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Factor VIII antibody

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https://www.readbyqxmd.com/read/27913544/treatment-of-rare-factor-deficiencies-in-2016
#1
Flora Peyvandi, Marzia Menegatti
Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation disorders characterized by fibrinogen, prothrombin, factors V, VII, X, XI, or XIII (FV, FVII, FX, FXI, or FXIII, respectively), and the combined factor V + VIII and vitamin K-dependent proteins deficiencies, representing roughly 5% of all bleeding disorders. They are usually transmitted as autosomal, recessive disorders, and the prevalence of the severe forms could range from 1 case in 500 000 for FVII up to 1 in 2-3 million for FXIII in the general population...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27904904/clinical-evaluation-of-glycopegylated-recombinant-fviii-efficacy-and-safety-in-severe-haemophilia-a
#2
Paul Giangrande, Tatiana Andreeva, Pratima Chowdary, Silke Ehrenforth, Hideji Hanabusa, Frank W G Leebeek, Steven R Lentz, Laszlo Nemes, Lone Hvitfeldt Poulsen, Elena Santagostino, Chur Woo You, Wan Hui Ong Clausen, Peter G Jönsson, Johannes Oldenburg
Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A...
December 1, 2016: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/27891721/extended-half-life-pegylated-full-length-recombinant-factor-viii-for-prophylaxis-in-children-with-severe-haemophilia-a
#3
E S Mullins, O Stasyshyn, M T Alvarez-Román, D Osman, R Liesner, W Engl, M Sharkhawy, B E Abbuehl
INTRODUCTION: Primary factor VIII (FVIII) prophylaxis is the optimal treatment in children with severe haemophilia A. They are expected to benefit from extended half-life (T1/2 ) FVIII coverage by reduced infusion frequency while maintaining haemostatic efficacy. AIMS: To determine immunogenicity, pharmacokinetics (PK), efficacy, safety and quality of life of prophylaxis with a polyethylene glycol (peg)-ylated FVIII (BAX 855) based on full-length recombinant FVIII (ADVATE) in paediatric previously treated patients (PTPs) with severe haemophilia A...
November 27, 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/27885373/a-new-era-of-treatment-for-patients-with-haemophilia-a
#4
Robert Klamroth
Treatment and prevention of bleeding episodes in patients with severe haemophilia A require frequent intravenous injection of factor VIII. Inhibitory antibodies against factor VIII occur in approximately 30 % of these patients during the first exposure days and immune tolerance induction to eradicate the inhibitor is challenging. Prevention of bleeds in patients with haemophilia A and inhibitors is less effective and there is ongoing research for alternative treatment options. A promising approach in 2016 is the development of emicizumab (ACE910), a bi-specific IgG antibody to factor IXa and factor X, that mimics the cofactor function of factor VIII...
November 25, 2016: Hämostaseologie
https://www.readbyqxmd.com/read/27868337/enhanced-uptake-of-blood-coagulation-factor-viii-containing-immune-complexes-by-antigen-presenting-cells
#5
R B Hartholt, A Wroblewska, E Herczenik, I Peyron, A Ten Brinke, T Rispens, M A Nolte, E Slot, J W Claassens, F Nimmerjahn, J S Verbeek, J Voorberg
BACKGROUND: A major complication in the treatment of hemophilia A is the development of inhibitory antibodies targeting coagulation factor VIII (FVIII). Eradication of these inhibitors can be established by immune tolerance induction (ITI) which consists of daily administration of high dosages of FVIII. FVIII immune complexes (FVIII-IC) could be formed following FVIII infusion in patients with pre-existing anti-FVIII antibodies. OBJECTIVES: Here we studied endocytosis of FVIII-IC by bone marrow derived dendritic cells (BMDCs)...
