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Special Issue "Outstanding Advances in Hemophilia Therapies"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383).

Deadline for manuscript submissions: closed (31 January 2017)

Special Issue Editors

Guest Editor
Dr. Massimo Morfini

Italian Association of Haemophilia Centres (AICE), Italy
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Interests: hemophilic arthropathy; myeloprolipherative disorders; pharmacokinetics in hemophiliacs; hepatitis safety of clotting factor concentrates; human parvovirus B19 in hemophiliacs; bleeding disorders; FVIII/IX inhibitors
Guest Editor
Prof. Giovanni Di Minno

Department of Clinical Medicine and Surgery, Regional Reference Center for Coagulation Disorders, Federico II University, Naples, Italy
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Special Issue Information

Dear Colleague,

Since 2010 a multitude of new recombinant clotting factor concentrates (CFC) have been produced by various pharmaceutical companies. In order to improve the biocompatibility of CFC with the recipients, human embryonic kidney (HEK) cells have been transfected with FVIII or FIX genes and even with Fc of IgG. Another protein-fused FIX concentrate derived from Albumin and FIX co-expression. The cellular recycling mechanism of Albumin and Fc by means of FcnR enabled a half-life increase of both rFIX-Albumin and FIX-Fc fused. Other substantial results have been achieved by Pegylation of rFVIII/IX molecules or by modification of the FVIII molecule in order to increase the affinity with the carrier, the VWF. Also, improvements in the immunoaffinity purification procedures determined more homogeneous and probably less immunogenic FVIII concentrates. The new Extended Half-Life (EHL) CFC will address the issue of reducing the interval between bolus administration during prophylaxis, i.e., the venous access which is the biggest obstacle to implementation of prophylaxis in children. On the other hand, the EHL CFC pose some other issues: first of all, their immunogenicity, with the new fused or PEGylated proteins, which is completely exogenous for the recipients. The outcomes of the randomized clinical trial, SIPPET, published recently in N. Engl. J. Med., decisively established that old generation rFVIII concentrates are significantly more immunogenic than the plasma derived concentrates. Studies of EHL CFC on previously untreated patients (PUPs), requested by EMA, are now in progress and we hope their incidence proves lower than that scored by SIPPET: 44.5% of PUPs seroconverted against rFVIII. The efficacy of EHL CFC as shown in phase III studies to date seems to be very good: The annualized bleeding rate (ABR) decreased dramatically during prophylaxis with respect to on demand treatment. Pharmacokinetics of EHL CFC, especially of new rFIX concentrates, improved significantly. A single dose PK study of current vs. the new EHL CFC is recommended in order to verify the true advantages of switching to the new concentrates, as the variability of PK outcomes is very large among hemophilia patients. The PK characteristics of EHL CFC will also determine the cost of therapy. Pharmacoeconomics will further take into account the improved PK and efficacy. Probably, issues of immunotolerance induction (ITI) will be better addressed in the future, as well as primary, secondary and tertiary prophylaxis of hemophilic arthropathy. The mechanism of physiopathology of arthropathy is now better known due to the introduction of humoral biomarkers of inflammation. Early detection of arthropathy is now possible by prospective evaluation of joints through ultrasonography. Recent progress in joint replacement by means of modern prostheses allows a better quality of life in elder hemophilia patients with severe joint damage. Also rare diseases, such as FVII deficiency, type III VWD, and Glanzmann’s disease have recently received much more attention and ministrations than in the past. Most recently, new clinical trials started on gene therapy of both hemophilia A and B and we hope that the success of previous pivotal trials carried out in UK, will be validated worldwide.

Dr. Massimo Morfin
Prof. Giovanni Di Minn
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 650 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Extended half-life concentrates
  • Albumin-fused rFIX, Fc-fused rFVIII
  • Fc-fused rFIX
  • PEGylated rFIX/rFVIII
  • rFVIII single chain
  • Pharmacokinetics
  • ITI
  • Prophylaxis
  • FVII deficiency
  • Glanzmann’s thrombasthenia
  • Hemophilic arthropathy
  • Total joint replacement
  • Ultrasonography
  • Gene therapy

Published Papers (10 papers)

