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Recombinant FVIIa

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
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...
November 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
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
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...
July 5, 2016: Oncotarget
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
Anca Matei, Sean Dolan, James Andrews, Georges-Étienne Rivard
BACKGROUND: Acquired factor VII (FVII) deficiency with inhibitor increases the risk of hemorrhage during pregnancy. However, there are no published reports guiding its management in the peripartum period. CASE: A 24-year-old woman with inhibitory antibodies to FVII delivered at 34 weeks of gestation. The patient was administered recombinant factor VIIa (rFVIIa) and tranexamic acid. There were no bleeding-related complications; however, the FVII level was supratherapeutic...
February 2016: Journal of Obstetrics and Gynaecology Canada: JOGC, Journal D'obstétrique et Gynécologie du Canada: JOGC
M Hoffman, J-Y Chang, M Ezban, D M Monroe
UNLABELLED: Essentials Disorders of hemostasis can lead to delayed and defective wound healing. In hemophilia B (HB) mice, 7 days of Factor (F)IX or VIIa are needed to normalize wound healing. One dose of a highly active FVIIa variant (DVQ) restored normal wound closure time in HB mice. Coagulation factors with enhanced activity may acquire biological effects not due to hemostasis. SUMMARY: Introduction We have previously reported that hemophilia B (HB) mice have delayed healing of cutaneous wounds and alterations in wound histology...
June 2016: Journal of Thrombosis and Haemostasis: JTH
Thomas J Cramer, Kristin Anderson, Karanjia Navaz, Justin M Brown, Laurent O Mosnier, Annette von Drygalski
BACKGROUND: In congenital Factor (F) VII deficiency bleeding phenotype and intrinsic FVII activity levels don't always correlate. Patients with FVII activity levels <30% appear to have a higher bleeding propensity, but bleeding can also occur at higher FVII activity levels. Reasons for bleeding at higher FVII activity levels are unknown, and it remains challenging to manage such patients clinically. CASE: A 19year old male with spontaneous intracranial hemorrhage and FVII activity levels of 44%, requiring emergent surgical intervention and a strategy for FVII replacement...
March 2016: Blood Cells, Molecules & Diseases
William P Sheffield, Varsha Bhakta
The naturally occurring M358R mutation of the plasma serpin α1-proteinase inhibitor (API) changes both its cleavable reactive centre bond to Arg-Ser and the efficacy with which it inhibits different proteases, reducing the rate of inhibition of neutrophil elastase, and enhancing that of thrombin, factor XIa, and kallikrein, by several orders of magnitude. Although another plasma serpin with an Arg-Ser reactive centre, antithrombin (AT), has been shown to inhibit factor VIIa (FVIIa), no published data are available with respect to FVIIa inhibition by API M358R...
February 12, 2016: Biochemical and Biophysical Research Communications
Jody L Kujovich
Liver disease results in complex alterations of all 3 phases of hemostasis. It is now recognized that hemostasis is rebalanced in chronic liver disease. The fall in clotting factor levels is accompanied by a parallel fall in anticoagulant proteins. High von Willebrand factor levels counteract defects in primary hemostasis. Conventional coagulation tests do not fully reflect the derangement in hemostasis and do not accurately predict the risk of bleeding. Global coagulation assays (thrombin generation, thromboelastography) reflect the interaction between procoagulant factors, anticoagulant factors, platelets, and the fibrinolytic system and show promise for assessing bleeding risk and guiding therapy...
2015: Hematology—the Education Program of the American Society of Hematology
J N Mahlangu, K N Weldingh, S R Lentz, S Kaicker, F A Karim, T Matsushita, M Recht, W Tomczak, J Windyga, S Ehrenforth, K Knobe
BACKGROUND: Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept(™) 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. OBJECTIVES: To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors...
November 2015: Journal of Thrombosis and Haemostasis: JTH
S Nayak, D Lee, S Patel-Hett, D D Pittman, S W Martin, A C Heatherington, P Vicini, F Hua
A number of therapeutics have been developed or are under development aiming to modulate the coagulation network to treat various diseases. We used a systems model to better understand the effect of modulating various components on blood coagulation. A computational model of the coagulation network was built to match in-house in vitro thrombin generation and activated Partial Thromboplastin Time (aPTT) data with various concentrations of recombinant factor VIIa (FVIIa) or factor Xa added to normal human plasma or factor VIII-deficient plasma...
July 2015: CPT: Pharmacometrics & Systems Pharmacology
Elena Santagostino, Miguel Escobar, Margareth Ozelo, Luigi Solimeno, Per Arkhammar, Hye Youn Lee, Gabriela Rosu, Paul Giangrande
The availability of recombinant activated factor VII (rFVIIa, eptacog alfa activated) has greatly advanced the care of patients with haemophilia A or B who have developed inhibitors against the infused replacement factor. Recombinant FVIIa is licensed for the on-demand treatment of bleeding episodes and the prevention of bleeding in surgery or invasive procedures in patients with congenital haemophilia with inhibitors. This article attempts to review in detail the extensive evidence of rFVIIa in congenital haemophilia patients with inhibitors...