November 21, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27862687/anti-factor-viii-antibodies-in-brothers-with-haemophilia-a-share-similar-characteristics
#6
J Kahle, A Orlowski, D Stichel, J F Healey, E T Parker, S M Donfield, J Astermark, E Berntorp, P Lollar, D Schwabe, C Königs
INTRODUCTION: The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) is currently the most serious complication for patients with haemophilia A undergoing FVIII replacement therapy. Several genetic factors have been acknowledged as risk factors for inhibitor development. AIM: To analyze the influence of genetic factors on the nature of the humoral immune response to FVIII in eight brother pairs with inhibitors. METHODS: The domain specificity of FVIII-specific IgG was analysed by antibody binding to FVIII fragments and homologue-scanning mutagenesis (HSM)...
November 8, 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/27795538/trends-in-novel-treatments-for-hemophilia
#7
Midori Shima
The principle of hemophilia treatment is replacement therapy with factor VIII and factor IX concentrates. Recently, extended half-life factor VIII and factor IX concentrates have been developed. With these concentrates, improvements in patient QOL can be expected. More recently, a novel hemophilia therapy based on a very new concept was developed. ACE910 (emicizumab) is a humanized bispecific antibody recognizing factor IXa and X mimicking factor VIII function. The half-life is reportedly 4-5 weeks and remarkably decreased annual bleeding rates have been achieved with subcutaneous weekly injections in the phase 1 clinical trial...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27789479/design-and-characterization-of-an-apc-specific-serpin-for-the-treatment-of-hemophilia
#8
Stéphanie G I Polderdijk, Ty E Adams, Lacramioara Ivanciu, Rodney M Camire, Trevor P Baglin, James A Huntington
Hemophilia is a bleeding disorder caused by deficiency in factors VIII or IX, the two components of the intrinsic Xase complex. Treatment with replacement factor can lead to the development of inhibitory antibodies, requiring the use of bypassing agents such as factor VIIa and factor concentrates. An alternative approach to bypass the Xase complex is to inhibit endogenous anticoagulant activities. Activated protein C (APC) breaks down the complex that produces thrombin by proteolytically inactivating factor Va...
October 27, 2016: Blood
https://www.readbyqxmd.com/read/27780008/severe-hemophilia-a-in-a-male-old-english-sheep-dog-with-a-c%C3%A2-t-transition-that-created-a-premature-stop-codon-in-factor-viii
#9
Jay N Lozier, Mark T Kloos, Elizabeth P Merricks, Nathaly Lemoine, Margaret H Whitford, Robin A Raymer, Dwight A Bellinger, Timothy C Nichols
Animals with hemophilia are models for gene therapy, factor replacement, and inhibitor development in humans. We have actively sought dogs with severe hemophilia A that have novel factor VIII mutations unlike the previously described factor VIII intron 22 inversion. A male Old English Sheepdog with recurrent soft-tissue hemorrhage and hemarthrosis was diagnosed with severe hemophilia A (factor VIII activity less than 1% of normal). We purified genomic DNA from this dog and ruled out the common intron 22 inversion; we then sequenced all 26 exons...
2016: Comparative Medicine
https://www.readbyqxmd.com/read/27766066/hemophilia-a-gene-therapy-via-intraosseous-delivery-of-factor-viii-lentiviral-vectors
#10
Carol H Miao
Current treatment of hemophilia A (HemA) patients with repeated infusions of factor VIII (FVIII; abbreviated as F8 in constructs) is costly, inconvenient, and incompletely effective. In addition, approximately 25 % of treated patients develop anti-factor VIII immune responses. Gene therapy that can achieve long-term phenotypic correction without the complication of anti-factor VIII antibody formation is highly desired. Lentiviral vector (LV)-mediated gene transfer into hematopoietic stem cells (HSCs) results in stable integration of FVIII gene into the host genome, leading to persistent therapeutic effect...
