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Death in the blood : the inside story of the NHS infected blood scandal
Caroline Wheeler has been reporting on the contaminated blood scandal - the worst treatment disaster in the history of the NHS - for over two decades. She has been integral to the campaign for justice for the victims and their families, and played a pivotal role in persuading Prime Minister Theresa May to agree to the infected blood inquiry in 2019.'Death in the Blood' is based on thousands of government documents, court and inquiry transcripts, plus interviews with prime ministers, cabinet ministers, Downing Street advisers, senior civil servants, doctors, and above all the victims and their families whose personal testimony forms the beating heart of this book.
Book
A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A
In a randomized, multicenter trial involving boys with severe hemophilia A, the incidence of neutralizing antibodies to factor VIII was 87% higher with recombinant factor VIII products than with plasma-derived factor VIII products.
Hemophilia A is an inherited bleeding disorder characterized by plasma deficiency of coagulation factor VIII.
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,
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A major complication in 30% of patients is the occurrence of alloantibodies (inhibitors) that inactivate factor VIII activity and may nullify replacement therapy.
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–
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Risk factors include unmodifiable patient-related factors such as residual plasma factor VIII concentration and gene mutation.
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Putative treatment-related risk factors are early replacement therapy and the source of factor VIII (i.e., human plasma or recombinant DNA technology).
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Experimental studies have shown that plasma-derived factor VIII in complex with the chaperone protein von Willebrand factor, which masks . . .
Journal Article
Efanesoctocog Alfa Prophylaxis for Children with Severe Hemophilia A
Efanesoctocog alfa is an engineered form of factor VIII that overcomes the half-life ceiling imposed by von Willebrand factor. In this study, once-weekly prophylaxis in children led to highly effective bleeding prevention.
Journal Article
Emicizumab Prophylaxis in Hemophilia A with Inhibitors
Inhibitors develop in many patients with hemophilia who receive recombinant factor VIII. Prophylaxis with emicizumab, an antibody that functionally replaces factor VIII in the clotting pathway, reduced the rate of bleeding events among patients with hemophilia with inhibitors.
Journal Article
Factor VIII–Mimetic Function of Humanized Bispecific Antibody in Hemophilia A
Emicizumab is a humanized bispecific antibody that mimics the cofactor function of factor VIII. In a dose-escalation study in Japanese persons with hemophilia A, including those with factor VIII inhibitors, emicizumab markedly reduced the number of bleeding episodes.
Hemophilia A is a serious bleeding disorder caused by a deficiency of clotting factor VIII. Approximately 50% of patients have severe hemophilia A,
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defined as less than 1% residual factor VIII activity (<1 IU per deciliter).
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Such patients have severe bleeding from early childhood, and without appropriate treatment, recurrent bleeding into joints can lead to irreversible hemoarthropathy.
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Standard treatment for hemophilia A includes regular prophylaxis and episodic treatment with recombinant or plasma-derived factor VIII. The goals of prophylaxis with factor VIII are to increase factor VIII activity to at least a moderate level (1 to 5 IU per deciliter) . . .
Journal Article
A randomized, two-armed, double-blind, single-dose, cross-over, bioequivalence clinical trial to compare pharmacokinetic parameters and safety of recombinant human factor VIII with Fc fusion produced by AryoGen Pharmed Company versus Elocta® (reference product) in previously treated patients with severe haemophilia A
This clinical study evaluates the bioequivalence of recombinant factor VIII with Fc fusion protein (rFVIII-Fc) developed by AryoGen Pharmed Company compared to the reference product, Elocta
®
by Sobi Co., in severe haemophilia A patients. Fc-fused recombinant factor VIII represents a significant advancement in haemophilia A treatment, offering extended half-life and reduced infusion frequency, thus improving patients’ adherence to treatment and quality of life. In a randomized, double-blind, single-dose crossover trial, 50 Iranian patients were assigned to treatment groups in a 1:1 ratio. Subjects received both the test and the reference product with a 7-day washout period between treatments. Pharmacokinetic assessments were conducted over five days post-administration to evaluate the primary outcome, the dose-normalized area under the curve (DNAUC). The results established bioequivalence between rFVIII-Fc (AryoGen Pharmed Company) and Elocta
®
, based on the DNAUC as the primary outcome, in which the ratio of test and reference products was calculated to be 108.56 (90% confidence interval 104.88 to 112.37), falling within the pre-defined equivalence margin of 80–125%. Secondary outcomes, including area under the curve (AUC
inf
), maximum concentration (C
max
), and half-life, further supported bioequivalence. Safety profiles were comparable, with adverse events mainly related to haemophilia A rather than the intervention. In conclusion, the rFVIII-Fc product is bioequivalent to Elocta
®
with a similar safety profile, offering an effective alternative for severe haemophilia A patients. This trial was registered in ClinicalTrials.gov (NCT06137092).
Journal Article
Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors
Emicizumab binds to activated factor IX and factor X, reproducing the bridging function of the missing factor VIII. In a trial of emicizumab prophylaxis, emicizumab every 1 or 2 weeks led to a lower bleeding rate than no prophylaxis.
Journal Article
Anti-Inhibitor Coagulant Complex Prophylaxis in Hemophilia with Inhibitors
In patients with hemophilia A in whom inhibitors of factor VIII develop, the prophylactic use of a factor VIII bypassing agent (anti-inhibitor coagulant complex) three times a week significantly reduced the risk of bleeding.
After exposure to factor VIII, alloantibodies (inhibitors) that neutralize factor VIII clotting function develop in approximately 30% of patients with severe hemophilia A.
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The development of high-titer factor VIII inhibitors (>5 Bethesda units [BU]) complicates treatment because bleeding no longer responds to standard factor VIII replacement.
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Alternative forms of clotting-factor concentrates, known as bypassing agents, are used to treat bleeding in these patients.
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Two bypassing agents are currently available: anti-inhibitor coagulant complex (AICC) and recombinant activated factor VII (rFVIIa). Both agents control approximately 80% of bleeding episodes in patients with hemophilia and inhibitors.
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Nonetheless, their hemostatic efficacy is difficult . . .
Journal Article
Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A
Patients with severe hemophilia A were treated with an adenoviral construct containing coagulation factor VIII cDNA and followed for 1 to 3 years. Median factor VIII activity at 49 to 52 weeks was 24 IU per deciliter, and annualized bleeding rates decreased after treatment. Elevations in alanine aminotransferase were the most common toxic effect and were mainly controlled with glucocorticoids.
Journal Article
A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells
Nine dogs with hemophilia A were treated with adeno-associated viral (AAV) gene therapy and followed for up to 10 years. Administration of AAV8 or AAV9 vectors expressing canine factor VIII (AAV-cFVIII) corrected the FVIII deficiency to 1.9–11.3% of normal FVIII levels. In two of nine dogs, levels of FVIII activity increased gradually starting about 4 years after treatment. None of the dogs showed evidence of tumors or altered liver function. Analysis of integration sites in liver samples from six treated dogs identified 1,741 unique AAV integration events in genomic DNA and expanded cell clones in five dogs, with 44% of the integrations near genes involved in cell growth. All recovered integrated vectors were partially deleted and/or rearranged. Our data suggest that the increase in FVIII protein expression in two dogs may have been due to clonal expansion of cells harboring integrated vectors. These results support the clinical development of liver-directed AAV gene therapy for hemophilia A, while emphasizing the importance of long-term monitoring for potential genotoxicity.
AAV therapy in dogs leads to clonal expansions of transduced cells.
Journal Article