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Michael Losos, Scott Scrape, Sarita Joshi, Aaron Shmookler, Jian Chen
Acquired hemophilia A (AHA) is a rare autoimmune disorder that leads to factor VIII (FVIII) deficiency via autoantibody formation. Standard treatment options include FVIII bypassing factors and immunosuppression. However, the role of therapeutic plasma exchange (TPE) is not clear in the treatment of AHA. We present a case of idiopathic AHA in a 66 year old female with severe bleeding and a FVIII inhibitor of 17.6 Bethesda units (BU). She failed to respond to standard treatment including maximum dose of recombinant FVIIa (rFVIIa), rituximab, and other immunosuppressive agents...
September 20, 2016: Journal of Clinical Apheresis
Judicael G Fazavana, Vincent Muczynski, Valerie Proulle, Nikolett Wohner, Olivier D Christophe, Peter J Lenting, Cécile V Denis
BACKGROUND: Recent findings point to activated factor VII (FVIIa) being cleared predominantly (±65% of the injected protein) as part of a complex with the serpin antithrombin. FVIIa/antithrombin complexes are targeted to hepatocytes and liver macrophages. Both cells lines abundantly express LRP1, a scavenger-receptor mediating clearance of protease/serpin complexes. OBJECTIVES: To investigate whether the FVIIa/antithrombin complex is a ligand for LRP1. METHODS: Binding of FVIIa and pre-formed FVIIa/antithrombin complexes to purified LRP1-fragment Cluster-IV (sLRP1-cIV/Fc) and to human & murine macrophages was analyzed...
September 10, 2016: Journal of Thrombosis and Haemostasis: JTH
Vladimir Uladzimir Ladziata, Peter W Glunz, Yan Zou, Xiaojun Zhang, Wen Jiang, Swanee Jacutin-Porte, Daniel L Cheney, Anzhi Wei, Joseph M Luettgen, Timothy M Harper, Pancras C Wong, Dietmar Seiffert, Ruth R Wexler, E Scott Priestley
Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity...
October 15, 2016: Bioorganic & Medicinal Chemistry Letters
Elzinandes Leal de Azeredo, Victor Edgar Fiestas Solórzano, Débora Batista de Oliveira, Cintia Ferreira Marinho, Luiz José de Souza, Rivaldo Venâncio da Cunha, Paulo Vieira Damasco, Claire Fernandes Kubelka, Luzia Maria de-Oliveira-Pinto
Tissue Factor (TF) is the initiator of coagulation and Tissue Factor Inhibitor (TFPI) is the physiological inhibitor of the TF/FVIIa complex. Circulating levels of TF and TFPI were quantified in dengue patients and the relationships with disease severity and infecting serotype analysed. A significant decrease in TF and TPFI plasma levels was observed in mild DF patients compared with severe dengue. Furthermore, both factors were associated with haemorrhagic manifestations. Finally, TF levels were significantly increased in DENV-1/2 infected patients as compared with DENV-4...
August 31, 2016: Microbes and Infection
Luca Spiezia, Elena Campello, Fabio Dalla Valle, Barry Woodhams, Paolo Simioni
The activation of the extrinsic coagulation pathway occurs after endothelial injury when the tissue factor (TF), a transmembrane protein located outside the vasculature, binds factor VII (FVII) or activated FVII (FVIIa). Once formed, the TF-VIIa complex activates both factor IX and X and initiates the coagulation process. The TF-VIIa complex is inhibited by both TF pathway inhibitor (TFPI) and antithrombin (AT). The interaction between TF-VIIa and AT induces FVIIa-AT complex formation, which is released into the plasma...
August 15, 2016: Clinical Chemistry and Laboratory Medicine: CCLM
J Mahlangu, P Paz, M Hardtke, F Aswad, J Schroeder
INTRODUCTION: The most serious and challenging complication of haemophilia treatment is development of inhibitors to replacement factors VIII or IX. Innovative therapies currently being explored for patients with haemophilia and inhibitors include BAY 86-6150, a modified recombinant activated factor VII (FVIIa). Immunogenicity remains a substantial barrier in this endeavour. AIM: To present safety and efficacy results of the BAY 86-6150 study in patients with inhibitors and report detailed analysis of epitope mapping in a patient who developed anti-BAY 86-6150 antibodies...
