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B Boylan, C H Miller
INTRODUCTION: The use of pre-analytical heat treatment (PHT) with the Nijmegen-Bethesda assay (NBA) for inhibitors to factor VIII (FVIII) can remove/destroy infused or endogenous FVIII from patient plasma samples, allowing testing of recently infused patients with haemophilia. Two PHT methods have been described as follows: heating to 56°C for 30 minutes and heating to 58°C for 90 minutes. Data examining the effects of PHT on anti-FVIII IgG4 , the antibodies known to correlate most closely with the presence of FVIII inhibitors, are limited...
February 20, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
Ruth A Ettinger, Joseph A Liberman, Devi Gunasekera, Komal Puranik, Eddie A James, Arthur R Thompson, Kathleen P Pratt
Factor VIII (FVIII)-neutralizing antibodies (inhibitors) are a serious complication in hemophilia A (HA). The peptide FVIII 2194-2213 contains an immunodominant HLA-DRA*01-DRB1*01:01 (DRB1*01:01)-restricted epitope recognized by CD4 + T-effector cells from HA subjects. The aim of this study was to identify amino acid substitutions to deimmunize this epitope while retaining procoagulant function and expression levels comparable to those of wild-type (WT) FVIII proteins. The shortest DRB1*01:01-binding peptide was FVIII 2194-2205 , and residues important for affinity were identified as F2196, M2199, A2201, and S2204...
February 27, 2018: Blood Advances
C Wang, G Young
INTRODUCTION: Although clinical trials have demonstrated extended half-life (EHL) VIII and IX fusion proteins to be safe and efficacious in patients with haemophilia A and B, studies on real-world clinical application have not been performed. AIM: To retrospectively examine the real-world experience of rFVIII Fc and rFIX Fc in patients. METHODS: A retrospective review of existing medical records of patients with haemophilia A or haemophilia B who had been prescribed rFVIII Fc or rFIX Fc was conducted from the Children's Hospital Los Angeles Haemostasis and Thrombosis Centre database...
February 5, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
Silva Zupančić-Šalek, Marijo Vodanović, Dražen Pulanić, Boško Skorić, Irina Matytsina, Jolanta Klovaite
RATIONALE: The extent of protective effects of hemophilia against thrombotic events such as myocardial infarction (MI) and other acute coronary syndromes remains to be determined, as major risk factors for cardiovascular disease exist despite factor VIII (FVIII) deficiency. We present a case report of a 41-year-old male with severe hemophilia A and several cardiovascular risk factors. PATIENT CONCERNS: This morbidly obese patient developed chest pressure, followed by chest pain and difficulty in breathing shortly after receiving on-demand treatment with intravenous recombinant FVIII (rFVIII) (turoctocog alfa) dosed per body weight...
December 2017: Medicine (Baltimore)
Malte Selch Larsen, Rasmus Vestergaard Juul, Andreas Velsing Groth, Ulrika S H Simonsson, Annemarie T Kristensen, Tom Knudsen, Henrik Agersø, Mads Kreilgaard
Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK...
January 21, 2018: European Journal of Pharmaceutical Sciences
Katie St Ledger, Annette Feussner, Uwe Kalina, Carsten Horn, Hubert J Metzner, Debra Bensen-Kennedy, Nicole Blackman, Alex Veldman, Anthony Stowers, Kenneth D Friedman
INTRODUCTION: AFSTYLA (antihemophilic factor [recombinant] single chain) is a novel B-domain truncated recombinant Factor VIII (rFVIII). For AFSTYLA, an approximate 50% discrepancy was observed between results of the one-stage (OS) and chromogenic substrate (ChS) FVIII activity AFSTYLA assays. An investigation was undertaken to test whether there is a linear relationship between ChS and OS assay results that would allow reliable clinical interpretation of results independent of the assay method used...
December 23, 2017: Journal of Thrombosis and Haemostasis: JTH
Nathaniel Henry, Jelena Jovanović, Max Schlueter, Persefoni Kritikou, Koo Wilson, Karl-Johan Myrén
AIMS: Prophylaxis with recombinant factor VIII (rFVIII) is the standard of care for severe hemophilia A in Sweden. The need for frequent injections with existing rFVIII products may, however, result in poor adherence to prophylaxis, leading to increased bleeding and long-term joint damage. Recombinant FVIIIFc (rFVIIIFc) is an extended half-life fusion protein which can offer prolonged protection and reduced dosing frequency. The objective of this study was to evaluate the cost-utility of prophylaxis with rFVIIIFc in severe hemophilia A from the perspective of the Swedish health system...
