LPS-induced Expression of Monocyte Tissue Factor (TF) Antigen Correlates with Markers of Systemic Inflammation in Patients with Hemophilia A and B

2019 ◽  
Author(s):  
K. Holstein ◽  
A. Matysiak ◽  
L. Witt ◽  
B. Sievers ◽  
C. Lehr ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Systemic Inflammation ◽  
Hemophilia A ◽  
Induced Expression

scholarly journals IL-4 inhibits LPS-, IL-1β- and TNFα-induced expression of tissue factor in endothelial cells and monocytes

FEBS Letters ◽  
1992 ◽  
Vol 310 (1) ◽  
pp. 31-33 ◽  
Author(s):  
J.M. Herbert ◽  
P. Savi ◽  
M.C. Laplace ◽  
A. Lale
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Induced Expression

scholarly journals In Hemophilia Α Plasma Treated with Emicizumab, Factor IX Activation By Factor VIIa Drives Thrombin Generation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-17
Author(s):  
Dougald Monroe ◽  
Mirella Ezban ◽  
Maureane Hoffman
Keyword(s):  
Factor Viii ◽  
Tissue Factor ◽  
Plasma Levels ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Factor Viia ◽  
Factor Ix ◽  
Factor X ◽  
Dose Dependent

Background.Recently a novel bifunctional antibody (emicizumab) that binds both factor IXa (FIXa) and factor X (FX) has been used to treat hemophilia A. Emicizumab has proven remarkably effective as a prophylactic treatment for hemophilia A; however there are patients that still experience bleeding. An approach to safely and effectively treating this bleeding in hemophilia A patients with inhibitors is recombinant factor VIIa (rFVIIa). When given at therapeutic levels, rFVIIa can enhance tissue factor (TF) dependent activation of FX as well as activating FX independently of TF. At therapeutic levels rFVIIa can also activate FIX. The goal of this study was to assess the role of the FIXa activated by rFVIIa when emicizumab is added to hemophilia A plasma. Methods. Thrombin generation assays were done in plasma using 100 µM lipid and 420 µM Z-Gly-Gly-Arg-AMC with or without emicizumab at 55 µg/mL which is the clinical steady state level. The reactions were initiated with low (1 pM) tissue factor (TF). rFVIIa was added at concentrations of 25-100 nM with 25 nM corresponding to the plasma levels achieved by a single clinical dose of 90 µg/mL. To study to the role of factor IX in the absence of factor VIII, it was necessary to create a double deficient plasma (factors VIII and IX deficient). This was done by taking antigen negative hemophilia B plasma and adding a neutralizing antibody to factor VIII (Haematologic Technologies, Essex Junction, VT, USA). Now varying concentrations of factor IX could be reconstituted into the plasma to give hemophilia A plasma. Results. As expected, in the double deficient plasma with low TF there was essentially no thrombin generation. Also as expected from previous studies, addition of rFVIIa to double deficient plasma gave a dose dependent increase in thrombin generation through activation of FX. Interestingly addition of plasma levels of FIX to the rFVIIa did not increase thrombin generation. Starting from double deficient plasma, as expected emicizumab did not increase thrombin generation since no factor IX was present. Also, in double deficient plasma with rFVIIa, emicizumab did not increase thrombin generation. But in double deficient plasma with FIX and rFVIIa, emicizumab significantly increased thrombin generation. The levels of thrombin generation increased in a dose dependent fashion with higher concentrations of rFVIIa giving higher levels of thrombin generation. Conclusion. Since addition of FIX to the double deficient plasma with rFVIIa did not increase thrombin generation, it suggests that rFVIIa activation of FX is the only source of the FXa needed for thrombin generation. So in the absence of factor VIII (or emicizumab) FIX activation does not contribute to thrombin generation. However, in the presence of emicizumab, while rFVIIa can still activate FX, FIXa formed by rFVIIa can complex with emicizumab to provide an additional source of FX activation. Thus rFVIIa activation of FIX explains the synergistic effect in thrombin generation observed when combining rFVIIa with emicizumab. The generation of FIXa at a site of injury is consistent with the safety profile observed in clinical use. Disclosures Monroe: Novo Nordisk:Research Funding.Ezban:Novo Nordisk:Current Employment.Hoffman:Novo Nordisk:Research Funding.

Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1330-1335 ◽  
Author(s):  
Cornelis van 't Veer ◽  
Neal J. Golden ◽  
Kenneth G. Mann
Keyword(s):  
Factor Viii ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Factor Viia ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Factor Vii ◽  
Lag Phase ◽  
Single Chain

Factor VII circulates as a single chain inactive zymogen (10 nmol/L) and a trace (∼10-100 pmol/L) circulates as the 2-chain form, factor VIIa. Factor VII and factor VIIa were studied in a coagulation model using plasma concentrations of purified coagulation factors with reactions initiated with relipidated tissue factor (TF). Factor VII (10 nmol/L) extended the lag phase of thrombin generation initiated by 100 pmol/L factor VIIa and low TF. With the coagulation inhibitors TFPI and AT-III present, factor VII both extended the lag phase of the reaction and depressed the rate of thrombin generation. The inhibition of factor Xa generation by factor VII is consistent with its competition with factor VIIa for TF. Thrombin generation with TF concentrations >100 pmol/L was not inhibited by factor VII. At low tissue factor concentrations (<25 pmol/L) thrombin generation becomes sensitive to the absence of factor VIII. In the absence of factor VIII, factor VII significantly inhibits TF-initiated thrombin generation by 100 pmol/L factor VIIa. In this hemophilia A model, approximately 2 nmol/L factor VIIa is needed to overcome the inhibition of physiologic (10 nmol/L) factor VII. At 10 nmol/L, factor VIIa provided a thrombin generation response in the hemophilia model (0% factor VIII, 10 nmol/L factor VII) equivalent to that observed with normal plasma, (100% factor VIII, 10 nmol/L factor VII, 100 pmol/L factor VIIa). These results suggest that the therapeutic efficacy of factor VIIa in the medical treatment of hemophiliacs with inhibitors is, in part, based on overcoming the factor VII inhibitory effect.

Activation of mTOR is involved in anti-β 2 GPI/β 2 GPI-induced expression of tissue factor and IL-8 in monocytes

2017 ◽  
Vol 157 ◽  
pp. 103-110 ◽  
Author(s):  
Longfei Xia ◽  
Hong Zhou ◽  
Ting Wang ◽  
Yachao Xie ◽  
Ting Wang ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Induced Expression

Recombinant Activated FVII (rFVIIa) Corrects Platelet Dysfunction in Hemophilic Patients: Study on Collagen and Tissue Factor Surfaces at High Shear Rates.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4034-4034
Author(s):  
Raul Tonda ◽  
Ana M. Galan ◽  
Irene Lopez-Vilchez ◽  
Marcos Pino ◽  
Antonio Ordinas ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Cross Sections ◽  
Platelet Adhesion ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Platelet Dysfunction ◽  
Blood Samples ◽  
Shear Rates ◽  
High Shear Rates ◽  
Exogenous Addition

Abstract Hemophilic patients suffer bleeding episodes despite having a normal bleeding time. A possible platelet dysfunction in these patients has not been deeply investigated. rFVIIa improves hemostasis of hemophilic patients, even in those who develop inhibitors. Clinical efficacy of this drug has been widely confirmed, though, its mechanism of action is not fully understood. We used the PFA-100® with specially devised cartridges whose membrane apertures were coated with collagen alone (COL) or collagen-tissue factor (COL-TF). Blood samples from normal donors or from a group of patients with severe hemophilia A, were anticoagulated with low molecular weight heparin (LMWH). We tested the ability of rFVIIa to shorten the closure times under the previous conditions. The structure of the hemostatic plugs formed on the membrane apertures were further analyzed using light microscopy on thin cross-sections. Closure times were statistically prolonged in blood samples from hemophilic patients tested with COL cartridges (255±22 s.vs.187±15 s in normal donors; p<0.05). Presence of TF in the apertures (COL-TF) caused a 20% shortening in closure times, both in normal donors and in hemophilic patients. Exogenous addition of 10 μg/ml rFVIIa to blood samples from hemophilic patients induced a further statistically significant reduction of closure times (p<0.05). This further reduction in closure times was not observed in blood samples drawn from normal individuals. Microscopical analysis of the plugs formed on the apertures showed that occlusive thrombi formed in the presence of TF are more compact and have higher occlusive capacity. Addition of FVIIa led to the formation of more organized platelet plugs which appeared further consolidated with fibrin strands within platelet masses. Patients with severe hemophilia showed platelet dysfunction that could be detected with the PFA-100® using specific cartridges. It is likely that the platelet dysfunction observed in these patients could be related to concurrent reductions in VWF that could affect platelet adhesion in these patients revealed at the very elevated shear rates used in the PFA-100®. Under these conditions, TF deposited onto the collagen-coated apertures proved to play a significant role in the initiation of hemostasis. rFVIIa improved the recruitment of platelets on COL-TF and contributed to a partial correction of the platelet dysfunction observed in patients with hemophilia A as further confirmed by the formation of more efficient aggregates in the PFA-100. In essence, rFVIIa circumvented a pre-existent platelet adhesion defect in hemophiliac patients. The pro-hemostatic action of rFVIIa was not observed in parallel studies with blood from healthy donors, indirectly suggesting a good safety profile for this agent when hemostasis is well preserved. PFA-100 could be considered as a possible monitoring system of FVIIa when hemostasis is impaired.