August 8, 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
Y Shinkoda, A Shirahata, K Fukutake, J Takamatsu, M Shima, H Hanabusa, H Mugishima, H Takedani, K Kawasugi, M Taki, T Matsushita, A Tawa, K Nogami, S Higasa, Y Kosaka, T Fujii, M Sakai, M Migita, M Uchiba, K Kawakami, K Sameshima, Y Ohashi, H Saito
INTRODUCTION: MC710, a 1:10 protein weight ratio mixture of plasma-derived activated factor VII (FVIIa) and factor X (FX), is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. We evaluated the haemostatic efficacy and safety of one to two administrations of MC710 in 21 joint, muscle, and subcutaneous bleeding episodes in 14 male patients, in a multi-centre, open-label, non-randomized clinical trial. METHODS: Subjects were intravenously administered one or two doses of 60 or 120 μg kg(-1) MC710 (as FVIIa) once or twice (to a maximum of 180 μg kg(-1) ) over up to five bleeding episodes per subject...
August 1, 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
Xiaojun Zhang, Peter W Glunz, James A Johnson, Wen Jiang, Swanee Jacutin-Porte, Vladimir Ladziata, Yan Zou, Monique S Phillips, Nicholas R Wurtz, Brandon Parkhurst, Alan R Rendina, Timothy M Harper, Daniel L Cheney, Joseph M Luettgen, Pancras C Wong, Dietmar Seiffert, Ruth R Wexler, E Scott Priestley
Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing...
August 11, 2016: Journal of Medicinal Chemistry
Souad Lakbakbi, Alexandre Debrumetz, Christine Terryn, Jean Szymezak, Philippe Rieu, Philippe Nguyen
End-stage renal patients present a high risk of thrombosis and bleeding. Consequently, it is challenging to prevent clotting during hemodialysis. If a contact system induces thrombin generation in the extra corporeal circuit, recent data suggest a role of tissue factor (TF) in hemodialysis-associated thrombosis. Using a method of elution, we collected adhering cells to an acrylonitrile membrane layered by polythyleneimine (AN69-ST). Using optic microscopy and flow cytometry, we observed that adherent cells were mainly constituted by activated polymorphonuclear neutrophils (PMNs)...
August 2016: Thrombosis Research
Patrícia Nessralla Alpoim, Lara Carvalho Godoi, Melina de Barros Pinheiro, Letícia Gonçalves Freitas, Maria das Graças Carvalho, Luci Maria Dusse
We have recently investigated the association between the risk of developing PE and clinical, hemostatic, inflammatory and genetic parameters of 108 severe preeclamptic women. A multivariate logistic regression analysis was performed to assess what variables are independent risk factors for PE. Univariate analysis was performed including the variables in age, smoking condition, multiple pregnancy, blood group, phenotypes and alleles of IL-4, IL-5, IL-10, IL-6, IL-8, IL-12, IL-1β, IFN-γ, TNF-α, and the plasma levels of FVII, FVIIa, FVIIa-AT, FVIII, FVW, ADAMTS13, D-Di, PAI-1, ADMA...
August 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
Lu Yang, Yun Li, Arup Bhattacharya, Yuesheng Zhang
Coagulation factors are essential for hemostasis. Here, we show that these factors also team up to degrade plasma proteins that are unrelated to hemostasis. Prolidase, SRC and amyloid β1-42 (Aβ1-42) are used as probes. Each probe, upon entering the blood circulation, binds and activates factor XII (FXII), triggering the intrinsic and common coagulation cascades, which in turn activate factor VII, a component of the extrinsic coagulation cascade. Activated factor VII (FVIIa) rapidly degrades the circulating probes...
February 7, 2016: Oncotarget
Birgit J Waldner, Julian E Fuchs, Michael Schauperl, Christian Kramer, Klaus R Liedl
Protease substrate profiling has nowadays almost become a routine task for experimentalists, and the knowledge on protease peptide substrates is easily accessible via the MEROPS database. We present a shape-based virtual screening workflow using vROCS that applies the information about the specificity of the proteases to find new small-molecule inhibitors. Peptide substrate sequences for three to four substrate positions of each substrate from the MEROPS database were used to build the training set. Two-dimensional substrate sequences were converted to three-dimensional conformations through mutation of a template peptide substrate...
June 27, 2016: Journal of Chemical Information and Modeling
Oskar Eriksson, Åsa Thulin, Anna Asplund, Geeta Hegde, Sanjay Navani, Agneta Siegbahn
BACKGROUND: Tissue Factor (TF) forms a proteolytically active complex together with coagulation factor VIIa (FVIIa) and functions as the trigger of blood coagulation or alternatively activates cell signaling. We recently described that EphA2 of the Eph tyrosine kinase receptor family is cleaved directly by the TF/FVIIa complex. The aim of the present study was to further characterize the cross-talk between TF/FVIIa and EphA2 using in vitro model systems and human cancer specimens. METHODS: Cleavage and phosphorylation of EphA2 was studied by Western blot...