December 4, 2017: Journal of Medical Economics
F Peyvandi, A Cannavò, I Garagiola, R Palla, P M Mannucci, F R Rosendaal
Essentials Recombinant factor VIII (rFVIII) was contrasted with plasma-derived FVIII (pdFVIII). In previously untreated patients with hemophilia A, rFVIII led to more inhibitors than pdFVIII. Inhibitors with rFVIII developed earlier, and the peak rate was higher than with pdFVIII. Inhibitors with rFVIII were more severe (higher titre) than with pdFVIII. SUMMARY: Background The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) is the most severe complication in the early phases of treatment of severe hemophilia A...
January 2018: Journal of Thrombosis and Haemostasis: JTH
Padraic G Fallon, Michelle Lavin, James S O'Donnell
In this issue of the Journal of Thrombosis and Haemostasis, Peyvandi et al present further insights from the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) study regarding the relative immunogenicity of recombinant- (rFVIII) versus plasma-derived FVIII (pdFVIII) in patients with haemophilia A [1]. In a post-hoc analysis of this prospective randomised controlled trial, the timing and severity of inhibitor development for previously untreated patients (PUPs) treated with rFVIII was compared with that in PUPs treated with pdFVIII...
October 28, 2017: Journal of Thrombosis and Haemostasis: JTH
Massimo Morfini
Hemophilia A is the most frequent inherited bleeding disorder and most challenging coagulation disorder. To combat this, a number of new improved rFVIII/IX concentrates have recently been approved. Some of them are derived from protein fusion biotechnology or pegylation to extend their half-life (HL). However, prophylaxis has become a standard of care to prevent arthropathy in hemophiliacs though the need of frequent venipunctures is a major obstacle to primary prophylaxis. The new Extended Half-Life (EHL) rFIX concentrates allow increased intervals, while the improved HL of new rFVIII was moderate...
October 20, 2017: Expert Opinion on Biological Therapy
Vladimir Granovski, Mario Soares Abreu-Neto, Dimas Tadeu Covas
Coagulation factor VIII is one of the largest proteins attempted to be expressed in recombinant form. A very complex and labile protein which has a very short half-live and need a fast and efficient purification chain. Here, we describe a simple purification sequence using multimodal Capto MMC, affinity FVIII select and ion exchange SP-Fastflow chromatography steps without subjecting the target molecule to mechanical and temperature stress, separating impurities from rFVIII using net charge, hydrophobicity, and affinity of the molecules...
2018: Methods in Molecular Biology
Daianne Maciely Carvalho Fantacini, Virgínia Picanço-Castro
Human cell lines can produce recombinant proteins much more similar to their natural counterpart, compared to other mammalian cell lines, reducing potential immunogenic reactions. Recombinant proteins produced in nonhuman cells can have in its structure glycan epitopes, such as Galα1,3-Gal (alpha-Gal) and N-glycolylneuraminic acid (Neu5Gc) residues, that are antigenic to humans and can potentially affect the efficacy of the recombinant product. Therefore, the production of recombinant factor VIII (rFVIII) in human cell lines is a new approach to avoid nonhuman glycosylation...
2018: Methods in Molecular Biology
M J Manco-Johnson, B Lundin, S Funk, C Peterfy, D Raunig, M Werk, C L Kempton, M T Reding, S Goranov, L Gercheva, L Rusen, V Uscatescu, M Pierdominici, S Engelen, J Pocoski, D Walker, W Hong
Essentials High-quality data are lacking on use of prophylaxis in adults with hemophilia and arthropathy. SPINART was a 3-year randomized clinical trial of late/tertiary prophylaxis vs on-demand therapy. Prophylaxis improved function, quality of life, activity and pain but not joint structure by MRI. Prophylaxis improves function but must start before joint bleeding onset to prevent arthropathy. SUMMARY: Background Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre-existing joint disease...
August 24, 2017: Journal of Thrombosis and Haemostasis: JTH
Frits R Rosendaal, Roberta Palla, Isabella Garagiola, Pier M Mannucci, Flora Peyvandi
A recent randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET), showed a higher risk of inhibitor development with recombinant factor VIII (rFVIII) than plasma-derived concentrates (pdFVIII). We investigated whether risk stratification by F8 mutation identifies patients who do not suffer this deleterious effect of rFVIII. Among 235 randomized patients with severe hemophilia A previously untreated with FVIII concentrate, 197 with null mutations were classified as high risk and 38 with non-null mutations were classified as low risk...