Polymorphisms in Coagulant and Inflammatory Genes Modify the Phenotype of Severe Hemophilia A and B.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1009-1009 ◽  
Author(s):  
G. Jayandharan ◽  
Mercy Devadharshini ◽  
Auro Viswabandya ◽  
Sukesh C. Nair ◽  
R.V. Shaji ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tissue Factor ◽  
Plasminogen Activator ◽  
Protein C ◽  
Tumor Necrosis ◽  
Hemophilia A ◽  
Tnf Alpha ◽  
Severe Hemophilia ◽  
Tgf Beta ◽  
Necrosis Factor

Abstract Among patients with severe hemophilia (<1% factor level), 10–15% are known to have a clinically mild phenotype. The basis for this phenomenon is unclear. We hypothesized that functionally significant polymorphisms in the coagulant, inflammatory and immunoregulatory genes may affect the phenotype of severe hemophilia. A total 114 patients with hemophilia A (n=95) and hemophilia B (n=19) were studied. All these patients were on minimal on-demand treatment. Patients were evaluated for the frequency and site of hemorrhage. Their clinical and radiological joint scores were documented. They were categorized as ‘mild’ (<1 affected joint and < 5 bleeds in the preceding year, n=15) or ‘severe’ (>1 affected joint and >5bleeds, n=99). Functional polymorphisms in the coagulant system (human platelet alloantigen; tissue factor; fibrinogen; factors II; V; VII; XIIIA; thrombin activable fibrinolysis inhibitor (TAFI); endothelial protein C receptor; endothelial nitric oxide synthase 3; tissue plasminogen activator; plasminogen activator inhibitor; tissue factor pathway inhibitor; protein C and S; thrombomodulin), known procoagulant factors (methylene tetrahydrofolate reductase gene), inflammatory cytokine genes (tumor necrosis factor alpha; transforming growth factor beta; interleukin (IL) 10; IL 6; IL 1beta; IL 1 beta receptor antagonist; tumor necrosis factor beta), immunoregulatory cytokine genes (interferon gamma; HLA B27; FC gamma receptor), MDM2, angiotensin converting enzyme and HFE genes were genotyped. The mean age in the two groups was 18.5 & 14.85, p=0.124. The clinical features showing significant difference are shown in the table. Of the polymorphisms studied, the FVII RQ/QQ (lower levels) (RR-3.99, p=0.022, 95% CI 1.2–13.4), TNF alpha-308AA/AG (pro-inflammatory) (RR-3.4, p=0.037, 95% CI, 1.07–10.7), TGF beta Codon 10 CC/CT (pro-inflammatory) (RR-2.8, p=0.07, 95% CI, 0.91–8.3), have been associated with a severe phenotype while MDM2GG (anti-inflammatory, RR-0.3, p=0.038, 95% CI, 0.1–0.93) was associated with a milder phenotype. We hypothesize that the bleeding frequency in severe hemophilia may be increased due to relatively lower FVII levels and a combination of cytokine driven pro-inflammatory state involving TNF alpha, TGF beta and MDM2 would cause destruction of the cartilage resulting in elaboration of metalloproteinases from chondrocytes leading to the development of arthropathy. Parameter Severe, n=99 Median (Range) Mild, n=15 Median (Range) p Value Number of bleeds /yr 15(3–74) 2(0–5) 0.000 Number of joints /yr 3 (1–6) 1 (0–1) 0.000 Age at first clinical symptom (months) 21(1–300) 60(6–90) 0.056 WFH clinical score 10 (0–27) 4 (0–21) 0.000 Pettersson score 13 (0–57) 6 (0–20) 0.001

