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Hemophilia B

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https://www.readbyqxmd.com/read/29665242/comparative-analysis-of-marketed-factor-viii-products-recombinant-products-are-not-alike-vis-a-vis-soluble-protein-aggregates-and-subvisible-particles
#1
J Anzengruber, C Lubich, T Prenninger, A Gringeri, F Scheiflinger, B M Reipert, M Malisauskas
BACKGROUND: Recombinant protein technologies have facilitated the development of novel FVIII therapeutics with improved production efficiency, potency, half-live, and low risk of viral transmission. The increasing number of recombinant Factor VIII (rFVIII) products and information on their efficacy, safety, and cost allow patients and healthcare professionals to adjust treatment to individual needs. Nonetheless, 20-32% of previously untreated patients with severe hemophilia A develop inhibitory antibodies to rFVIII following treatment...
April 17, 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29662861/global-hemostatic-assay-of-different-target-procoagulant-activities-of-factor-viii-and-factor-ix
#2
Ki-Young Yoo, Soo-Young Jung, Sung-Ho Hwang, Su-Min Lee, Jong-Ho Park, Hyun-Ja Nam
Background: Korean National Health Insurance reimburses factor VIII (FVIII) and factor IX (FIX) clotting factor concentrate (CFC) infusions to discrepant activity levels, allowing elevation of FVIII activity to 60 IU/dL and FIX to 40 IU/dL. We aimed to assess hemostatic response to these target levels using global hemostatic assays. Methods: We enrolled 34 normal healthy men, 34 patients with hemophilia A, and 36 with hemophilia B, with residual factor activity of 3 IU/dL or less and without inhibitors...
March 2018: Blood Research
https://www.readbyqxmd.com/read/29655485/-cost-of-clotting-factors-in-hospitalization
#3
P Randuineau, N Stieltjes, V Perut, P Paubel, I Lopez
OBJECTIVES: Hemophilia is a rare genetic disease, characterized by uncontrolled bleeding. Injections of clotting factor are the principal are the principal treatment. This drug is very expensive. The objectives of this study are to determine the cost of clotting factor for in patients and the factor impacting this cost. METHODS: A retrospective study was carried on hemophiliac in patients between 1 January 2014 and 31 December 2015 in Cochin hospital and having received at least an injection of clotting factor during their hospitalization...
April 11, 2018: Annales Pharmaceutiques Françaises
https://www.readbyqxmd.com/read/29649469/phosphatidylserine-is-not-just-a-cleanup-crew-but-also-a-well-meaning-teacher
#4
Fiona Y Glassman, Jennifer L Schneider, Radha Ramakrishnan, Robert K Dingman, Murali Ramanathan, Richard B Bankert, Sathy V Balu-Iyer
Phosphatidylserine (PS) exposure during apoptosis leads to silent clearance of cells without adverse immune reactions to self-proteins. Given the biological functions of PS in cellular cleanup and global immunosuppression, we hypothesized that administration of PS-protein complexes would reduce immunogenicity. Here, we report that exposing Pompe disease mice to acid alpha glucosidase (rhGAA) with PS or immunosuppressant dexamethasone (Dex) resulted in lower anti-rhGAA-antibodies than in animals receiving rhGAA alone...
April 9, 2018: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29625575/targeted-genome-engineering-in-human-induced-pluripotent-stem-cells-from-patients-with-hemophilia-b-using-the-crispr-cas9-system
#5
Cuicui Lyu, Jun Shen, Rui Wang, Haihui Gu, Jianping Zhang, Feng Xue, Xiaofan Liu, Wei Liu, Rongfeng Fu, Liyan Zhang, Huiyuan Li, Xiaobing Zhang, Tao Cheng, Renchi Yang, Lei Zhang
BACKGROUND: Replacement therapy for hemophilia remains a lifelong treatment. Only gene therapy can cure hemophilia at a fundamental level. The clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9 (CRISPR-Cas9) system is a versatile and convenient genome editing tool which can be applied to gene therapy for hemophilia. METHODS: A patient's induced pluripotent stem cells (iPSCs) were generated from their peripheral blood mononuclear cells (PBMNCs) using episomal vectors...
