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Hemophilia A and B

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https://www.readbyqxmd.com/read/27913543/hemophilia-and-inhibitors-current-treatment-options-and-potential-new-therapeutic-approaches
#1
Shannon L Meeks, Glaivy Batsuli
The immune response to infused factor concentrates remains a major source of morbidity and mortality in the treatment of patients with hemophilia A and B. This review focuses on current treatment options and novel therapies currently in clinical trials. After a brief review of immune tolerance regimens, the focus of the discussion is on preventing bleeding in patients with hemophilia and inhibitors. Recombinant factor VIIa and activated prothrombin complex concentrates are the mainstays in treating bleeds in patients with inhibitors...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27898092/transposon-mediated-generation-of-cellular-and-mouse-models-of-splicing-mutations-to-assess-the-efficacy-of-snrna-based-therapeutics
#2
Elena Barbon, Mattia Ferrarese, Laetitia van Wittenberghe, Peggy Sanatine, Giuseppe Ronzitti, Fanny Collaud, Pasqualina Colella, Mirko Pinotti, Federico Mingozzi
Disease-causing splicing mutations can be rescued by variants of the U1 small nuclear RNA (U1snRNAs). However, the evaluation of the efficacy and safety of modified U1snRNAs as therapeutic tools is limited by the availability of cellular and animal models specific for a given mutation. Hence, we exploited the hyperactive Sleeping Beauty transposon system (SB100X) to integrate human factor IX (hFIX) minigenes into genomic DNA in vitro and in vivo. We generated stable HEK293 cell lines and C57BL/6 mice harboring splicing-competent hFIX minigenes either wild type (SChFIX-wt) or mutated (SChFIXex5-2C)...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27897038/aav-gene-therapy-for-liver-disease
#3
Lisa M Kattenhorn, Christopher H Tipper, Lorelei Stoica, Deborah S Geraghty, Teresa L Wright, K Reed Clark, Samuel Wadsworth
The field of adeno-associated virus (AAV) gene therapy has progressed rapidly over the past decade, with the advent of novel capsid serotypes, organ-specific promoters and an increasing understanding of the immune response to AAV administration. Liver-directed therapy, in particular, has made remarkable strides with a number of clinical trials currently planned and on-going in hemophilia A and B, as well as other liver disorders. This review focuses on liver-directed AAV gene therapy, including historic context, current challenges, and future developments...
November 29, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27885871/continuous-prophylaxis-with-recombinant-factor-ix-fc-fusion-protein-and-conventional-recombinant-factor-ix-products-comparisons-of-efficacy-and-weekly-factor-consumption
#4
Alfonso Iorio, Sangeeta Krishnan, Karl-Johan Myrén, Stefan Lethagen, Nora McCormick, Sander Yermakov, Paul Karner
BACKGROUND: Continuous prophylaxis for patients with hemophilia B requires frequent injections that are burdensome and that may lead to suboptimal adherence and outcomes. Hence, therapies requiring less-frequent injections are needed. In the absence of head-to-head comparisons, we compared the first extended-half-life-recombinant factor IX (rFIX) product- recombinant factor IX Fc fusion protein (rFIXFc) - with conventional rFIX products based on annualized bleed rates (ABRs) and factor consumption reported in studies of continuous prophylaxis...
November 25, 2016: Journal of Medical Economics
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/27863665/biodegradable-hydrophilic-carriers-for-the-oral-delivery-of-hematological-factor-ix-for-hemophilia-b-treatment
#6
Sarena D Horava, Katie J Moy, Nicholas A Peppas
Current protein replacement therapies for hemophilia B, a genetic bleeding disorder caused by a deficiency in coagulation factor IX, rely on IV injections and infusions. Oral delivery of factor IX is a desirable needle-free option, especially for prophylaxis. We have developed a biodegradable, pH-responsive hydrogel microcarrier system based on the poly(methacrylic acid)-grafted-poly(ethylene glycol) [P(MAA-g-EG)]. Incorporation of an enzymatically degradable peptide crosslinking agent allows for site-specific degradation by trypsin in the small intestine...
November 30, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27834949/direct-interaction-of-human-serum-proteins-with-aav-virions-to-enhance-aav-transduction-immediate-impact-on-clinical-applications
#7
M Wang, J Sun, A Crosby, K Woodard, M L Hirsch, R J Samulski, C Li
Recent hemophilia B clinical trials using adeno-associated virus (AAV) gene delivery have demonstrated much lower coagulation factor IX (FIX) production in patients compared with the high levels observed in animal models and AAV capsid-specific cytotoxic T lymphocyte response elicited at high doses of AAV vectors. These results emphasize the necessity to explore effective approaches for enhancement of AAV transduction. Initially, we found that incubation of all AAV vectors with human serum enhanced AAV transduction...