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Research

Jump to: Review

Open AccessArticle Hip Arthropathy in Haemophilia
J. Clin. Med. 2017, 6(4), 44; doi:10.3390/jcm6040044
Received: 26 January 2017 / Revised: 28 March 2017 / Accepted: 3 April 2017 / Published: 8 April 2017
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Abstract
Hip arthropathy in haemophilic patients is disabling for hip and other common target joints. Even if bleedings in the hip are not frequent, femoroacetabular alterations may affect the functional ability of patients at a very young age. A haematologic prophylaxis combined with an
[...] Read more.
Hip arthropathy in haemophilic patients is disabling for hip and other common target joints. Even if bleedings in the hip are not frequent, femoroacetabular alterations may affect the functional ability of patients at a very young age. A haematologic prophylaxis combined with an adequate lifestyle and regular and low-traumatic physical activity are the keys to preventing such arthropathy. In the early stages of arthropathy, anti-inflammatory drugs and physical therapy may be sufficient to limit its progression. In cases of recurrent symptoms, viscosupplementation with hyaluronic acid, and chemical synoviorthesis are useful options. In more advanced stages, hip arthroscopy may be treated by synovectomy or loose body removal. For late stages, total hip arthroplasty (THA) is mandatory. Until a few decades ago, the clinical outcomes after hip arthroplasty were variable, due to the different management of patients and the use of old generation implants and couplings. In the last decade, the introduction of the multidisciplinary management and the use of modern cementless implants with high performing materials and less invasive surgical techniques have dramatically improved the functional results. Nowadays, as is the case for other target joints, the purpose of the management in haemophilia centers is the early detection of any hip alterations—by clinical and ultrasound (US) evaluations of patients in childhood—to reveal any early articular damage and to provide adequate treatment in case of symptoms. The present paper represents an updated review of the several approaches to hip arthropathy in haemophilia. Full article
(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
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Open AccessFeature PaperArticle Italian Registry of Congenital Bleeding Disorders
J. Clin. Med. 2017, 6(3), 0034; doi:10.3390/jcm6030034
Received: 28 January 2017 / Revised: 14 March 2017 / Accepted: 15 March 2017 / Published: 19 March 2017
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Abstract
In Italy, the surveillance of people with bleeding disorders is based on the National Registry of Congenital Coagulopathies (NRCC) managed by the Italian National Institute of Health (Istituto Superiore di Sanità). The NRCC collects epidemiological and therapeutic data from the 54 Hemophilia Treatment
[...] Read more.
In Italy, the surveillance of people with bleeding disorders is based on the National Registry of Congenital Coagulopathies (NRCC) managed by the Italian National Institute of Health (Istituto Superiore di Sanità). The NRCC collects epidemiological and therapeutic data from the 54 Hemophilia Treatment Centers, members of the Italian Association of Hemophilia Centres (AICE). The number of people identified with bleeding disorders has increased over the years, with the number rising from approx. 7000 in 2000 to over 11,000 in 2015. The NRCC includes 4020 patients with hemophilia A and 859 patients with hemophilia B. The prevalence of the rare type 3 vWD is 0.20/100,000 inhabitants. Less common congenital bleeding disorders include the following deficiencies: Factor I (fibrinogen), Factor II (prothrombin), Factor V, Factor VII, Factor X, Factor XI and Factor XIII, which affect 1953 patients. Hepatitis C Virus (HCV) infection affects 1561 patients, more than 200 of whom have two infections (HCV + HIV). Estimated hemophilia-related drug consumption in 2015 was approx. 550 million IU of FVIII for hemophilia A patients and approx. 70 million IU of FIX for hemophilia B patients. The NRCC, with its bleeding disorder data set, is a tool that can provide answers to fundamental questions in public health, monitoring care provision and drug treatment, as well as facilitating clinical and epidemiological research.
Full article
(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
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Review