June 2015: Blood Reviews
Ulla Hedner
Recombinant activated factor VII (rFVIIa) was initially developed to treat bleeding episodes in patients with congenital haemophilia and inhibitors. The story of its development began in the 1970s, when FVIIa was identified as one of the activated coagulation factors that has minimal potential for inducing thromboembolic side-effects. Extensive research over the last 30 years has greatly increased our knowledge of the characteristics of FVII, its activation, and the mechanisms by which rFVIIa restores haemostasis...
June 2015: Blood Reviews
Ellis J Neufeld, Claude Négrier, Per Arkhammar, Soraya Benchikh el Fegoun, Mette Duelund Simonsen, Anders Rosholm, Stephanie Seremetis
This updated safety review summarises the large body of safety data available on the use of recombinant activated factor VII (rFVIIa) in approved indications: haemophilia with inhibitors, congenital factor VII (FVII) deficiency, acquired haemophilia and Glanzmann's thrombasthenia. Accumulated data up to 31 December 2013 from clinical trials as well as post-marketing data (registries, literature reports and spontaneous reports) were included. Overall, rFVIIa has shown a consistently favourable safety profile, with no unexpected safety concerns, in all approved indications...
June 2015: Blood Reviews
M Baroni, G Pavani, M Pinotti, A Branchini, F Bernardi, R M Camire
Alterations in coagulation factor X (FX) activation, mediated by the extrinsic VIIa/tissue factor (FVIIa/TF) or the intrinsic factor IXa/factor VIIIa (FIXa/FVIIIa) complexes, can result in hemorrhagic/prothrombotic tendencies. However, the molecular determinants involved in substrate recognition by these enzymes are poorly defined. Here, we investigated the role of arginine 386 (chymotrypsin numbering c202), a surface-exposed residue on the FX catalytic domain. The naturally occurring FX386Cys mutant and FX386Ala variant were characterized...
October 2015: Biochimica et Biophysica Acta
Giovanni Di Minno, Rainer B Zotz, Roseline d'Oiron, Niels Bindslev, Matteo Nicola Dario Di Minno, Man-Chiu Poon
Standard treatment for Glanzmann thrombasthenia is platelet transfusion. Recombinant activated factor VII has been shown to be successful in patients with Glanzmann thrombasthenia with platelet antibodies or who are refractory to platelet transfusions. The Glanzmann Thrombasthenia Registry prospectively collected worldwide information on the effectiveness and safety of platelet transfusion, recombinant activated factor VII and/or antifibrinolytics for the treatment of bleeds in patients with Glanzmann thrombasthenia...
August 2015: Haematologica
N Enjolras, E Perot, S Le Quellec, A Indalecio, J Girard, C Negrier, Y Dargaud
INTRODUCTION: Post-translational modifications of the CHO-cell-derived-recombinant human factor IX (FIX) currently used for the treatment of hemophilia B (HB) are different from plasma derived FIX. Our previous studies described a rFIX (HIX) having better profile of post-translational modifications than rFIX produced by CHO cells. The aim of the study consisted to verify the improved post-translational modifications effect of HIX on in vivo recovery. MATERIALS AND METHODS: HIX has been produced in a bioreactor and then purified from supernatants...
July 2015: Haemophilia: the Official Journal of the World Federation of Hemophilia
Antonio Girolami, Elisabetta Cosi, Claudia Santarossa, Silvia Ferrari, Maria Luigia Randi
Factor VII (FVII) deficiency is one of the two congenital coagulation disorders that was not discovered by the description of a new bleeding patient whose clotting pattern did not fit the blood coagulation knowledge of the time (the other is factor XIII deficiency). The existence of an additional factor capable of accelerating the conversion of prothrombin into thrombin was suspected before 1951, the year in which the first family with FVII deficiency was discovered. As several investigators were involved in the discovery of FVII deficiency from both sides of the Atlantic, several different names were tentatively suggested to define this entity, namely stable factor (in contrast with labile factor or FV), cothromboplastin, proconvertin, serum prothrombin conversion accelerator, prothrombin acceleration, and autoprothrombin I...
June 2015: Seminars in Thrombosis and Hemostasis
Sara P Y Che, Christine DeLeonardis, Michael L Shuler, Tracy Stokol
Mammary tumors and malignant breast cancer cell lines over-express the coagulation factor, tissue factor (TF). High expression of TF is associated with a poor prognosis in breast cancer. Tissue factor pathway inhibitor (TFPI), the endogenous inhibitor of TF, is constitutively expressed on the endothelium. We hypothesized that TF-expressing tumor cells can bind to immobilized recombinant TFPI, leading to arrest of the tumor cells under shear in vitro. We evaluated the adhesion of breast cancer cells to immobilized TFPI under static and shear conditions (0...
2015: PloS One
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