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Factor VIII antibody

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https://www.readbyqxmd.com/read/29769259/novel-therapeutics-for-hemophilia-and-other-bleeding-disorders
#1
Michael U Callaghan, Robert Sidonio, Steven W Pipe
Hemophilia and von Willebrand disease are the most common congenital bleeding disorders. Treatment for these disorders has focused on replacement of the missing coagulation factor to prevent or treat bleeding. New technologies and insights into hemostasis have driven the development of many promising new therapies for hemophilia and von Willebrand disease. Emerging bypass agents including zymogen-like factor IXa and Xa molecules are in development and a bispecific antibody, emicizumab, demonstrated efficacy in a phase III trial in people with hemophilia A and inhibitors...
May 16, 2018: Blood
https://www.readbyqxmd.com/read/29767844/comorbidities-associated-with-higher-von-willebrand-factor-vwf-levels-may-explain-the-age-related-increase-of-vwf-in-von-willebrand-disease
#2
Ferdows Atiq, Karina Meijer, Jeroen Eikenboom, Karin Fijnvandraat, Eveline P Mauser-Bunschoten, Karin P M van Galen, Marten R Nijziel, Paula F Ypma, Joke de Meris, Britta A P Laros-van Gorkom, Johanna G van der Bom, Moniek P de Maat, Marjon H Cnossen, Frank W G Leebeek
Some comorbidities, such as hypertension, are associated with higher von Willebrand factor (VWF) levels in the general population. No studies have been conducted to assess this association in patients with von Willebrand disease (VWD). Therefore, we studied this association in patients with type 1 (n = 333) and type 2 (n = 203) VWD from the 'WiN" study. VWF antigen (VWF:Ag) was higher in type 1 VWD patients with hypertension [difference: 0·23 iu/ml, 95% confidence interval (CI): 0·11-0·35], diabetes mellitus (0·11 iu/ml, 95% CI: -0·02 to 0·23), cancer (0·14 iu/ml, 95% CI: 0·03-0·25) and thyroid dysfunction (0·14 iu/ml, 95% CI: 0·03-0·26) than in patients without these comorbidities (all corrected for age, sex and blood group)...
May 16, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29765291/the-potential-close-future-of-hemophilia-treatment-gene-therapy-tfpi-inhibition-antithrombin-silencing-and-mimicking-factor-viii-with-an-engineered-antibody
#3
REVIEW
Wolfgang Korte, Lukas Graf
Summary Hemophilia is one of the best researched monogenic diseases. Hemophilia A will affect approximately 1:5,000 male live births. In recent decades, great progress has been made with the introduction of recombinant proteins in the 1990s for therapy and prophylaxis, securing adequate availability and, with the introduction of the prophylaxis concept, reducing the negative impact of hemophilia on morbidity (especially arthropathy). Despite this progress, there are still challenges to overcome to secure adequate prophylaxis and treatment: for the time being, causal pharmacological hemophilia prophylaxis and therapy requires repeated i...
April 2018: Transfusion Medicine and Hemotherapy
https://www.readbyqxmd.com/read/29741261/new-challenges-and-best-practices-for-the-laboratory-monitoring-of-factor-viii-and-factor-ix-replacement
#4
REVIEW
D Van den Bossche, K Peerlinck, M Jacquemin
Several recombinant factor VIII and factor IX concentrates with extended half-life (EHL) have recently been validated by clinical studies. The availability of these novel concentrates is expected to significantly facilitate the treatment of patients with hemophilia A and B. However, the modification applied to these molecules has introduced variations in their activity measurement in routine coagulation assays. Depending on the assays, underestimations of up to 10-fold or overestimations of up to approximately 30-fold in the measurements of the recovery have been reported in some factor concentrates...
May 2018: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/29734520/routine-measurements-of-factor-viii-activity-and-inhibitor-titer-in-the-presence-of-emicizumab-utilizing-anti-idiotype-monoclonal-antibodies
#5
Keiji Nogami, Tetsuhiro Soeda, Tomoko Matsumoto, Yoshiki Kawabe, Takehisa Kitazawa, Midori Shima
BACKGROUND: Emicizumab is an anti-factor (F)IXa/X bispecific monoclonal antibody (mAb), mimicking the Factor (F)VIIIa cofactor activity. Emicizumab does not require activation by thrombin and its shortening effect on the activated partial prothrombin time (aPTT) is more pronounced than that of Factor (F)VIII. aPTT-based FVIII activity (FVIII:C) and FVIII inhibiter titer measurements are influenced by the presence of emicizumab. AIM: To establish a reliable aPTT-based assay to measure FVIII in the presence of emicizumab...
