrombinase activity assays using purified proteins, TFPIα was a 1.7-fold weaker inhibitor of prothrombinase assembled with FVL compared to FV. Thus, in addition to its aPC-mediated effect on the propagation of coagulation, FVL is resistant to TFPIα inhibition, exerting a procoagulant effect on coagulation initiation. This is evident in responses to small stimuli, where TFPIα blocks clotting in plasmas with FV but not FVL. The TFPIα-mediated modulation of the procoagulant threshold may explain the severe perinatal thrombosis in FVL mice with decreased TFPI and be clinically relevant in the clotting associated with oral contraceptives, which cause acquired TFPI deficiency.

Plasma free tissue factor pathway inhibitor (TFPI) levels and TF-induced thrombin generation ex vivo in men with low testosterone levels

2009 ◽  
Vol 101 (03) ◽  
pp. 471-477 ◽  
Author(s):  
Ingvild Agledahl ◽  
Johan Svartberg ◽  
Bjarne Hansen ◽  
Ellen Brodin
Keyword(s):  
Tissue Factor ◽  
Thrombin Generation ◽  
Tissue Factor Pathway Inhibitor ◽  
Ex Vivo ◽  
Elderly Men ◽  
Lower Plasma ◽  
Testosterone Levels ◽  
Initiation Phase ◽  
Tissue Factor Pathway ◽  
Low Testosterone

SummaryLow testosterone levels in men have been associated with cardiovascular risk factors, some prothrombotic factors, and lately also an increased risk of both cardiovascular disease and all-cause mortality. Experimental studies have shown increased synthesis and release of tissue factor pathway inhibitor (TFPI) by physiological levels of testosterone in endothelial cells. Our hypothesis was that elderly men with low testosterone levels would have lower plasma levels of plasma free TFPI with subsequent increased thrombin generation. Elderly men with low (n=37) and normal (n=41) testosterone levels were recruited from a general population, and tissue factor (TF)-induced thrombin generation ex vivo and plasma free TFPI Ag were measured. Elderly men with low testosterone levels had lower plasma free TFPI Ag (10.9 ± 2.3 ng/ml vs. 12.3 ± 3.0 ng/ml, p=0.027) and shorter initiation phase of TF-induced coagulation assessed by lag-time (5.1 ± 1.0 min vs. 5.7 ± 1.3, p=0.039). The differences between groups remained significant and were strengthened after adjustment for waist circumference and other cardiovascular risk factors. Lag-time increased linearly across quartiles of plasma free TFPI Ag (p<0.001). Multiple regression analysis revealed that total and free testosterone were independent predictors of plasma free TFPI Ag. Our findings suggest that low testosterone levels in elderly men is associated with low plasma free TFPI Ag and subsequent shortened initiation phase of TF-induced coagulation.

Tissue factor pathway inhibitor is the main determinant of thrombin generation in haemophilic patients

Haemophilia ◽  
2019 ◽  
Vol 25 (2) ◽  
pp. 343-348 ◽  
Author(s):  
Pierre Chelle ◽  
Aurélie Montmartin ◽  
Pauline Damien ◽  
Michèle Piot ◽  
Michel Cournil ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Thrombin Generation ◽  
Tissue Factor Pathway Inhibitor ◽  
Main Determinant ◽  
Tissue Factor Pathway
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