Jump to: Research

Open AccessFeature PaperReview Ultrasound for Early Detection of Joint Disease in Patients with Hemophilic Arthropathy
J. Clin. Med. 2017, 6(8), 77; doi:10.3390/jcm6080077
Received: 17 May 2017 / Revised: 12 July 2017 / Accepted: 24 July 2017 / Published: 31 July 2017
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Abstract
Joint bleeding represents the most commonly reported type of hemorrhage in patients affected by hemophilia. Although the widespread use of prophylaxis has been able to significantly reduce the onset of arthropathy, it has been shown that a non-negligible percentage of patients develop degenerative
[...] Read more.
Joint bleeding represents the most commonly reported type of hemorrhage in patients affected by hemophilia. Although the widespread use of prophylaxis has been able to significantly reduce the onset of arthropathy, it has been shown that a non-negligible percentage of patients develop degenerative changes in their joints despite this type of treatment. Thus, periodic monitoring of the joint status in hemophilia patients has been recommended to identify early arthropathic changes and prevent the development or progression of hemophilic arthropathy. Ultrasound (US) has proven able to detect and quantify the most relevant biomarkers of disease activity (i.e., joint effusion and synovial hypertrophy) and degenerative damages (i.e., osteo-chondral changes) by means of scoring scales of increasing disease severity. In the present review, we have detailed major literature evidence about the use of US to assess joint status in hemophilia patients, focusing on signs of disease activity and degenerative damages. In particular, we have discussed recent evidence about “point-of-care” use patients with hemophilia. Full article
(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
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Open AccessReview Pathophysiology of Hemophilic Arthropathy
J. Clin. Med. 2017, 6(7), 63; doi:10.3390/jcm6070063
Received: 4 March 2017 / Revised: 16 June 2017 / Accepted: 22 June 2017 / Published: 25 June 2017
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Abstract
Spontaneous joint bleeding and repeated hemarthroses lead to hemophilic arthropathy—a debilitating disease with a significant negative impact on mobility and quality of life. Iron, cytokines, and angiogenic growth factors play a pivotal role in the onset of the inflammatory process that involves the
[...] Read more.
Spontaneous joint bleeding and repeated hemarthroses lead to hemophilic arthropathy—a debilitating disease with a significant negative impact on mobility and quality of life. Iron, cytokines, and angiogenic growth factors play a pivotal role in the onset of the inflammatory process that involves the synovial tissue, articular cartilage, and subchondral bone, with early damages and molecular changes determining the perpetuation of a chronic inflammatory condition. Synovitis is one of the earliest complications of hemarthrosis, and is characterized by synovial hypertrophy, migration of inflammatory cells, and a high degree of neo-angiogenesis with subsequent bleeding. The pathogenic mechanisms and molecular pathways by which blood in the joint cavity causes articular cartilage and subchondral bone destruction have yet to be fully elucidated. Both cytokines and matrix metalloproteinases and hydroxyl radicals may induce chondrocyte apoptosis. Members of the tumor necrosis factor receptor superfamily (such as the molecular triad: osteoprotegerin—OPG; receptor activator of nuclear factor κB—RANK; RANK ligand—RANKL) seem instead to play a major role in the inflammatory process. These pathogenic processes interact with each other and ultimately lead to a fibrotic joint and the disabling condition characteristic of hemophilic arthropathy. Full article
(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
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Open AccessFeature PaperReview Hemophilia Care in the Pediatric Age
J. Clin. Med. 2017, 6(5), 54; doi:10.3390/jcm6050054
Received: 31 January 2017 / Revised: 12 May 2017 / Accepted: 16 May 2017 / Published: 19 May 2017
Cited by 1 | PDF Full-text (239 KB) | HTML Full-text | XML Full-text
Abstract
Hemophilia is the most common of the severe bleeding disorders and if not properly managed since early infancy can lead to chronic disease and lifelong disabilities. However, it enjoys the most efficacious and safe treatment among the most prevalent monogenic disorders. Hemophilia should
[...] Read more.
Hemophilia is the most common of the severe bleeding disorders and if not properly managed since early infancy can lead to chronic disease and lifelong disabilities. However, it enjoys the most efficacious and safe treatment among the most prevalent monogenic disorders. Hemophilia should be considered in the neonatal period in the case of unusual bleeding or in the case of positive family history. Later, hemophilia should be suspected mainly in males because of abnormal bruising/bleeding or unusual bleeding following invasive procedures—for example, tonsillectomy or circumcision. Prophylactic treatment that is started early with clotting-factor concentrates has been shown to prevent hemophilic arthropathy and is, therefore, the gold standard of care for hemophilia A and B in most countries with adequate resources. Central venous access catheters and arterovenous fistulas play an important role in the management of hemophilia children requiring repeated and/or urgent administration of coagulation factor concentrates. During childhood and adolescence, personalized treatment strategies that suit the patient and his lifestyle are essential to ensure optimal outcomes. Physical activity is important and can contribute to better coordination, endurance, flexibility and strength. The present article focuses also on questions frequently posed to pediatric hematologists like vaccinations, day-care/school access and dental care. Full article