May 7, 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29729717/immunohistochemical-characterization-of-immune-cell-infiltration-in-feline-glioma
#6
D R Rissi, B F Porter, C E Boudreau, P M Krimer, A D Miller
The relationship between inflammatory cells and tumour biology has been defined in many human intracranial neoplasms, but it is relatively poorly characterized in veterinary medicine. The aim of this study was to define the immune cell infiltration in cases of feline glioma and its possible association with tumour morphology and type. A retrospective search identified 18 gliomas that met inclusion criteria. Tumours were subjected to immunohistochemistry (IHC) for CD3, CD20, Iba1, MAC387 and factor VIII-related antigen...
April 2018: Journal of Comparative Pathology
https://www.readbyqxmd.com/read/29723892/treatment-regimens-with-bypassing-agents-in-patients-with-hemophilia-a-and-inhibitors-a-survey-from-the-italian-association-of-hemophilia-centers-aice
#7
Antonio Coppola, Massimo Franchini, Giancarlo Castaman, Elena Santagostino, Cristina Santoro, Rita Carlotta Santoro, Massimo Morfini, Giovanni Di Minno, Angiola Rocino
The development of neutralizing antibodies (inhibitors) against infused factor VIII currently represents the main complication of replacement therapy in patients with severe hemophilia A. Inhibitors, indeed, particularly high-titer inhibitors (>5 BU/mL), greatly complicate the management of bleeding, exposing patients to an increased morbidity and mortality risk, thus representing a significant burden for physicians of Hemophilia Treatment Centers (HTCs). Although bypassing agents (i.e., activated prothrombin complex concentrate [APCC] and recombinant activated factor VII [rFVIIa]) are available for the treatment and prevention of bleeding in inhibitor patients, their efficacy, safety, and cost-benefit outcomes are poorly known in the long term and should be further improved...
May 3, 2018: Seminars in Thrombosis and Hemostasis
https://www.readbyqxmd.com/read/29674503/dexamethasone-promotes-durable-factor-viii-specific-tolerance-in-hemophilia-a-mice-via-thymic-mechanisms
#8
Maria T Georgescu, Paul C Moorehead, Alice S van Velzen, Kate Nesbitt, Birgit M Reipert, Katharina N Steinitz, Maria Schuster, Christine Hough, David Lillicrap
The development of inhibitory antibodies to factor VIII is the most serious complication of replacement therapy in hemophilia A. Activation of the innate immune system during exposure to this protein contributes to inhibitor development. However, avoidance of factor VIII exposure during innate immune system activation by external stimuli (e.g. vaccines) has not been consistently shown to prevent inhibitors. We hypothesized that dexamethasone, a drug with potent anti-inflammatory effects, could prevent inhibitors by promoting immunologic tolerance to factor VIII in hemophilia A mice...
April 19, 2018: Haematologica
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
#9
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/29651351/acquired-von-willebrand-disease-associated-with-mantle-cell-lymphoma
#10
Dominique Maas, Britta Laros-van Gorkom, Sanne Gianotten, Marjan Cruijsen, Waander van Heerde, Marten Nijziel
We present a rare case of acquired von Willebrand syndrome (AVWS) caused by a mantle cell lymphoma. A 61-year-old male suffered from recurrent bleeding symptoms since a few months. Initially, physical examination was normal. von Willebrand factor antigen (VWF:Ag) level and factor VIII activity (FVIII:C) were low (0.31 IU/ml and 0.43 IU/ml, resp.). Ristocetin cofactor activity (VWF:RCo) was 0.09 IU/ml, and collagen binding activity (VWF:CB) was 0.10 IU/ml. VWF:RCo/VWF:Ag ratio was 0.29, and RIPA value was normal...
2018: Case Reports in Hematology
https://www.readbyqxmd.com/read/29649469/phosphatidylserine-is-not-just-a-cleanup-crew-but-also-a-well-meaning-teacher
#11
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/29625480/microvascular-density-is-associated-with-retinal-ganglion-cell-axonal-volume-in-the-laminar-compartments-of-the-human-optic-nerve-head
#12
Min H Kang, Mengchen Suo, Chandrakumar Balaratnasingam, Paula K Yu, William H Morgan, Dao-Yi Yu
Purpose: To quantify associations between microvascular density and retinal ganglion cell (RGC) axonal volume in the laminar compartments of the human optic nerve head (ONH). Methods: Eleven normal human ONHs were evaluated. Antibodies were used to label the vascular endothelium (factor VIII-related antigen/von Willebrand factor antibody) and RGC axons (neurofilament heavy antibody). Three-dimensional analysis of confocal scanning laser microscope images was used to study microvascular density and RGC axonal volume in the prelaminar, anterior lamina cribrosa, posterior lamina cribrosa, and retrolaminar compartments...