April 6, 2018: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/29624465/practical-implications-of-factor-ix-gene-transfer-for-individuals-with-hemophilia-b-a-clinical-perspective
#6
Wolfgang Miesbach, Eileen K Sawyer
Gene therapy for severe hemophilia is on the cusp of entering clinical practice. However, there is limited clinical experience in this area given that gene transfer is a relatively recent technology. Therefore, this clinical perspective article will review the evidence supporting gene therapy in this field, examine ways to open a dialogue about gene therapy with patients in the clinic setting, and present a case of a participant in a recent clinical trial of gene therapy for hemophilia. Clinical trials in hemophilia using adeno-associated virus (AAV) vectors to transfer functional factor IX (FIX) have reported increases in FIX activity to functional levels, reduced bleed frequency, and a lessening or abrogation of the need for costly FIX replacement...
April 6, 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29618686/-giant-hemophilic-pseudotumors-in-brothers-with-non-severe-hemophilia-b
#7
Ikuko Matsumura, Kunio Yanagisawa, Yoshiyuki Ogawa, Hiroaki Shimizu, Takuma Ishizaki, Takeki Mitsui, Hideki Uchiumi, Yuri Uchiyama, Naomichi Matsumuto, Hiroshi Handa
Hemophilic pseudotumors can occur in patients with hemophilia because of recurrent bleeding and poor hemostasis. A man in his 30s with hemophilia B and human immunodeficiency virus/hepatitis C virus co-infection complicated by liver cirrhosis presented with a large pseudotumor in the left iliopsoas muscle. However, resting to stop bleeding was difficult with his daily work. Osteolytic changes in the left ilium progressed over 8 years. A large osteolytic pseudotumor in the pelvis was also incidentally identified in his younger brother during his 30s...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/29610166/b-6-and-bleeding-a-case-report-of-a-novel-vitamin-toxicity
#8
Alexandra J Borst, Dmitry Tchapyjnikov
Pyridox(am)ine-5-phosphate oxidase deficiency is an inborn error of vitamin B6 metabolism that is characterized by neonatal seizures, requiring lifelong therapy with pyridoxal-5-phosphate. We present the first case of a patient with pyridox(am)ine-5-phosphate oxidase deficiency and mild hemophilia A, whose bleeding symptoms were exacerbated by the vitamin B6 therapy essential for his epileptic disorder. This report expands the spectrum of known vitamin B6 toxicity and demonstrates a need for vigilance in monitoring for bleeding symptoms in patients requiring pyridoxine or pyridoxal-5-phosphate supplementation...
April 2018: Pediatrics
https://www.readbyqxmd.com/read/29608237/designer-nuclease-mediated-gene-correction-via-homology-directed-repair-in-an-in-vitro-model-of-canine-hemophilia-b
#9
Thorsten Bergmann, Eric Ehrke-Schulz, Jian Gao, Maren Schiwon, Verena Schildgen, Stephan David, Oliver Schildgen, Anja Ehrhardt
BACKGROUND: Gene correction at specific target loci provides a powerful strategy to overcome genetic diseases. Here we aimed at using an in vitro model for canine hemophilia B containing a single point mutation in the catalytic domain of the canine coagulation factor IX (cFIX) gene. To correct the defective gene via homology-directed repair (HDR), we designed transcription-activator like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats including Cas9 (CRISPR/Cas9) for introduction of double strand breaks at the mutation site...
April 2, 2018: Journal of Gene Medicine
https://www.readbyqxmd.com/read/29599079/efficient-in-vivo-liver-directed-gene-editing-using-crispr-cas9
#10
Kshitiz Singh, Hanneke Evens, Nisha Nair, Melvin Y Rincón, Shilpita Sarcar, Ermira Samara-Kuko, Marinee K Chuah, Thierry VandenDriessche
In vivo tissue-specific genome editing at the desired loci is still a challenge. Here, we report that AAV9-delivery of truncated guide RNAs (gRNAs) and Cas9 under the control of a computationally designed hepatocyte-specific promoter lead to liver-specific and sequence-specific targeting in the mouse factor IX (F9) gene. The efficiency of in vivo targeting was assessed by T7E1 assays, site-specific Sanger sequencing, and deep sequencing of on-target and putative off-target sites. Though AAV9 transduction was apparent in multiple tissues and organs, Cas9 expression was restricted mainly to the liver, with only minimal or no expression in other non-hepatic tissues...