December 1, 2016: Gene Therapy
https://www.readbyqxmd.com/read/27825181/blood-group-o-protects-against-inhibitor-development-in-severe-hemophilia-a-patients
#8
Massimo Franchini, Antonio Coppola, Carlo Mengoli, Gianna Franca Rivolta, Federica Riccardi, Giovanni Di Minno, Annarita Tagliaferri
Increasing evidence supports the link between ABO(H) blood group determinants and hemostasis. In particular, the ABO-related different glycosylation patterns of von Willebrand factor strongly influence its clearance and functional levels, and this may contribute to the inter-individual variations in the half-life of infused Factor VIII (FVIII) in hemophilia A (HA) patients. We investigated the role of ABO blood groups in regulating FVIII immunogenicity by evaluating their distribution in patients with severe (FVIII < 1 IU/dL) HA according to inhibitor development and other known relevant factors...
November 8, 2016: Seminars in Thrombosis and Hemostasis
https://www.readbyqxmd.com/read/27822257/co-infection-of-the-hepatitis-c-virus-with-other-blood-borne-and-hepatotropic-viruses-among-hemophilia-patients-in-poland
#9
Marta Kucharska, Malgorzata Inglot, Aleksandra Szymczak, Weronika Rymer, Malgorzata Zalewska, Krzysztof Malyszczak, Urszula Zaleska-Dorobisz, Malgorzata Kuliszkiewicz-Janus
BACKGROUND: The prevalence of HCV infection in people with hemophilia is substantially higher than that in the general population (63% - 98%). Multiple transfusions and substitutive therapy have also been linked to a high risk of HBV and HIV transmission. However, the prevalence of other blood-borne viral infections in this population is less well known. OBJECTIVES: This study aimed to assess the prevalence of co-infection with HBV and other blood-borne viruses in Polish HCV-infected hemophiliacs...
September 2016: Hepatitis Monthly
https://www.readbyqxmd.com/read/27818588/update-on-occult-hepatitis-b-virus-infection
#10
REVIEW
Manoochehr Makvandi
The event of mutations in the surface antigen gene of hepatitis B virus (HBV) results in undetectable hepatitis B surface antigen with positive/negative anti-hepatitis B core (anti-HBc) antibody status in serum and this phenomenon is named occult hepatitis B infection (OBI). The presence of anti-HBc antibody in serum is an important key for OBI tracking, although about 20% of OBI cases are negative for anti-HBc antibody. The diagnosis of OBI is mainly based on polymerase chain reaction (PCR) and real-time PCR assays...
October 21, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27813214/complications-of-haemophilia-in-babies-first-two-years-of-life-a-report-from-the-centers-for-disease-control-and-prevention-universal-data-collection-system
#11
R Kulkarni, R J Presley, J M Lusher, A D Shapiro, J C Gill, M Manco-Johnson, M A Koerper, T C Abshire, D DiMichele, W K Hoots, P Mathew, D J Nugent, S Geraghty, B L Evatt, J M Soucie
AIM: To describe the prevalence and complications in babies ≤2 years with haemophilia. METHODS: We used a standardized collection tool to obtain consented data on eligible babies aged ≤2 years with haemophilia enrolled in the Centers for Disease Control and Prevention Universal Data Collection System surveillance project at US Hemophilia Treatment Centers (HTCs). RESULTS: Of 547 babies, 82% had haemophilia A, and 70% were diagnosed within one month of birth...
November 4, 2016: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/27799968/evaluation-of-aryoseven-safety-recombinant-activated-factor-vii-in-patients-with-bleeding-disorders-an-observational-post-marketing-surveillance-study
#12
Gholamreza Toogeh, Hassan Abolghasemi, Peyman Eshghi, Mohammadreza Managhchi, Mohammadreza Shaverdi-Niasari, Katayoon Karimi, Samin Roostaei, Neda Emran, Alireza Abdollahi
BACKGROUND: Recombinant activated factor VII induces hemostasis in patients with coagulopathy disorders. AryoSeven™ as a safe Iranian Recombinant activated factor VII has been available on our market. This study was performed to establish the safety of AryoSeven on patients with coagulopathy disorder. METHODS: This single-center, descriptive, cross sectional study was carried out in Thrombus and Homeostasis Research Center ValiAsr Hospital during 2013-2014. Fifty one patients with bleeding disorders who received at least one dose of Aryoseven were enrolled...
2016: Iranian Journal of Pathology
https://www.readbyqxmd.com/read/27789479/design-and-characterization-of-an-apc-specific-serpin-for-the-treatment-of-hemophilia
#13
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/27784381/-clinical-characteristics-of-223-chinese-patients-with-hemophilia-in-a-medical-center-of-gansu-province-in-china
#14
Xiao-Li Mou, Yue Zhao, Ze-Hua Chen, Yong-Qiang Ding, Ming Li, Ming-Feng Jia, Ya-Ming Xi
OBJECTIVE: To analyze the clinical characteristics, diagonsis and treatment of patients with hemophilia in Gansu province of China. METHODS: The clinical data of 223 cases of hemophilia in our center between January 2010 and May 2015 were collected and analyzed retrospectively, these 223 cases of hemophilia were from 14 cities in Gansu and neighboring provinces, including 203 cases of hemophili A (HA) and 20 cases of hemophili B (HB), among them 222 cases were male, only 1 female(HA), 177 cases were from Rural areas (79...