March 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29577605/increased-factor-viii-plays-a-significant-role-in-plasma-hypercoagulability-phenotype-of-patients-with-cirrhosis
#13
T Sinegre, C Duron, T Lecompte, B Pereira, S Massoulier, G Lamblin, A Abergel, A Lebreton
Essentials The role of increased factor VIII in cirrhosis-induced hypercoagulability has never been demonstrated. Factor VIII and protein C effects were characterized by thrombin generation with thrombomodulin. Factor VIII elevation plays a significant role in cirrhosis-induced plasma hypercoagulability. Only protein C and factor VIII normalization led to thrombin generation similar to controls. SUMMARY: Background In cirrhosis, thrombin generation (TG) studied in the presence of thrombomodulin (TM) indicates plasma hypercoagulability...
March 26, 2018: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29554701/human-dendritic-cells-synergistically-activated-by-fviii-plus-lps-induce-activation-of-autologous-cd4-t-cells
#14
Lilija Miller, Eva Ringler, Klaus Maximilian Kistner, Zoe Waibler
The most severe side effect in haemophilia A (HA) treatment is the development of anti-factor VIII antibodies, also called inhibitors. Why inhibitors develop in a proportion of treated HA patients and how this can be prevented remains largely unanswered. Among numerous theories, the presence of immunological danger signals, associated with events such as surgery or infection, has been proposed to play a role. In this study, we demonstrate that human dendritic cells (DC) synergistically activated by a combination of factor VIII (FVIII) concentrate plus the bacterial danger signal lipopolysaccharide (LPS) induce a significantly stronger activation of autologous CD4+ T cells than DC pretreated with FVIII or LPS alone...
March 19, 2018: Thrombosis and Haemostasis
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
#15
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/29543371/immune-tolerance-induction-what-have-we-learned-over-time
#16
REVIEW
H-H Brackmann, G C White, E Berntorp, T Andersen, C Escuriola-Ettingshausen
Development of inhibitory antibodies to infused factor VIII (FVIII) concentrates continues to be the most serious complication of haemophilia A management. Induction of immune tolerance by administering high doses of FVIII concentrate (antigen) and prothrombin complex concentrates to control bleeding was originated in the 1970s in Bonn, Germany, by Dr Hans-Hermann Brackmann, and became known as the Bonn protocol. ITI transformed the life of the index patient, who was 19 years of age when he began treatment, and dramatically improved the medical landscape for all patients with haemophilia and inhibitors...
April 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/29520365/platelet-targeted-gene-therapy-for-hemophilia
#17
REVIEW
Qizhen Shi
Gene therapy is an attractive approach for disease treatment. Since platelets are abundant cells circulating in blood with the distinctive abilities of storage and delivery and fundamental roles in hemostasis and immunity, they could be a unique target for gene therapy of diseases. Recent studies have demonstrated that ectopic expression of factor VIII (FVIII) in platelets under control of the platelet-specific promoter results in FVIII storage together with its carrier protein von Willebrand factor (VWF) in α-granules and the phenotypic correction of hemophilia A...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29482894/review-of-immune-tolerance-induction-in-hemophilia-a
#18
REVIEW
S J Schep, R E G Schutgens, K Fischer, M L Boes
At first sight the bleeding disorder hemophilia A seems to have little in common with immune disorders, but immunology research intersects with other disciplines including hematology. Nowadays, the most important complication in the treatment of hemophilia A is the development of neutralizing antibodies (inhibitors) against exogenous administered factor VIII (FVIII), which occurs in approximately 30% of all patients with severe hemophilia A. This antibody response renders FVIII replacement therapy ineffective, thereby increasing the risk for uncontrollable bleeding and morbidity, decreasing quality of life and increasing healthcare costs...
February 15, 2018: Blood Reviews
https://www.readbyqxmd.com/read/29472355/use-of-thrombin-generation-assay-to-personalize-treatment-of-breakthrough-bleeds-in-a-patient-with-hemophilia-and-inhibitors-receiving-prophylaxis-with-emicizumab
#19
LETTER
Yesim Dargaud, Anne Lienhart, Maissaa Janbain, Sandra Le Quellec, Nathalie Enjolras, Claude Negrier
No abstract text is available yet for this article.
April 2018: Haematologica
https://www.readbyqxmd.com/read/29461004/effects-of-pre-analytical-heat-treatment-in-factor-viii-fviii-inhibitor-assays-on-fviii-antibody-levels
#20
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
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