2016: BMC Cancer
Stacy E Croteau, Charles Nakar, Ellis J Neufeld, Amy Shapiro, David L Cooper
BACKGROUND: The relative safety and efficacy of recombinant activated coagulation factor VII (rFVIIa, NovoSeven® RT) across pediatric age cohorts is poorly defined. The objective of this analysis was to assess the safety and efficacy of rFVIIa in pediatric patients with congenital hemophilia with inhibitors (CHwI) in the clinical studies supporting the U.S. labeling. PROCEDURE: Pediatric data were derived from seven studies (five acute and two perioperative treatments) and pooled...
October 2016: Pediatric Blood & Cancer
Shaobin Wang, Brandi Reeves, Rafal Pawlinski
Tissue factor is the primary initiator of the coagulation cascade. Formation of the TF:FVIIa complex activates both FX and FIX, with subsequent thrombin generation, fibrin deposition and activation of platelets. In addition to playing important role in hemostasis and thrombosis, TF and downstream coagulation proteases can mediate intracellular signaling via activation of protease-activated receptors (PARs). Maintaining hemostasis in the brain is of utmost importance: bleeding or thrombosis within this organ can lead to significant morbidity and mortality...
May 2016: Thrombosis Research
Paris Margaritis, Nigel S Key
It has been 14 years since the first symposium on hemostasis at UNC Chapel Hill that focused primarily on the tissue factor (TF) and Factor VIIa (FVIIa) biology, biochemistry and translational work for the treatment of bleeding. Concepts, mechanistic data and therapeutic agents have since emerged that permeate not only aspects of the TF and FVIIa functions, but also broader processes in hemostasis and thrombosis. These processes involve circulating proteins, receptors, cells and cellular components that interact within the coagulation system as well as with additional systems that are dysregulated in disorders seemingly unrelated to bleeding/thrombosis...
May 2016: Thrombosis Research
Bhaskar Barnwal, Chacko Jobichen, Vallerinteavide Mavelli Girish, Chun Shin Foo, J Sivaraman, R Manjunatha Kini
Anticoagulant therapy is used for the prevention and treatment of thromboembolic disorders. Blood coagulation is initiated by the interaction of factor VIIa (FVIIa) with membrane-bound tissue factor (TF) to form the extrinsic tenase complex which activates FX to FXa. Thus, it is an important target for the development of novel anticoagulants. Here, we report the isolation and characterization of a novel anticoagulant ringhalexin from the venom of Hemachatus haemachatus (African Ringhals Cobra). Amino acid sequence of the protein indicates that it belongs to the three-finger toxin family and exhibits 94% identity to an uncharacterized Neurotoxin-like protein NTL2 from Naja atra...
2016: Scientific Reports
P Boura, I Evmorfiadis, A Rousseau, A Charpidou, G Giozos, P Van Dreden, K Syrigos, A Larsen, I Elalamy, G T Gerotziafas
INTRODUCTION: In patients with lung adenocarcinoma (LA), metastasis (MTS), advanced stage and chemotherapy (CTx) are risk factors for thromboembolism (VTE). Routine thromboprophylaxis is not recommended but individualized risk assessment is encouraged. AIM: The selection of the most relevant hypercoagulability biomarkers (HB) for incorporation into the risk assessment models (RAM) for VTE. MATERIALS AND METHODS: Patients with documented LA eligible for CTx at distance of at least 3months from surgery or hospitalization were included...
April 2016: Thrombosis Research
H W Clouston, R Lamb, S Duff, C C Kirwan
INTRODUCTION: Tissue factor (TF) is abnormally expressed in many cancers including colorectal and is associated with a poor cancer prognosis. Colorectal cancer cell lines expressing TF produce faster growing tumours. In lung cancer, TF inhibition has been shown to reduce proliferation AIM: We aimed to determine if TF expression and activity increases cellular proliferation in colorectal cancer cell lines. MATERIALS AND METHODS: DLD-1 and SW620 colorectal cell lines were transduced with cDNA to over express TF (TF+ve)...
April 2016: Thrombosis Research
C C Kirwan, N J Bundred, J Castle, R Clarke, C Dive, J Morris, C Holcombe, J R Harvey
INTRODUCTION: Breast cancer is associated with a 3-4 fold increased risk of VTE. These patients have a 4-fold lower survival than those remaining free of VTE, implying VTE is a surrogate marker for aggressive cancer. Tumour expression of thrombin pathway markers are increased in the oestrogen receptor negative (ER-), high Ki67, more aggressive breast cancer subtypes. In in vitro and in vivo studies, the thrombin pathway promotes cancer growth and metastases, highlighting the potential role of the thrombin pathway as a therapeutic target in cancer...
April 2016: Thrombosis Research
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