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1.
Real-world case series and summary of current literature of infants and toddlers with severe hemophilia A with inhibitor on prophylaxis with emicizumab.
Garcia, J, Zia, A
Pediatric blood & cancer. 2021;(5):e28942
Abstract
Emicizumab is a recombinant, humanized, and a bispecific monoclonal antibody that bridges activated factor (F) IX and FX in place of FVIII to restore hemostasis in persons with hemophilia A (PHA). Data on the efficacy and safety of emicizumab in young children is limited. Immunologic naivety, physiologically decreased production of vitamin K dependent proteins, specifically FIX, and enhanced clearance of emicizumab in infants may support decreased emicizumab effectiveness. We report on the facilitation of care rendered by using emicizumab in young PHA with inhibitors and extend data on the efficacy and safety in PHA < 3 years.
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2.
Inhibition of Fenton reaction is a novel mechanism to explain the therapeutic effect of intra-articular injection of PRP in patients with chronic haemophilic synovitis.
Caviglia, H, Daffunchio, C, Galatro, G, Cambiaggi, G, Oneto, P, Douglas Price, AL, Landro, ME, Etulain, J
Haemophilia : the official journal of the World Federation of Hemophilia. 2020;(4):e187-e193
Abstract
INTRODUCTION AND AIM Haemarthroses cause major morbidity in haemophilia resulting in chronic haemophilic synovitis (CHS) and arthropathy. Oxidation of haemoglobin-coupled iron released in synovium after haemolysis induces chondrocytes death and cartilage damage, allowing postulate using iron-chelating drugs as potential therapeutic tool for haemophilic joint damage. Considering that albumin, the most abundant plasma protein, is a physiologic iron chelator, we aim to demonstrate that impediment of haemoglobin oxidation is exerted by plasma as a mechanism involved in the therapeutic effect of intra-articular injection of platelet-rich plasma in CHS. METHODS Oxidation of haemoglobin (Hb) to methaemoglobin (MeHb) through Fenton reaction was induced in vitro by addition of potassium ferricyanide in the presence or absence of peripheral blood-derived platelets-rich or platelets-poor plasma (PRP/PPP) or albumin. The relevance of in vitro findings was analysed in synovial fluid (SF) samples from one patient with CHS obtained before and after 6 months of PRP intra-articular injection. RESULTS MeHb formation was completely impaired either by of PPP, PRP or albumin indicating that PRP exerts an anti-oxidative effect, probably due by plasma albumin. Analysis of SF samples revealed the presence of MeHb levels and haemosiderin-laden macrophages in SF obtained before PRP treatment. Reduction of synovial MeHb, normalization of cellular composition and improvement of health joint haemophilic score, pain and bleeding episodes were registered after 6 months of PRP intra-articular injection. CONCLUSION Inhibition of Fenton reaction and the consequent normalization of joint cellular composition is a noncanonical mechanism underlying the therapeutic effect of PRP intra-articular injection in CHS.
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3.
Impact of Prophylaxis on Bone Mineral Metabolism in Children With Hemophilia.
Culha, V, Akpinar Tekgündüz, S, Yarali, HN, Tunç, B, Özbek, NY
Journal of pediatric hematology/oncology. 2019;(2):121-123
Abstract
In this study, we aimed to investigate changes in calcium (Ca) metabolism in hemophilia patients (PWH). We also aimed to investigate the importance of diagnosis and treatment of factors impairing calcium metabolism and the significance of early diagnosis and prophylaxis with respect to these subjects. For all patients, serum calcium, phosphorus, alkaline phosphatase, 25 hydroxy vitamin D (25-OHD), parathormone (PTH), and calcitonin levels were evaluated. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry. Low BMD scores and 25-OHD deficiency were observed in 29 (74.4%) and 34 (87.2%) patients, respectively. Prophylaxis of PWH did not differ significantly in terms of 25-OHD levels and BMD scores. Patients in the prophylaxis group had significantly higher PTH levels (P=0.042). A negative correlation was found between PTH measurements and Z-score (P=0.008). In summary, our findings, with a small number of PWH in our study group, suggest that biochemical markers of bone turnover may be used to detect bone loss. Follow-up through annual BMD measurements coupled with appropriate exercise programs could be recommended.
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4.
Acquired haemophilia A in a patient with breast cancer and lung carcinoma: a case report and literature review.
Biesheuvel, V, Hiddema, SM, Levenga, H, Eikenboom, J, van der Deure, WM
The Netherlands journal of medicine. 2019;(4):153-155
Abstract
Acquired haemophilia A is a rare disorder caused by spontaneous formation of auto-antibodies (inhibitors) against coagulation factor VIII. This can lead tolife-threatening haemorrhages. Six to twenty-two percent of patients with acquired haemophilia have an underlying malignancy. We describe a 69-year-old woman with metastatic breast cancer and non-small cell lung carcinoma who presented at the emergency room with spontaneous bruising, and who was using a vitamin K antagonist. She had a prolonged activated partial thromboplastin time (aPTT) due to a coagulation factor VIII deficiency caused by factor VIII antibodies. She was treated with prednisone and cyclophosphamide.