(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
Open AccessFeature PaperReview Treatment and Prevention of Bleeds in Haemophilia Patients with Inhibitors to Factor VIII/IX
J. Clin. Med. 2017, 6(4), 46; doi:10.3390/jcm6040046
Received: 28 January 2017 / Revised: 6 April 2017 / Accepted: 10 April 2017 / Published: 17 April 2017
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Abstract
The development of alloantibodies neutralising therapeutically administered factor (F) VIII/IX (inhibitors) is currently the most severe complication of the treatment of haemophilia. When persistent and at a high titre, inhibitors preclude the standard replacement treatment with FVIII/FIX concentrates, making patients’ management challenging. Indeed,
[...] Read more.
The development of alloantibodies neutralising therapeutically administered factor (F) VIII/IX (inhibitors) is currently the most severe complication of the treatment of haemophilia. When persistent and at a high titre, inhibitors preclude the standard replacement treatment with FVIII/FIX concentrates, making patients’ management challenging. Indeed, the efficacy of bypassing agents, i.e., activated prothrombin complex concentrates (aPCC) and recombinant activated factor VII (rFVIIa), needed to overcome the haemostatic interference of the inhibitor, is not comparable to that of factor concentrates. In addition, the therapeutical response is unpredictable, with a relevant inter-individual and even intra-individual variability, and no laboratory assay is validated to monitor the efficacy and safety of the treatment. As a result, inhibitor patients have a worse joint status and quality of life compared to inhibitor-free subjects and the eradication of the inhibitor by immune tolerance induction is the preeminent therapeutic goal, particularly in children. However, over the last decades, treatment with bypassing agents has been optimised, allowing home treatment and the individualisation of regimens aimed at improving clinical outcomes. In this respect, a growing body of evidence supports the efficacy of prophylaxis with both bypassing agents in reducing bleeding rates and improving the quality of life, although the impact on long-term outcomes (in particular on preventing/reducing joint deterioration) is still unknown. This review offers an update on the current knowledge and practice of the use of bypassing agents in haemophiliacs with inhibitors, as well as on debated issues and unmet needs in this challenging setting. Full article
(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
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Open AccessFeature PaperReview Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders
J. Clin. Med. 2017, 6(4), 45; doi:10.3390/jcm6040045
Received: 23 February 2017 / Revised: 4 April 2017 / Accepted: 5 April 2017 / Published: 10 April 2017
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Abstract
Along with haemophilia A and B, von Willebrand disease (VWD) and rare bleeding disorders (RBDs) cover all inherited bleeding disorders of coagulation. Bleeding tendency, which can range from extremely severe to mild, is the common symptom. VWD, due to a deficiency and/or abnormality
[...] Read more.
Along with haemophilia A and B, von Willebrand disease (VWD) and rare bleeding disorders (RBDs) cover all inherited bleeding disorders of coagulation. Bleeding tendency, which can range from extremely severe to mild, is the common symptom. VWD, due to a deficiency and/or abnormality of von Willebrand factor (VWF), represents the most frequent bleeding disorder, mostly inherited as an autosomal dominant trait. The diagnosis may be difficult, based on a bleeding history and different diagnostic assays, which evaluate the pleiotropic functions of VWF. Different treatment options are available for optimal management of bleeding and their prevention, and long-term outcomes are generally good. RBDs are autosomal recessive disorders caused by a deficiency of any other clotting factor, apart from factor XII, and cover roughly 5% of all bleeding disorders. The prevalence of the severe forms can range from 1 case in 500,000 up to 1 in 2–3 million, according to the defect. Diagnosis is based on bleeding history, coagulation screening tests and specific factor assays. A crucial problem in RBDs diagnosis is represented by the non-linear relationship between clinical bleeding severity and residual clotting levels; genetic diagnosis may help in understanding the phenotype. Replacement therapies are differently available for patients with RBDs, allowing the successful treatment of the vast majority of bleeding symptoms. Full article
(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
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Open AccessFeature PaperReview Factor VII Deficiency: Clinical Phenotype, Genotype and Therapy
J. Clin. Med. 2017, 6(4), 38; doi:10.3390/jcm6040038
Received: 30 January 2017 / Revised: 12 March 2017 / Accepted: 23 March 2017 / Published: 28 March 2017
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Abstract