March 6, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29588277/tolerogenic-properties-of-fc-portion-of-igg-and-its-relevance-to-the-treatment-and-management-of-hemophilia
#11
Richard S Blumberg, David Lillicrap
Hemophilia, or inherited genetic deficiencies in coagulation factors result in uncontrolled bleeding requiring replacement therapy with recombinant proteins given preventively or on-demand. However, a major problem with these approaches is the potential for development of immune responses to the administered proteins due to the underlying genetic deficiency of the factor(s) throughout life. As such, there is great interest in developing strategies that avoid immunogenicity and induce immune tolerance. Recently, recombinant Factor VIII and Factor IX fused to the Fc domain of IgG have been developed as therapeutic agents for hemophilia A and B, respectively...
March 27, 2018: Blood
https://www.readbyqxmd.com/read/29582559/preclinical-pharmacokinetics-and-biodistribution-of-subcutaneously-administered-glycopegylated-recombinant-factor-viii-n8-gp-and-development-of-a-human-pharmacokinetic-prediction-model
#12
F Rode, K Almholt, M Petersen, M Kreilgaard, M Kjalke, D M Karpf, A V Groth, P B Johansen, L F Larsen, M Loftager, J Haaning
BACKGROUND: N8-GP is an extended half-life recombinant factor VIII (FVIII) for hemophilia A. Subcutaneous (SC) administration of FVIII may reduce treatment burden of prophylaxis; however, standard FVIII products have low bioavailability after SC dosing in animals. OBJECTIVE: Evaluate the pharmacokinetics (PK), effectiveness and local distribution of SC-administered N8-GP (SC N8-GP) in preclinical models and predict the human PK profile. METHODS: PK of SC N8-GP were evaluated in FVIII knockout (F8-KO) mice and cynomolgus monkeys; a human PK prediction model in hemophilia A patients was developed...
March 26, 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29563336/enzymatically-oxidized-phospholipids-restore-thrombin-generation-in-coagulation-factor-deficiencies
#13
David A Slatter, Charles L Percy, Keith Allen-Redpath, Joshua M Gajsiewicz, Nick J Brooks, Aled Clayton, Victoria J Tyrrell, Marcela Rosas, Sarah N Lauder, Andrew Watson, Maria Dul, Yoel Garcia-Diaz, Maceler Aldrovandi, Meike Heurich, Judith Hall, James H Morrissey, Sebastien Lacroix-Desmazes, Sandrine Delignat, P Vincent Jenkins, Peter W Collins, Valerie B O'Donnell
Hemostatic defects are treated using coagulation factors; however, clot formation also requires a procoagulant phospholipid (PL) surface. Here, we show that innate immune cell-derived enzymatically oxidized phospholipids (eoxPL) termed hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) restore hemostasis in human and murine conditions of pathological bleeding. HETE-PLs abolished blood loss in murine hemophilia A and enhanced coagulation in factor VIII- (FVIII-), FIX-, and FX-deficient human plasma . HETE-PLs were decreased in platelets from patients after cardiopulmonary bypass (CPB)...
March 22, 2018: JCI Insight
https://www.readbyqxmd.com/read/29562772/in-utero-transplantation-of-placenta-derived-mesenchymal-stromal-cells-for-potential-fetal-treatment-of-hemophilia-a
#14
Priyadarsini Kumar, Kewa Gao, Chuwang Wang, Christopher Pivetti, Lee Lankford, Diana Farmer, Aijun Wang
Hemophilia A (HA) is an X-linked recessive disorder caused by mutations in the factor VIII ( FVIII) gene leading to deficient blood coagulation. The current standard of care is frequent infusions of plasma-derived FVIII or recombinant B-domain-deleted FVIII (BDD-FVIII). While this treatment is effective, many patients eventually develop FVIII inhibitors that limit the effectiveness of the infused FVIII. As a monogenic disorder, HA is an ideal target for gene or cell-based therapy. Several studies have investigated allogeneic stem cell therapy targeting in utero or postnatal treatment of HA but have not been successful in completely correcting HA...
January 2018: Cell Transplantation
https://www.readbyqxmd.com/read/29562448/-clinical-application-and-optimization-of-head-us-quantitative-ultrasound-assessment-scale-for-hemophilic-arthropathy
#15
J Li, X J Guo, X L Ding, B M Lyu, J Xiao, Q L Sun, D S Li, W F Zhang, J C Zhou, C P Li, R C Yang
Objective: To assess the feasibility of HEAD-US scale in the clinical application of hemophilic arthropathy (HA) and propose an optimized ultrasound scoring system. Methods: From July 2015 to August 2017, 1 035 joints ultrasonographic examinations were performed in 91 patients. Melchiorre, HEAD-US (Hemophilic Early Arthropathy Detection with UltraSound) and HEAD-US-C (HEAD-US in China) scale scores were used respectively to analyze the results. The correlations between three ultrasound scales and Hemophilia Joint Health Scores (HJHS) were evaluated...
