Res Pract Thromb Haemost
January 2025
Adeno-associated virus-based gene therapy for hemophilia has emerged as a revolutionary treatment option, offering potential correction of clotting factor deficiency through a single intravenous infusion of functional genes directed to hepatocytes. With 3 gene therapies recently approved, this approach shows promise in transforming the lives of individuals with hemophilia. However, the complexity of gene therapy and the lack of standardization of methods in different components of this therapy can lead to unique challenges for clinical implementation.
View Article and Find Full Text PDFIntroduction: The 2024 ISTH clinical practice guideline (CPG) for treatment of congenital haemophilia, the NBDF-McMaster Guideline on Care Models for Haemophilia Management, and ASH ISTH NBDF WFH guidelines on the diagnosis and management of VWD all utilised GRADE methodology.
Aim: Discuss missed opportunities and the methodological approach of the ISTH Guideline in contrast to how GRADE was previously applied in rare diseases.
Methods: Critically analyse the methodology of each guideline along with best practices in the use of GRADE.
Introduction: Evidence-based clinical practice guidelines drive optimal patient care and facilitate access to high-quality treatment. Creating guidelines for rare diseases such as haemophilia, where evidence does not often come from randomized controlled trials but from non-randomized and well-designed observational studies and real-world data, is challenging. The methodology used for assessing available evidence should consider this critical fact.
View Article and Find Full Text PDFBackground: Patients with hemophilia have a life-long risk of developing neutralizing antibodies (inhibitors) against clotting factor concentrates. After the first 50 exposure days (EDs), ie, in previously treated patients (PTPs), data on inhibitor development are limited.
Objectives: To report inhibitor development according to factor (F)VIII or FIX concentrate use in PTPs with severe hemophilia A and B.
We present a case of bilateral endogenous endophthalmitis with an extremely rare etiology of . A 42-year-old asplenic patient with bilateral deterioration of visual acuity presented to the Emergency Department. The sudden deterioration of visual acuity, which prompted the patient to visit the ophthalmologist, was the first sign of the onset of sepsis.
View Article and Find Full Text PDFGene therapy for severe hemophilia A uses an adeno-associated virus (AAV) vector and liver-specific promoters that depend on healthy hepatocyte function to achieve safe and long-lasting increases in factor VIII (FVIII) activity. Thus, hepatocyte health is an essential aspect of safe and successful gene therapy. Many people living with hemophilia A have current or past chronic hepatitis C virus infection, metabolic dysfunction-associated steatosis or steatohepatitis, or other conditions that may compromise the efficacy and safety of AAV-mediated gene therapy.
View Article and Find Full Text PDF: Endotamponade of the vitreous body with silicone oil is a common procedure, being the basis of many vitreoretinal surgeries. However, emulsification may happen, which is a clinically relevant adverse event of silicone oil use. : This review provides a thorough analysis of the emulsification process.
View Article and Find Full Text PDFBackground: Factor IX inhibitor formation is the most serious complication of replacement therapy for the bleeding disorder hemophilia B, exacerbated by severe allergic reactions occurring in up to 60% of patients with inhibitors. Low success rates of immune tolerance induction therapy in hemophilia B necessitate the search for novel immune tolerance therapies. Skin-associated lymphoid tissues have been successfully targeted in allergen-specific immunotherapy.
View Article and Find Full Text PDFBackground: Clotting factor concentrates have been the mainstay of severe hemophilia treatment over the last 50 years. Differences in risk of neutralizing antibody (inhibitor) formation according to concentrate used remain clinically relevant.
Objectives: To assess inhibitor development according to type of clotting factor concentrate in previously untreated patients (PUPs) with severe hemophilia A and B.
Adeno-associated virus gene therapy has been the subject of intensive investigation for monogenic disease gene addition therapy for more than 25 years, yet few therapies have been approved by regulatory agencies. Most have not progressed beyond phase 1/2 due to toxicity, lack of efficacy, or both. The liver is a natural target for adeno-associated virus since most serotypes have a high degree of tropism for hepatocytes due to cell surface receptors for the virus and the unique liver sinusoidal geometry facilitating high volumes of blood contact with hepatocyte cell surfaces.
View Article and Find Full Text PDFIntroduction: The aim was to detect subclinical structural retinal abnormalities in optical coherence tomography (OCT) in ophthalmologically asymptomatic systemic lupus erythematosus (SLE) patients without signs of lupus retinopathy or drug toxicity in fundus examination and in OCT and to assess the relationship between OCT parameters and disease activity, therapy type and burden on other organs to demonstrate the utility of OCT in early retinal impairment in SLE patients.
Material And Methods: Cross-sectional study. Thirty-three SLE patients (57 eyes) and 31 healthy individuals (56 eyes) were enrolled in the study.
Dicobalt hexacarbonyl 5-alkynyl furopyrimidine nucleoside analogs, with 4-methylphenyl (-tolyl) and 4-pentylphenyl substituents attached at the C-6 base position, designed in the form of ribose acetyl esters, were synthesized (42-96%). Attached at the C-5 position were propargyl alcohol, its methyl ether and acetate derivatives, butynol, and the 4-methylphenyl- (-tolyl) and 4-pentylphenyl-substituted alkynyl groups, which were coordinated to a dicobalt hexacarbonyl unit. The structure of 5-(3-acetoxyprop-1-yn-1-yl)-6--tolyl-2'-deoxyribofuranosyl-furo[2,3-]pyrimidin-2-one was determined by X-ray crystallography.
View Article and Find Full Text PDFDespite >80 years of clinical experience with coagulation factor VIII (FVIII) inhibitors, surprisingly little is known about the in vivo mechanism of this most serious complication of replacement therapy for hemophilia A. These neutralizing antidrug alloantibodies arise in ∼30% of patients. Inhibitor formation is T-cell dependent, but events leading up to helper T-cell activation have been elusive because of, in part, the complex anatomy and cellular makeup of the spleen.
View Article and Find Full Text PDFBackground: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously.
Methods: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×10 vector genomes of valoctocogene roxaparvovec per kilogram of body weight.
MicroRNAs (miRNAs) are small noncoding RNAs which mediate some of the pathological mechanisms of diabetic retinopathy. The aim of this study was to identify differentially expressed miRNAs in the vitreal exosomes of proliferative diabetic retinopathy (PDR) patients and non-diabetic controls. Exosomes were extracted from the vitreous samples of 10 PDR patients and 10 controls.
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