Factor VII deficiency is the most common among rare inherited autosomal recessive bleeding disorders, and is a chameleon disease due to the lack of a direct correlation between plasma levels of coagulation Factor VII and bleeding manifestations. Clinical phenotypes range from asymptomatic condition—even
[...] Read more.
Factor VII deficiency is the most common among rare inherited autosomal recessive bleeding disorders, and is a chameleon disease due to the lack of a direct correlation between plasma levels of coagulation Factor VII and bleeding manifestations. Clinical phenotypes range from asymptomatic condition—even in homozygous subjects—to severe life-threatening bleedings (central nervous system, gastrointestinal bleeding). Prediction of bleeding risk is thus based on multiple parameters that challenge disease management. Spontaneous or surgical bleedings require accurate treatment schedules, and patients at high risk of severe hemorrhages may need prophylaxis from childhood onwards. The aim of the current review is to depict an updated summary of clinical phenotype, laboratory diagnosis, and treatment of inherited Factor VII deficiency. Full article
(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
Open AccessFeature PaperReview Outcome of Clinical Trials with New Extended Half-Life FVIII/IX Concentrates
J. Clin. Med. 2017, 6(4), 39; doi:10.3390/jcm6040039
Received: 29 January 2017 / Revised: 9 March 2017 / Accepted: 11 March 2017 / Published: 28 March 2017
Cited by 1 | PDF Full-text (239 KB) | HTML Full-text | XML Full-text
Abstract
The development of a new generation of coagulation factors with improved pharmacokinetic profile will change the paradigm of treatment of persons with hemophilia (PWH). The standard treatment in PWH is represented by regular long-term prophylaxis that, given intravenously twice or thrice weekly, is
[...] Read more.
The development of a new generation of coagulation factors with improved pharmacokinetic profile will change the paradigm of treatment of persons with hemophilia (PWH). The standard treatment in PWH is represented by regular long-term prophylaxis that, given intravenously twice or thrice weekly, is associated with a not-negligible burden on patients’ quality of life. The availability of drugs with improved pharmacokinetic profile may improve prophylaxis feasibility and protection against bleeding episodes. This article summarizes the main results obtained from clinical trials with modified factor VIII (FVIII) and factor IX (FIX) molecules. Published literature on new molecules for replacement treatment in hemophilia A and B was retrieved using PubMed search, and all ongoing clinical trials have been researched via www.clinicaltrials.gov. Such new molecules are usually engineered to have a longer plasma half-life than that which has been obtained by chemical modification (i.e., conjugation with polyethylene glycol, PEG) or by creating recombinant fusion proteins. Results from phase I/III studies in previously treated adults and children are now available for the vast majority of new products, including the results of their use in a surgical setting. On the contrary, trials involving previously untreated patients are still ongoing for all and results not yet available. Full article
(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
Open AccessFeature PaperReview The History of Clotting Factor Concentrates Pharmacokinetics
J. Clin. Med. 2017, 6(3), 35; doi:10.3390/jcm6030035
Received: 29 January 2017 / Revised: 3 February 2017 / Accepted: 7 March 2017 / Published: 20 March 2017
Cited by 1 | PDF Full-text (253 KB) | HTML Full-text | XML Full-text
Abstract
Clotting factor concentrates (CFCs) underwent tremendous modifications during the last forty years. Plasma-derived concentrates made the replacement therapy feasible not only in the hospital but also at patients’ home by on-demand or prophylactic regimen. Virucidal methods, implemented soon after hepatitis and AIDS outbreak,
[...] Read more.
Clotting factor concentrates (CFCs) underwent tremendous modifications during the last forty years. Plasma-derived concentrates made the replacement therapy feasible not only in the hospital but also at patients’ home by on-demand or prophylactic regimen. Virucidal methods, implemented soon after hepatitis and AIDS outbreak, and purification by Mabs made the plasma-derived concentrates safer and purer. CFCs were considered equivalent to the other drugs and general rules and methods of pharmacokinetics (PK) were applied to their study. After the first attempts by graphical methods and calculation of In Vivo Recovery, compartment and non-compartment methods were applied also to the study of PK of CFCs. The bioequivalence of the new concentrates produced by means of recombinant DNA biotechnology was evaluated in head-to-head PK studies. Since the beginning, the large inter-patient variability of dose/response of replacement therapy was realized. PK allowed tailoring haemophilia therapy and PK driven prophylaxis resulted more cost effective. Unfortunately, the need of several blood samples and logistic difficulties made the PK studies very demanding. Recently, population PK (PopPK) has been applied to the prediction of CFCs dosing by Bayesian methodology. By PopPK also sparse data may allow evaluating the appropriateness of replacement therapy. Full article
(This article belongs to the Special Issue Outstanding Advances in Hemophilia Therapies)
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