October 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/27766061/extravascular-fix-and-coagulation
#15
Darrel W Stafford
This review summarizes the evidence that collagen IV binding is physiologically important, and that the extravascular compartment of FIX is composed of type IV collagen. As we have previously demonstrated, 7 days post-infusion, FIXWT (BeneFIX) is able to control bleeding as well as the same dosage of Alprolix in hemophilia B mice, tested using the saphenous vein bleeding model (Alprolix is a chimeric FIX molecule joined at its C terminus to a Fc domain). Furthermore, we have shown that in hemophilia B mice, doses of BeneFIX or Alprolix (up to a dose of 150 IU/kg) have increased bleeding-control effectiveness in proportion to the dose up to a certain limit: higher doses are no more effective than the 150 IU/kg dose...
2016: Thrombosis Journal
https://www.readbyqxmd.com/read/27766056/aspects-of-prophylactic-treatment-of-hemophilia
#16
Rolf Ljung
Retrospective and prospective studies unambiguously show that prophylactic treatment of severe hemophilia A or B should be started as primary prophylaxis at 1-2 years' of age and ideally before the first joint bleed. The dose and dose frequency should be individually tailored depending on the goal of treatment, venous access and the bleeding phenotype. The circumstances during the first exposures of factor VIII concentrates in hemophilia A may have an impact on the risk of developing inhibitors. Enhanced half-life products, in particular in hemophilia B, will facilitate treatment in patients with difficult venous access but also in achieving a higher trough level...
2016: Thrombosis Journal
https://www.readbyqxmd.com/read/27749002/novel-factor-viii-variants-with-a-modified-furin-cleavage-site-improve-the-efficacy-of-gene-therapy-for-hemophilia-a
#17
G N Nguyen, L A George, J I Siner, R J Davidson, C B Zander, X L Zheng, V R Arruda, R M Camire, D E Sabatino
BACKGROUND: The major challenge for developing gene-based therapies for hemophilia A is that human factor VIII (hFVIII) has intrinsic properties that result in inefficient biosynthesis. During intracellular processing, hFVIII is predominantly cleaved at a Paired basic Amino acid Cleaving Enzyme (PACE) or furin cleavage site to yield a heterodimer that is the major form of secreted protein. Previous studies with B-domain deleted (BDD) canine FVIII and hFVIII-R1645H, both differing from hFVIII by a single amino acid at this site, suggested that these proteins are secreted mainly in a single polypeptide chain (SC) form and exhibit enhanced function...
October 17, 2016: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/27745618/hemophilia-what-the-oral-and-maxillofacial-surgeon-needs-to-know
#18
Julie Ann Smith
Hemophilia will be encountered in the oral and maxillofacial surgeon's office. A thorough understanding of hemophilia is necessary to safely care for these patients. One must understand the severity of the patient's hemophilia as well as whether or not inhibitors are present. The patient's surgical management will be influenced by these two factors. In addition to the possible need to transfuse factors or desmopressin, special care must be taken perioperatively to avoid bleeding complications. This article reviews the overall management of hemophilia A and B as well as the specific perioperative management of these patients...
November 2016: Oral and Maxillofacial Surgery Clinics of North America
https://www.readbyqxmd.com/read/27738645/overexpression-of-factor-viii-after-aav-delivery-is-transiently-associated-with-cellular-stress-in-hemophilia-a-mice
#19
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/27738644/potential-for-cellular-stress-response-to-hepatic-factor-viii-expression-from-aav-vector
#20
Irene Zolotukhin, David M Markusic, Brett Palaschak, Brad E Hoffman, Meera A Srikanthan, Roland W Herzog
Hemophilia A and B are coagulation disorders resulting from the loss of functional coagulation factor VIII (FVIII) or factor IX proteins, respectively. Gene therapy for hemophilia with adeno-associated virus vectors has shown efficacy in hemophilia B patients. Although hemophilia A patients are more prevalent, the development of therapeutic adeno-associated virus vectors has been impeded by the size of the F8 cDNA and impaired secretion of FVIII protein. Further, it has been reported that over-expression of the FVIII protein induces endoplasmic reticulum stress and activates the unfolded protein response pathway both in vitro and in hepatocytes in vivo, presumably due to retention of misfolded FVIII protein within the endoplasmic reticulum...
2016: Molecular Therapy. Methods & Clinical Development
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