Unresolved issues in diagnosis and management of inherited bleeding disorders in the perinatal period: A White Paper of the Perinatal Task Force of the Medical and Scientific Advisory Council of the National Hemophilia Foundation, USA

Duke University, Durham, North Carolina, United States
Haemophilia (Impact Factor: 2.6). 06/2006; 12(3):205-11. DOI: 10.1111/j.1365-2516.2006.01277.x
Source: PubMed


Haemophilia and inherited bleeding disorders in newborns and their carrier mothers pose unique challenges. The pattern of bleeding and the causes and risk factors for bleeding are decidedly different than an older child or an adult with haemophilia/inherited bleeding disorder. This document outlines the needs for further research and education, summarizes the state of the art background information and provides guidance regarding research, education and access to care issues in this population.

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Available from: Andra H James
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    • "In approximately 40% of cases of severe hemophilia, the mutation involves a large inversion that interferes with the FVIII gene, while the remaining cases typically involve point mutations, deletions, and insertions.5–7 A diagnosis of congenital hemophilia in its severe form (less than 1% of circulating FVIII) is most often made during or shortly after birth, particularly during assisted deliveries and circumcisions.8 "
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    ABSTRACT: In the past, patients with severe hemophilia have suffered a substantially reduced quality of life with frequent bleeding episodes, disabling arthropathy, and shorter life expectancy. In addition, methods of treatment and management have been costly and time-consuming, and have placed a considerable burden on patients' physical and psychological well-being. With the advent of the on-demand therapy and prophylactic treatment paradigm, patients have been able to receive care with less interruption of daily activities. Treatments may be more challenging for hemophiliacs with inhibitors to replacement factor; however, recent advances in the use of bypassing agents and immune tolerance therapy have enabled them to aggressively manage their disease while maintaining their independence. This review focuses on the challenges of treating such a severe hemophiliac through examination of the lifetime experience of a young adult male with a severe form of congenital hemophilia A. At this stage of his life, the patient has minimal disabilities and is inhibitor-free through optimal care and strong family support. His aspiration to pursue a productive life has led him to a career in medicine. After receiving his medical degree, he pursued a specialty in the treatment of hemophilia. By assisting other hemophilia patients, he exemplifies both the rewards of persevering through episodes of bleeding and other complications and the fact that disabilities can be minimized when managed meticulously and in a timely fashion to enable a productive and dignified life.
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    • "Somewhat paradoxically, it was reported that inhibitor formation was more frequent in patients that initiated IV injections of human FVIII before 6 months of age than for those that started therapy after 6 months [Lorenzo et al., 2001; van der Bom et al., 2003], which would appear to argue against using early administration of protein therapy to prevent inhibitors. However, other studies suggest that the specific hFVIII mutation and/or initiation with episodic therapy in response to bleeds rather than frequent prophylaxis may be critical [Rivard et al., 2005; Chalmers et al., 2007; Santagostino et al., 2005; Kulkarni et al., 2006]. A trial in which protein therapy is initiated with high and frequent administration of human FVIII would be difficult due to problems with IV access in newborn patients. "
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    ABSTRACT: Gene therapy could result in the permanent correction or amelioration of the clinical manifestations of many genetic diseases. However, immune responses to the therapeutic protein pose a significant hurdle for successful gene therapy. Problematic immune responses can include the development of a cytotoxic T lymphocyte (CTL) response that results in the destruction of genetically-modified cells and/or the formation of antibodies directed against the therapeutic protein. One approach to avoid an immune response is to perform gene therapy in newborns, which takes advantage of the fact that the immune system is relatively immature at birth. This approach has been highly effective in mice, and has resulted in stable expression without antibody formation for proteins that are highly immunogenic after transfer to adults. High levels of expression after neonatal gene therapy were more effective at inducing tolerance than low levels of expression in mice, which suggests that high antigen levels are more efficient at inducing tolerance. A criticism of this approach is that the murine immune system is less mature at birth than the immune systems of larger animals. Indeed, neonatal gene therapy to cats with mucopolysaccharidosis I resulted in a CTL response that destroyed expressing cells. Nevertheless, the immune system was still relatively immature, as transient administration of a single immunosuppressive agent at the time of neonatal gene therapy resulted in stable expression. Neonatal administration can reduce, but not eliminate, immune responses after gene therapy.
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    ABSTRACT: In the last few decades dramatic improvements in the management of haemophilia patients have occurred. Haemophilia has moved from a fatal or disabling disease to a hereditary disorder with available treatment and much better clinical outcomes. The safety of antihaemophilic factor concentrates has been dramatically improved and, in a multidisciplinary environment including haematologists, orthopaedic surgeons, paediatrics, infectiologists, specialised nurses and physiotherapists, complications related to haemophilia are now limited, markedly improving the quality of life of haemophiliacs. One can even think that the cure of haemophilia through gene therapy might occur in the next decades. Keeping this ultimate aim in mind, efforts at present are mainly focused on bioengineered Factor VIII/Factor IX concentrates with increased efficacy or longer half-life or decreased immunogenicity. In addition, several preclinical and clinical studies are being carried out for optimising and individually tailoring the therapeutic regimens of antihaemophilic therapies using global haemostasis tests in combination with the routine coagulation assays.
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