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Hematology. American Society of... Dec 2019Gene therapy offers the potential for a cure for patients with hemophilia by establishing continuous endogenous expression of factor VIII or factor IX (FIX) following... (Review)
Review
Gene therapy offers the potential for a cure for patients with hemophilia by establishing continuous endogenous expression of factor VIII or factor IX (FIX) following transfer of a functional gene to replace the hemophilic patient's own defective gene. The hemophilias are ideally suited for gene therapy because a small increment in blood factor levels (≥5% of normal) is associated with significant amelioration of bleeding phenotype in severely affected patients. In 2011, the St. Jude/UCL phase 1/2 trial was the first to provide clear evidence of a stable dose-dependent increase in FIX levels in patients with severe hemophilia B following a single administration of adeno-associated viral (AAV) vectors. Transgenic FIX expression has remained stable at ∼5% of normal in the high-dose cohort over a 7-year follow-up period, resulting in a substantial reduction in spontaneous bleeding and FIX protein usage without toxicity. This study has been followed by unparalleled advances in gene therapy for hemophilia A and B, leading to clotting factor activity approaching normal or near-normal levels associated with a "zero bleed rates" in previously severely affected patients following a single administration of AAV vectors. Thus, AAV gene therapies are likely to alter the treatment paradigm for hemophilia A and B. This review explores recent progress and the remaining limitations that need to be overcome for wider availability of this novel treatment of inherited bleeding disorders.
Topics: Animals; Clinical Trials as Topic; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Hemophilia A; Humans
PubMed: 31808868
DOI: 10.1182/hematology.2019000007 -
Hematology. American Society of... Dec 2022The cloning of the factor VIII (FVIII) and factor IX (FIX) genes in the 1980s has led to a succession of clinical advances starting with the advent of molecular... (Review)
Review
The cloning of the factor VIII (FVIII) and factor IX (FIX) genes in the 1980s has led to a succession of clinical advances starting with the advent of molecular diagnostic for hemophilia, followed by the development of recombinant clotting factor replacement therapy. Now gene therapy beckons on the back of decades of research that has brought us to the final stages of the approval of 2 products in Europe and United States, thus heralding a new era in the treatment of the hemophilias. Valoctocogene roxaparvovec, the first gene therapy for treatment of hemophilia A, has been granted conditional marketing authorization in Europe. Another approach (etranacogene dezaparvovec, AMT-061) for hemophilia B is also under review by regulators. There are several other gene therapy approaches in earlier stages of development. These approaches entail a one-off infusion of a genetically modified adeno-associated virus (AAV) engineered to deliver either the FVIII or FIX gene to the liver, leading to the continuous endogenous synthesis and secretion of the missing coagulation factor into the circulation by the hepatocytes, thus preventing or reducing bleeding episodes. Ongoing observations show sustained clinical benefit of gene therapy for >5 years following a single administration of an AAV vector without long-lasting or late toxicities. An asymptomatic, self-limiting, immune-mediated rise in alanine aminotransferase is commonly observed within the first 12 months after gene transfer that has the potential to eliminate the transduced hepatocytes in the absence of treatment with immunosuppressive agents such as corticosteroids. The current state of this exciting and rapidly evolving field, as well as the challenges that need to be overcome for the widespread adaptation of this new treatment paradigm, is the subject of this review.
Topics: Humans; Genetic Vectors; Hemophilia A; Hemophilia B; Genetic Therapy; Factor VIII; Factor IX; Dependovirus; Blood Coagulation Factors
PubMed: 36485127
DOI: 10.1182/hematology.2022000388 -
American Journal of Hematology Jul 2017Acquired hemophilia A (AHA) is a rare disease resulting from autoantibodies (inhibitors) against endogenous factor VIII (FVIII) that leads to bleeding, which is often... (Meta-Analysis)
Meta-Analysis Review
Acquired hemophilia A (AHA) is a rare disease resulting from autoantibodies (inhibitors) against endogenous factor VIII (FVIII) that leads to bleeding, which is often spontaneous and severe. AHA tends to occur in elderly patients with comorbidities and is associated with high mortality risk from underlying comorbidities, bleeding, or treatment complications. Treatment, which consists of hemostatic management and eradication of the inhibitors, can be challenging to manage. Few data are available to guide the management of AHA-related bleeding and eradication of the disease-causing antibodies. Endorsed by the Hemostasis and Thrombosis Research Society of North America, an international panel of experts in AHA analyzed key questions, reviewed the literature, weighed the evidence and formed a consensus to update existing guidelines. AHA is likely underdiagnosed and misdiagnosed in real-world clinical practice. Recommendations for the management of AHA are summarized here based on the available data, integrated with the clinical experience of panel participants.