October 12, 2017: Blood
Yongqiang Zhao, Juan Xiao, Renchi Yang, Runhui Wu, Yu Hu, Horst Beckmann, Junde Wu, Qingsong Hou, Jing Sun
In China, care of patients with severe hemophilia primarily involves insufficient dosing of on-demand treatment and secondary low-dose prophylaxis (10 IU/kg 2× /wk). We sought to evaluate 3× /wk, standard-dose prophylaxis with sucrose-formulated recombinant factor VIII (rFVIII-FS; Bayer) compared with on-demand treatment in Chinese children with severe hemophilia A. Children and adolescents aged 2-16 years with severe hemophilia A, no inhibitors, and no prophylaxis for >6 consecutive months before study entry were eligible for this 24-week, interventional, sequential-treatment study...
April 2017: Pediatric Hematology and Oncology
Samantha Pasca, Marta Milan, Lucia Sarolo, Ezio Zanon
BACKGROUND: Prophylaxis is the gold standard for the treatment of children with severe hemophilia. In the last years a new approach to prophylaxis based on annual bleeding rate (ABR), pharmacokinetics (PK) and lifestyle of each patient has begun to be adopted in hemophilia treatment. AIM: Aim of our observational retrospective study was to evaluate whether in a group of children with severe hemophilia A (HA) a tailored approach may be used to replace standard therapy, reducing costs...
July 5, 2017: Thrombosis Research
Sandrine Meunier, Jayanthi Alamelu, Silke Ehrenforth, Hideji Hanabusa, Faraizah Abdul Karim, Kaan Kavakli, Melanie Khodaie, Janice Staber, Oleksandra Stasyshyn, Donald L Yee, Lina Rageliene
Turoctocog alfa pegol (N8-GP, Novo Nordisk, Bagsværd, Denmark), an extended half-life glycoPEGylated recombinant factor VIII (rFVIII), is being developed for prophylaxis and treatment of bleeds in haemophilia A patients. pathfinder™5 is a multinational, open-label, single-arm trial to assess safety, efficacy and pharmacokinetics of N8-GP in paediatric (<12 years), previously treated patients. Boys with severe haemophilia A (<1 % FVIII), no history of inhibitors and previously treated with FVIII products (>50 exposure days [ED] for patients aged 0-5 years [younger cohort]; >150 ED for patients aged 6-11 years [older cohort]) were included...
August 30, 2017: Thrombosis and Haemostasis
Matteo Rota, Paolo A Cortesi, Katharina N Steinitz-Trost, Armin J Reininger, Alessandro Gringeri, Lorenzo G Mantovani
: Recent cohort studies showed differences in inhibitor incidence in previously untreated patients (PUPs) with haemophilia A treated with recombinant factor VIII (rFVIII) concentrates. We carried out a systematic literature search and meta-analysis for all randomized clinical trials and observational studies published from 1 January 1988 to 31 August 2015, to assess the incidence of inhibitor development and the relationship with rFVIII product used in PUPs and minimally treated patients (MTPs, ≤5 previous exposure days), with severe haemophilia...
December 2017: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
Kenneth Lieuw
Hemophilia A (HA) is a common bleeding disorder caused by the deficiency of factor VIII (FVIII) with an incidence of ~1 in 5000 male births. Replacement of FVIII is necessary to prevent and treat bleeding episodes. However, with multiple new drugs in addition to old standards, choosing among the different FVIII treatment options is harder than ever. There are FVIII products that are plasma derived or recombinant, FVIII products designed to extend the half-life of FVIII, and the first single-chain FVIII product, recombinant factor VIII single chain (rFVIII-SC)...
2017: Journal of Blood Medicine
O Bulla, A Poncet, L Alberio, L M Asmis, A Gähler, L Graf, M Nagler, J-D Studt, D A Tsakiris, P Fontana
INTRODUCTION: Measuring factor VIII (FVIII) activity can be challenging when it has been modified, such as when FVIII is pegylated to increase its circulating half-life. Use of a product-specific reference standard may help avoid this issue. AIM: Evaluate the impact of using a product-specific reference standard for measuring the FVIII activity of BAX 855 - a pegylated FVIII - in eight of Switzerland's main laboratories. METHODS: Factor VIII-deficient plasma, spiked with five different concentrations of BAX 855, plus a control FVIII sample, was sent to the participating laboratories...
May 24, 2017: Haemophilia: the Official Journal of the World Federation of Hemophilia
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