Adenosine inhibits thrombin-induced expression of tissue factor on endothelial cells by a nitric oxide-mediated mechanism

2002 ◽  
Vol 102 (2) ◽  
pp. 167 ◽  
Author(s):  
Esteban C. GABAZZA ◽  
Tatsuya HAYASHI ◽  
Masaru IDO ◽  
Yukihiko ADACHI ◽  
Koji SUZUKI
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Tissue Factor ◽  
Induced Expression

scholarly journals Plasma Tissue Factor Pathway Inhibitor (TFPI) Levels in Healthy Subjects and Patients with Hemophilia A and B

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4672-4672 ◽  
Author(s):  
Jian-Ming Gu ◽  
Chandra Patel ◽  
Katalin Kauser
Keyword(s):  
Tissue Factor ◽  
Healthy Subjects ◽  
Tissue Factor Pathway Inhibitor ◽  
Hemophilia A ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Capture Assay ◽  
Healthy Donors ◽  
Tissue Factor Pathway

Abstract BAY 1093884 is a fully human monoclonal antibody against tissue factor pathway inhibitor (TFPI) developed as a potential bypass agent for patients with hemophilia with or without inhibitors. It restores insufficient thrombin burst, leading to stable clot formation in hemophilic conditions in vitro, and effectively stops bleeding in vivo. TFPI is a potent inhibitor of factor Xa (FXa) and the factor VIIa tissue factor complex in the extrinsic pathway. The majority of TFPI is associated with vascular endothelial cells. The mean plasma TFPI concentration in healthy individuals is ~70 ng/mL (1.6 nM) and about 80% of the circulating TFPI is bound to lipoproteins [Dahm, et al. Blood. 2003;101(11):4387-4392; Broze,et al. Front Biosci. 2012;17:262-280]. Some reports indicate that patients with hemophilia B have lower free TFPI levels than patients with hemophilia A, irrespective of phenotypic severity (Tardy-Poncet, et al. Haemophilia 2011;17:312-313). The objective of this study is to determine the plasma TFPI concentration in healthy donors and patients with hemophilia by a newly developed functional TFPI capture assay and to evaluate this assay with inhibition of TFPI by anti-TFPI neutralizing antibody (BAY 1093884) in vitro. A quantitative enzyme-linked immunosorbent assay using FXa as capture agent was developed and validated to measure TFPI levels in human plasma. The assay shows very good precision, accuracy, and reproducibility and should capture all coagulation-relevant forms of TFPI from plasma. Plasma TFPI was determined in 30 healthy donors (15 males and 15 females) and 30 patients with severe hemophilia (hemophilia A [n=12], hemophilia A with inhibitors [n=9], hemophilia B [n=9]). The plasma TFPI levels (mean ± SD) in healthy individuals, patients with severe hemophilia A without and with inhibitors, and severe hemophilia B were 59.5±18.4 ng/mL, 62.9±14.6 ng/mL, 47.3±4.3 ng/mL, and 68.1±8.8 ng/mL, respectively (Table 1). No statistical differences were found based on sex or race (Hispanic, African American, white) in the healthy population and between patients with hemophilia with and without inhibitors. TFPI levels were also not affected by addition of corn trypsin inhibitor (CTI) in citrate plasma. Furthermore, the concentration that inhibits 50% of TFPI levels (IC50) of anti-TFPI antibody (BAY 1093884) was determined to be 4.76 nM in normal human plasma using this assay. In conclusion,plasma TFPI does not appear to be affected by sex or race in healthy subjects, or the deficiency of factor VIII or IX in patients with hemophilia. The functional TFPI capture assay could potentially be used as a pharmacodynamic marker for monitoring plasma TFPI levels after the administration of anti-TFPI antibody and guide dosing strategies. Table 1. Plasma TFPI Levels in Healthy Subjects and Patients With Severe Hemophilia A and B HealthyHuman Donors(n=30) SevereHem A(n=12) Severe Hem AWith inhibitors(n=9) SevereHem B(n=9) TFPI, ng/mL Mean ± SD 59.5±18.4 62.9±14.6 47.3±4.3 68.1±8.8 Hem=hemophilia; TFPI=tissue factor pathway inhibitor. Disclosures Gu: Bayer HealthCare: Employment. Patel:Bayer HealthCare: Employment. Kauser:Bayer HealthCare LLC: Employment.

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