2016: Thrombosis Journal
https://www.readbyqxmd.com/read/27758819/the-c1-and-c2-domains-of-blood-coagulation-factor-viii-mediate-its-endocytosis-by-dendritic-cells
#11
Bagirath Gangadharan, Mathieu Ing, Sandrine Delignat, Ivan Peyron, Maud Teyssandier, Srinivas V Kaveri, Sébastien Lacroix-Desmazes
The development of inhibitory antibodies to therapeutic FVIII is the major complication of replacement therapy in patients with hemophilia A. The first step in the initiation of the anti-FVIII immune response is FVIII interaction with receptor(s) on antigen-presenting cells followed by endocytosis and presentation to naive CD4+ T cells. Recent studies indicate a role for the C1 domain in FVIII uptake. We investigated whether charged residues in the C2 domain participate in immunogenic FVIII uptake. Co-incubation of FVIII with BO2C11, a monoclonal C2-specific IgG, reduced FVIII endocytosis by dendritic cells and presentation to CD4+ T cells, and diminished FVIII immunogenicity in FVIII-deficient mice...
October 6, 2016: Haematologica
https://www.readbyqxmd.com/read/27757531/-metastatic-mechanisms-of-uterine-malignancies-and-therapeutic-consequences
#12
S F Lax, K F Tamussino, P F Lang
Malignancies of the uterus metastasize by direct invasion of neighboring structures, lymphatically or hematogenously. Endometrial and cervical cancers lymphatically spread to the pelvic and para-aortic lymph nodes. For endometrial cancer the depth of myometrial invasion, lymphosvascular space involvement (LVSI) and a microcystic, elongated and fragmented (MELF) glandular invasion pattern are predictors for lymph node metastases. Metastases to the pelvic lymph nodes occur in approximately 10 % of endometrial cancer patients and in 30 % of these cases the para-aortic lymph nodes are also involved...
October 18, 2016: Der Pathologe
https://www.readbyqxmd.com/read/27749010/platelets-are-a-safe-way-to-deliver-factor-viii-after-13-years-of-preclinical-research-it-is-now-time-for-a-clinical-trial
#13
Edward Tuddenham
The declarative title is a fair summary of research described in this paper (Targeting Factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice)(10) , is a fair summary of research described in this paper, which is itself the 14th in a series from the group of researchers led by Montgomery who, since 2003 have progressively advanced the idea of storing factor VIII in platelets to treat hemophilia A. Why, one might ask, would one do such a thing when evolution has selected endothelial cells as both the site for synthesis and release of factor VIII complexed with Von Willebrand factor to provide the cofactor when and where needed?(1,2) The answer lies in the unfortunate fact that a high proportion of patients with hemophilia develop resistance to factor VIII due to alloimmunity to the protein, which is foreign to their immune system, leading to production of inhibitory antibodies to the cofactor...
October 17, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27743753/lupus-anticoagulant-hypoprothrombinemia-syndrome-presenting-with-co-existing-cerebral-venous-thrombosis-and-subdural-hemorrhage
#14
N Bel Feki, S Zayet, I Ben Ghorbel, M-H Houman
The lupus anticoagulant-hypoprothrombinemia syndrome (LA-HPS) - the association of acquired factor II deficiency and lupus anticoagulant - is a rare disease that may cause a predisposition not only to thrombosis but also to severe bleeding. We are reporting on a 36-year-old female patient presenting with co-existing cerebral venous thrombosis and subdural hemorrhage. The coagulation screening showed a prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT), and a normal fibrinogen level and platelet count...
October 12, 2016: Journal des Maladies Vasculaires
https://www.readbyqxmd.com/read/27738645/overexpression-of-factor-viii-after-aav-delivery-is-transiently-associated-with-cellular-stress-in-hemophilia-a-mice
#15
Amy M Lange, Ekaterina S Altynova, Giang N Nguyen, Denise E Sabatino
Factor VIII (FVIII) is a large glycoprotein that is challenging to express both in vitro and in vivo. Several studies suggest that high levels of FVIII expression can lead to cellular stress. After gene transfer, transgene expression is restricted to a subset of cells and the increased FVIII load per cell may impact activation of the unfolded protein response. We sought to determine whether increased FVIII expression in mice after adeno-associated viral liver gene transfer would affect the unfolded protein response and/or immune response to the transgene...