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5.
Hemizygous F8 p.G201E mutation identified in a Chinese family with haemophilia A.
Wang, P, Yuan, L, Chen, H, Xu, H, Yang, Z, Deng, S, Deng, H
Journal of the Chinese Medical Association : JCMA. 2019;(1):25-29
Abstract
BACKGROUND Haemophilia A (HA), inherited via an X-linked recessive pattern, is the most common severe lifelong bleeding disorder caused by mutations in the coagulation factor VIII gene (F8). It has significant socio-economic effects due to its long course of disease and high cost of care. These impacts argue for a more accurate genetic diagnosis in an increasingly complex clinical environment. METHODS A three-generation Han-Chinese family with mild HA was recruited in the study. Exome sequencing was performed in the index case to detect potential disease-causing mutations, and Sanger sequencing was applied to verify the mutation in the family. RESULTS A hemizygous c.602G > A variant in the F8 gene, leading to a single amino acid substitution at codon 201 from glycine to glutamic acid (p.G201E) within the factor VIII (FVIII) A1 domain, was identified in the HA family. This mutation detected in the proband was found in his affected sibling, while it was absent in the unaffected family member and the two hundred ethnically-matched controls. The mutation affects an evolutionary conserved residue, which may impact the tertiary structure of FVIII. CONCLUSION The study findings should provide for more dependable and precise genetic counseling which may assist in perfecting family management.
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6.
Evaluation of Bone Mineral Density in Children With Hemophilia: An Observational Case-Control Study.
Ashritha, A, Delhi Kumar, CG, Sahoo, J, Nalini, P
Journal of pediatric hematology/oncology. 2019;(7):511-514
Abstract
OBJECTIVES The objectives of this study were to study bone mineral content (BMC), bone mineral density (BMD), vitamin D level, and bone turnover markers in children with hemophilia and compare it with their normal counterparts. DESIGN This was an observational case-control study. SETTING This study was conducted in our tertiary care institute during the period spanning from September 2016 to June 2018. MATERIALS AND METHODS A total of 38 children with hemophilia 2 to 18 years of age and 38 age-matched and sex-matched healthy controls were included. Children with symptomatic hypocalcemia and those receiving drugs affecting BMC and BMD were excluded. Dual-energy x-ray absorptiometry was performed to estimate BMC and BMD. 25-Hydroxyvitamin D [25(OH)D], intact parathormone, osteocalcin, calcium, phosphate and alkaline phosphatase, and spot urine pyrilinks-D/creatinine ratio were estimated in them. RESULTS BMC and BMD in cases was lower than that in controls (P<0.05). Prevalence of low BMC was seen in 22 (58%) and low BMD in 8 (21%) of cases. All controls had normal BMC and BMD for age. The prevalence of low vitamin D level (<20 ng/mL) was seen in 36 (95%) among cases and in 25 (65%) among controls (P<0.001). Serum phosphorus was lower, and serum alkaline phosphatase was higher in cases than in controls (P<0.05). CONCLUSION BMC, BMD, and vitamin D in hemophiliacs were lower than in the general population.
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7.
Haemophilic arthropathy: A narrative review on the use of intra-articular drugs for arthritis.
Buccheri, E, Avola, M, Vitale, N, Pavone, P, Vecchio, M
Haemophilia : the official journal of the World Federation of Hemophilia. 2019;(6):919-927
Abstract
INTRODUCTION Intra-articular injections of various drugs are commonly used in patients with degenerative osteoarthritis and also in haemophilic patients. Haemophilic arthropathy is a particular type of secondary osteoarthritis (OA), but the degeneration of strong synovial, cartilaginous and subchondral constituents is provoked by the direct action of iron and blood in the joint. AIM OF THE STUDY The aim of this study is to review the literature regarding the use of various intra-articular drugs in joints affected by haemophilic arthropathy. METHODS We reviewed the data from the literature; the search was performed on three medical electronic databases (PubMed, Cochrane Library and Scopus Web of Science) by three authors (B. E., A. M. and V. N.) from 3 December 2018 till 15 December 2018. The search string was as follows: (hyaluronic acid OR viscosupplementation OR platelet-rich plasma OR corticosteroid OR mesenchymal stem cells) AND (haemophilia OR haemophilic arthropathy OR haemophilic arthritis). RESULTS Once the research was performed, a total of 300 articles were identified. 47 selected articles were analysed by the reviewers, and the eligibility of the study inclusion was assessed independently. Twelve papers were included based on clear fulfilment of the inclusion criteria. Thirty-five articles were excluded for the following reasons: no full text or accessible data for 14 of them, 15 involved surgery or rehabilitation therapy as the primary topic and 6 were systematic reviews (the main topics were beyond the haemophilic arthropathy). CONCLUSION Although the degree of scientific evidence of the publications on intra-articular injections of various drugs (hyaluronic acid, corticosteriods, PRP and MSCs) in haemophilia is very low, it seems that intra-articular injections of hyaluronic acid can relieve joint pain for months and can be repeated every 6-12 months, which is why they can be recommended. Corticosteroid injections seem to relieve joint pain for a few weeks, but their routine use is not recommended in haemophilia. The efficacy of PRP and MSCs in haemophilic arthropathy is pending confirmation, which is why they are not currently recommended.