February 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29552578/target-cell-directed-bioengineering-approaches-for-gene-therapy-of-hemophilia-a
#16
Harrison C Brown, Philip M Zakas, Stephan N George, Ernest T Parker, H Trent Spencer, Christopher B Doering
Potency is a key optimization parameter for hemophilia A gene therapy product candidates. Optimization strategies include promoter engineering to increase transcription, codon optimization of mRNA to improve translation, and amino-acid substitution to promote secretion. Herein, we describe both rational and empirical design approaches to the development of a minimally sized, highly potent AAV-fVIII vector that incorporates three unique elements: a liver-directed 146-nt transcription regulatory module, a target-cell-specific codon optimization algorithm, and a high-expression bioengineered fVIII variant...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29550477/rd-05-a-novel-anti-cd154-antibody-efficiently-inhibits-generation-of-anti-drug-antibody-without-the-risk-of-thrombus-formation-in-non-human-primates
#17
Jae-Il Lee, Yun-Jung Choi, Hi-Jung Park, Kyeong Cheon Jung, Seong Hoe Park
Antibody formation against therapeutic agents, such as tumor necrosis factor inhibitors and Factor VIII, that leads to treatment failure has become a major challenge in the treatment of rheumatoid arthritis and hemophilia. It is well known that anti-CD154 antibodies have the highest potential to inhibit these types of adverse immune responses. Nevertheless, the formation of thromboemboli is the major hurdle in the clinical application of these anti-CD154 blocking antibodies. For this, we attempted to derive an idea as to how this major complication can be eliminated...
April 15, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29547114/-effective-gene-therapy-for-hemophilia-at-last%C3%A2
#18
Bertrand Jordan
Recent efforts at gene therapy for haemophilia A and B using AAV-derived vectors show durable expression of coagulation factors at significant levels, resulting in almost complete correction of the phenotype. This is the first success of gene therapy for a major hereditary disorder, and shows how continuous improvement of many components of the system has finally succeeded. Although these results must be confirmed with more patients and longer durations, they constitute a significant accomplishment for this approach after decades of frustration...
March 2018: Médecine Sciences: M/S
https://www.readbyqxmd.com/read/29523681/half-life-extended-recombinant-coagulation-factor-ix-albumin-fusion-protein-is-recycled-via-the-fcrn-mediated-pathway
#19
Jenny Chia, Jade Louber, Isabelle Glauser, Shirley Taylor, Greg T Bass, Steve K Dower, Paul A Gleeson, Anne M Verhagen
The neonatal Fc receptor (FcRn) has a pivotal role in albumin and IgG homeostasis. Internalized IgG captured by FcRn under acidic endosomal conditions is recycled to the cell surface where exocytosis and a shift to neutral pH promote extracellular IgG release. Although a similar mechanism is proposed for FcRn-mediated albumin intracellular trafficking and recycling, this pathway is less well defined, but is relevant to the development of therapeutics exploiting FcRn to extend the half-life of short-lived plasma proteins...
March 9, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29520794/critical-developments-of-2017-a-review-of-the-literature-from-selected-topics-in-transfusion-a-committee-report-from-the-aabb-clinical-transfusion-medicine-committee
#20
Melissa M Cushing, James Kelley, Ellen Klapper, David F Friedman, Ruchika Goel, Nancy M Heddle, Courtney K Hopkins, Julie Katz Karp, Monica B Pagano, Ajay Perumbeti, Glenn Ramsey, John D Roback, Joseph Schwartz, Beth H Shaz, Philip C Spinella, Claudia S Cohn, Claudia S Cohn, Melissa M Cushing, James Kelley, Ellen Klapper
BACKGROUND: The AABB compiles an annual synopsis of the published literature covering important developments in the field of Transfusion Medicine. For the first time, an abridged version of this work is being made available in TRANSFUSION, with the full-length report available as an Appendix S1 (available as supporting information in the online version of this paper). STUDY DESIGN AND METHODS: Papers published in 2016 and early 2017 are included, as well as earlier papers cited for background...
March 9, 2018: Transfusion
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