Topics: Combined Modality Therapy; Diagnosis, Differential; Disease Management; Female; Hemophilia A; Hemorrhage; Humans; Isoantibodies; Male; Mortality; Phenotype; Pregnancy
PubMed: 28470674
DOI: 10.1002/ajh.24777 -
European Journal of Haematology Jun 2021To establish clear priorities for the care of patients with acquired hemophilia A (AHA) by proposing 10 key principles of practical, holistic AHA management. (Review)
Review
OBJECTIVE
To establish clear priorities for the care of patients with acquired hemophilia A (AHA) by proposing 10 key principles of practical, holistic AHA management.
METHOD
These principles were developed by the Zürich Haemophilia Forum, an expert panel of European hemophilia specialists comprising physicians and nursing and laboratory specialists.
RESULTS
The 10 proposed principles for AHA care are as follows: (a) Improving initial diagnosis of AHA; (b) Differential diagnosis of AHA: laboratory assessment of patients with unusual bleeding; (c) Effective communication between laboratories, physicians, and specialists; (d) Improving clinical care: networking between healthcare professionals in the treating hospital and specialist hemophilia centers; (e) Comprehensive assessment of bleeding; (f) Appropriate use of bypassing agents; (g) Long-term follow-up and monitoring for efficacy and safety of immunosuppressive treatment; (h) Inpatient/outpatient settings; (i) Access to innovative and disruptive treatments; (j) Promotion of international collaborative research.
CONCLUSION
The proposed principles for holistic AHA care aim to ensure swift diagnosis and optimal patient management. Key to achieving this goal is training for healthcare personnel in non-specialist hospitals and collaboration between different specialists. We hope these principles will increase awareness of AHA in the wider medical community and catalyze efforts toward improving its practical, multidisciplinary management.
Topics: Delivery of Health Care; Health Personnel; Hemophilia A; Humans
PubMed: 33527471
DOI: 10.1111/ejh.13592 -
Journal of Thrombosis and Haemostasis :... Dec 2018
Topics: Consensus; Hematologic Tests; Hemophilia A; Hemostasis; Hemostatics; Humans; Predictive Value of Tests; Prognosis; Terminology as Topic
PubMed: 30430726
DOI: 10.1111/jth.14315 -
Blood Reviews May 2019Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is... (Review)
Review
Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is effective for treatment of bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with haemophilia A. Despite long experience in treating haemophilia A, we are only beginning to understand the functions of FVIII beyond its established role as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. Here, we review the current role of FVIII coagulant (FVIII:C) in haemophilia A management and emerging evidence for the role of FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health. For instance, supraphysiological FVIII levels are a risk factor for venous thromboembolism. von Willebrand factor (VWF), which forms a non-covalent complex with circulating FVIII, is an established marker and regulator of angiogenesis. In a mouse model of haemophilia, treatment with FVIII decreased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), a marker for bone turnover. Longitudinal follow-up data in people with haemophilia A are needed to confirm and extend these observations.
Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Brain; Comorbidity; Factor VIII; Hemophilia A; Hemorrhage; Hemostasis; Humans; Mutation; Thrombin
PubMed: 30922616
DOI: 10.1016/j.blre.2019.03.002 -
Human Gene Therapy Apr 2022Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA)....
Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa ( = 56), 46.2% in Russia ( = 91), 40% in Italy ( = 20), 37.2% in France ( = 86), 26.8% in the United States ( = 71), 26.9% in Brazil ( = 26), 28.1% in Germany ( = 89), 29.8% in Japan ( = 84), and 5.9% in the United Kingdom ( = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.
Topics: Antibodies, Neutralizing; Antibodies, Viral; Dependovirus; Genetic Vectors; Hemophilia A; Humans; Prospective Studies; Seroepidemiologic Studies; Serogroup
PubMed: 35156839
DOI: 10.1089/hum.2021.287 -
Stomatologija 2014The aim was to overview the oral health aspects in hemophilia patients. (Review)
Review
OBJECTIVE
The aim was to overview the oral health aspects in hemophilia patients.