2016: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/27683758/combination-therapy-for-inhibitor-reversal-in-haemophilia-a-using-monoclonal-anti-cd20-and-rapamycin
#16
Moanaro Biswas, Geoffrey L Rogers, Alexandra Sherman, Barry J Byrne, David M Markusic, Haiyan Jiang, Roland W Herzog
Development of antibodies (inhibitors) against coagulation factor VIII (FVIII) is a major complication of intravenous replacement therapy in haemophilia A (HA). Current immune tolerance induction (ITI) regimens are not universally effective. Rituximab, a B cell-depleting antibody against CD20, has shown mixed results for inhibitor reversal in patients. This study aims to develop a combinatorial therapy for inhibitor reversal in HA, using anti-murine CD20 (anti-mCD20) antibody and rapamycin, which targets both B and T cell responses...
September 29, 2016: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/27669166/enhancing-the-pharmaceutical-properties-of-protein-drugs-by-ancestral-sequence-reconstruction
#17
Philip M Zakas, Harrison C Brown, Kristopher Knight, Shannon L Meeks, H Trent Spencer, Eric A Gaucher, Christopher B Doering
Optimization of a protein's pharmaceutical properties is usually carried out by rational design and/or directed evolution. Here we test an alternative approach based on ancestral sequence reconstruction. Using available genomic sequence data on coagulation factor VIII and predictive models of molecular evolution, we engineer protein variants with improved activity, stability, and biosynthesis potential and reduced inhibition by anti-drug antibodies. In principle, this approach can be applied to any protein drug based on a conserved gene sequence...
September 26, 2016: Nature Biotechnology
https://www.readbyqxmd.com/read/27609734/life-threatening-hemorrhage-from-acquired-hemophilia-a-as-a-presenting-manifestation-of-prostate-cancer
#18
Chirag Sheth, Amandeep Gill, Sumeet Sekhon
Acquired factor VIII deficiency (acquired hemophilia A) is a rare condition characterized by the acquisition of autoantibodies that affect the clotting activity of factor VIII (fVIII). The most common manifestation in affected patients is a hemorrhagic diathesis. This disorder is associated with autoimmune diseases, pregnancy, postpartum period, drugs, and malignancy. Management of this condition begins with attempts to arrest an acute bleed based on the site and severity of bleeding and inhibitor titer. The next priority is eradication of the fVIII antibodies using immunosuppressive therapies...
2016: Journal of Community Hospital Internal Medicine Perspectives
https://www.readbyqxmd.com/read/27571001/chronic-thromboembolic-pulmonary-hypertension-epidemiology-and-risk-factors
#19
Marion Delcroix, Kim Kerr, Peter Fedullo
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of pulmonary embolism. As for most rare diseases, epidemiologic data are scarce, but recent registries suggest an incidence of at least 5 per million inhabitants per year. A history of massive or recurrent acute pulmonary embolism is observed in most patients with CTEPH, but the proportion of patients who develop CTEPH after acute pulmonary embolism is a matter of debate, further complicated by the possible misdiagnosis of CTEPH as acute pulmonary embolism...
July 2016: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/27563744/2017-clinical-trials-update-innovations-in-hemophilia-therapy
#20
Jan Hartmann, Stacy E Croteau
A surge in therapeutic clinical trials over recent years is paving the way for transformative treatment options for patients with hemophilia. The introduction of recombinant factor concentrates in the early 1990s facilitated the use of prophylactic replacement as standard care for hemophilia rather than on-demand treatment. This has revolutionized health outcomes for hemophilia patients, enabling participation in physical activities and reducing debilitating, chronic joint damage. Challenges of prophylactic factor infusion include the frequency of infusions needed to maintain factor levels greater than 1%, patient adherence, reliable intravenous access, and development of neutralizing alloantibodies ("inhibitors")...
December 2016: American Journal of Hematology
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