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8.
Joint disease in haemophilia: Pathophysiology, pain and imaging.
van Vulpen, LFD, Holstein, K, Martinoli, C
Haemophilia : the official journal of the World Federation of Hemophilia. 2018;:44-49
Abstract
Haemarthroses cause major morbidity in patients with haemophilia. Blood has devastating effects on all joint components, resulting in synovitis, osteochondral degeneration and ultimately end-stage haemophilic arthropathy. Key players in this process are iron and inflammation. Preventing joint bleeds is of utmost importance to maintain joint health as targeted therapies directed against blood-induced inflammation and iron-mediated processes are lacking. Joint bleeds result in acute pain as well as chronic pain due to synovitis or arthropathy. Acute pain originates from nociceptors activated by tissue damage. In chronic inflammation, central and peripheral sensitization of nociceptors might occur resulting in chronic pain. This also triggers a series of brain disorders such as emotional fear, anxiety, mood depression and impairment of cognitive functions. Treatment of haemophilia-related pain not only consists of analgesics, but also of exercise, education and in selected cases antidepressants and anticonvulsants. For objective assessment of joint structural outcome and detecting earlier changes of haemophilic arthropathy, both ultrasound (US) and magnetic resonance (MR) imaging have shown valuable. Both can be considered equally able to reveal signs of disease activity. MR imaging is able to visualize haemosiderin deposition and is more comprehensive in depicting osteochondral changes. Disadvantages of MR imaging are the duration of the examination, evaluation of a single joint at a time, costs and may require sedation, and it may need intraarticular contrast injection to depict initial osteochondral changes with accuracy. As such, US is a more useful screening tool and can be used for repeated follow-up examinations.
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9.
A phase III clinical trial of a mixture agent of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors.
Shinkoda, Y, Shirahata, A, Fukutake, K, Takamatsu, J, Shima, M, Hanabusa, H, Mugishima, H, Takedani, H, Kawasugi, K, Taki, M, et al
Haemophilia : the official journal of the World Federation of Hemophilia. 2017;(1):59-66
Abstract
INTRODUCTION MC710, a 1:10 protein weight ratio mixture of plasma-derived activated factor VII (FVIIa) and factor X (FX), is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. We evaluated the haemostatic efficacy and safety of one to two administrations of MC710 in 21 joint, muscle, and subcutaneous bleeding episodes in 14 male patients, in a multi-centre, open-label, non-randomized clinical trial. METHODS Subjects were intravenously administered one or two doses of 60 or 120 μg kg-1 MC710 (as FVIIa) once or twice (to a maximum of 180 μg kg-1 ) over up to five bleeding episodes per subject. The haemostatic efficacy of MC710 was determined for each episode by investigator evaluation, using changes in visual analogue scale (VAS) for pain relief, and/or knee joint or muscle circumference for swelling reduction, and range of motion (ROM) for improvement of joint mobility. RESULTS In 21 treatments for bleeding episodes, 19 were rated "excellent" or "effective" 8 h after the last treatment. VAS significantly decreased over time, and ROM significantly improved over time compared with the values before treatment. One mild adverse reaction, decreased blood potassium, and two serious adverse events, both knee joint bleeding, were observed within 1 week after first administration, with no significant effect on safety. Furthermore, diagnostic markers did not show any signs of disseminated intravascular coagulation (DIC). CONCLUSION These results show that MC710 has sufficient haemostatic efficacy and safety, and can be used as a potential bypassing agent to control bleeding in haemophilia patients with inhibitors.
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10.
Refining strategies to translate genome editing to the clinic.
Cornu, TI, Mussolino, C, Cathomen, T
Nature medicine. 2017;(4):415-423
Abstract
Recent progress in developing programmable nucleases, such as zinc-finger nucleases, transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas nucleases, have paved the way for gene editing to enter clinical practice. This translation is a result of combining high nuclease activity with high specificity and successfully applying this technology in various preclinical disease models, including infectious disease, primary immunodeficiencies, hemoglobinopathies, hemophilia and muscular dystrophy. Several clinical gene-editing trials, both ex vivo and in vivo, have been initiated in the past 2 years, including studies that aim to knockout genes as well as to add therapeutic transgenes. Here we discuss the advances made in the gene-editing field in recent years, and specify priorities that need to be addressed to expand therapeutic genome editing to further disease entities.