MATERIAL AND METHODS
An electronic search of Medline (Pub Med), Cochrane, SSCI (Social Citation Index), SCI (Science Citation Index) databases from 1982 to the present, using the following search words: hemophilia, oral health, dental caries, dental caries prevalence, gingivitis, periodontitis, primary dentition, permanent dentition, dental treatment and review, was performed. The search yielded 196 titles and abstracts on chosen words. All articles were full-text reviewed and 40 of publications were included.
RESULTS
Nowadays coagulation factor abnormalities are the most common of inherited bleeding disorders, but occur much less frequently approximating 10000-50000 male births than acquired coagulation defects. Von Willebrand disease, Hemophilia A and Hemophilia B account for 95-97% of all coagulation deficiencies. Hemophilias A and B are subdivided according to the factor's activity levels in the blood: mild, moderate or severe. The two main oral diseases affecting patients with hemophilia are the same as for the rest of population, i.e. dental caries and gingivitis/periodontitis. Only a few studies concerning oral health aspects in hemophilia patients were carried out. Some controversy exists concerning caries prevalence in both primary and permanent dentitions in children with hemophilia. People with congenital hemorrhagic diatheses constitute a very small proportion of the total population. Due to that fact treatment of such patients becomes a challenge to the most of dentists due to the fact that most of them have no experience in dealing with dental problems in such patients.
CONCLUSION
There is a lack of epidemiological studies in oral health status of hemophilia patient.
Topics: Dental Care for Chronically Ill; Hemophilia A; Humans; Mouth Diseases; Oral Health; Tooth Diseases
PubMed: 25896036
DOI: No ID Found -
British Journal of Haematology Jan 2023Marstacimab, an investigational human monoclonal antibody targeting tissue factor pathway inhibitor, demonstrated safety and efficacy in preventing bleeding episodes in...
Marstacimab, an investigational human monoclonal antibody targeting tissue factor pathway inhibitor, demonstrated safety and efficacy in preventing bleeding episodes in patients with haemophilia. This multicentre, open-label study investigated safety, tolerability, and efficacy of long-term weekly prophylactic marstacimab treatment in participants with severe haemophilia A and B, with or without inhibitors. Adult participants were enrolled from a previous phase Ib/II study or de novo and assigned to one of two subcutaneous (SC) marstacimab doses: once-weekly 300 mg or a 300-mg loading dose followed by once-weekly 150-mg doses, for up to 365 days. Study end-points included safety assessments and annualised bleeding rates (ABRs). Of 20 enrolled participants, 18 completed the study. Overall, 70% of participants had treatment-emergent adverse events, including injection site reactions, injection site haematoma, and haemarthrosis. No treatment-related serious adverse events or thrombotic events occurred. Across all dose cohorts, mean and median on-study ABRs ranged from 0 to 3.6 and 0 to 2.5 bleeding episodes/participant/year respectively, demonstrating comparable efficacy to that observed in the short-term parent study. No treatment-induced anti-drug antibodies were detected. Once-weekly SC marstacimab prophylaxis was well tolerated, with an acceptable safety profile, and maintained long-term efficacy up to 365 days. (Clinicaltrials.gov identifier, NCT03363321).
Topics: Adult; Humans; Hemophilia A; Antibodies, Monoclonal, Humanized; Hemorrhage; Hemarthrosis
PubMed: 36220152
DOI: 10.1111/bjh.18495 -
Ugeskrift For Laeger Dec 2022Acquired haemophilia A (AHA) is a rare autoimmune disorder resulting from antibodies against coagulation factor VIII. AHA causes severe, unexpected bleeding which may be...
Acquired haemophilia A (AHA) is a rare autoimmune disorder resulting from antibodies against coagulation factor VIII. AHA causes severe, unexpected bleeding which may be life-threatening and should be considered when a patient with no previous history of bleeding presents with spontaneous bleeding and a prolonged APTT. This case report describes onset of AHA of a 75-year-old male who was admitted to Vejle Hospital with acute need for intubation due to breathing and swallowing problems caused by supraglottic haematoma. The case was complicated by anticoagulant treatment with rivaroxaban.
Topics: Male; Humans; Aged; Hemophilia A; Hematoma; Autoimmune Diseases
PubMed: 36621876
DOI: No ID Found