Biological Variation in Hemophilia

FVIII(FVIII)替代疗法是发达国家治疗先天性血友病A的主要方法。这项TRC-THD U54申请，题为血友病中的生物变异，旨在提高我们对抑制物开发和严重血友病A人群表型异质性的潜在基础的理解。此外，它还提出了新的方法来将基本发现转化为抑制剂治疗的临床前模型和临床研究，以测试预测严重血友病A出血素质的新诊断。FVIII替代治疗最可怕的并发症是FVIII(抑制剂)抑制抗体的产生，这种抗体发生在大约30%的重度和中度血友病A患者中。此外，FVIII抑制剂可以发生在非血友病患者中，产生一种称为获得性血友病A的自身免疫性疾病。获得性血友病患者经常出现严重的、危及生命或肢体的出血，很难处理。患有血友病A的患者要么接受按需治疗以控制出血发作，要么接受预防性治疗以防止出血。为了限制发生致残性关节病的可能性，大多数患者接受预防性治疗。然而，提供预防治疗所需的输液频率经常导致依从性较差。因此，在美国，许多患有血友病A的人都会接受按需治疗。预防性治疗非常昂贵，给社会造成了经济负担。严重血友病A，由FVIII活性测定定义，其水平低于正常的1%，通常被诊断为 生命的第一年。患有严重血友病A的患者通常有自发性出血，即在没有明显创伤的情况下出血。然而，在严重的血友病A人群中，出血素质有相当大的差异。目前，还没有可以预测出血变异性的诊断测试。这种诊断的确定将指导早期患有严重血友病A的患者的治疗，例如，通过确定应积极采取预防措施以保护目标关节的个人。即使是目前最好的情况，即先天血友病A患者的成功预防治疗，也不代表治愈。基因治疗仍然是治愈血友病A的最佳机会，基于造血干细胞(HSC)的其他先天性疾病的基因治疗的进展，包括肾上腺脑白质营养不良和严重的联合免疫缺陷疾病，以及在埃默里大学的小鼠血友病A模型的临床前研究表明，包括抑制剂患者在内的血友病A的治愈迫在眉睫。血友病的最先进管理在多学科治疗中心进行。从婴儿期到成年，血友病患者的护理需要一个医生团队和相关人员来管理出现的问题的演变。此外，血友病治疗中心最好包括一个综合的基础、翻译和临床研究计划，以提供血友病管理方面的持续进展。还有一个尚未得到满足的需求，需要更多的内科科学家在血友病治疗中心提供专门的护理和进行研究。该项目的研究人员是埃默里大学Aflac癌症中心和血液疾病服务中心止血/血栓计划的内科科学家、临床调查员和分子生物学家，他们在血友病护理和血友病研究方面拥有广泛的专业知识。该计划为培养下一代止血疾病管理和研究方面的内科科学家、临床和基础研究人员提供了一个肥沃的环境。

FVIII (fVIII) replacement therapy is the mainstay of the management of congenital hemophilia A in developed countries. This TRC-THD U54 application, entitled Biological Variation in Hemophilia, seeks to improve our understanding of inhibitor development and the underlying basis for phenotypic heterogeneity in the severe hemophilia A population. Additionally, it proposes novel approaches to translate basic discovery into preclinical models of inhibitor treatment and into clinical studies to test novel diagnostics predictive of the bleeding diathesis n severe hemophilia A. The most dreaded complication of fVIII replacement therapy is the development of inhibitory antibodies to fVIII (inhibitors), which occur in approximately 30% of individuals with severe and moderately severe hemophilia A. Additionally, fVIII inhibitors can occur in nonhemophiliacs, producing an autoimmune condition called acquired hemophilia A. Acquired hemophilia A is the most common autoimmune bleeding disorder involving the coagulation system. Patients with acquired hemophilia frequently present with severe, life- or limb-threatening bleeding that is difficult to manage. Individuals with hemophilia A are treated either with on-demand therapy to manage bleeding episodes or with prophylactic therapy to prevent bleeding. To limit the potential for the development of crippling arthropathy most patients receive prophylactic therapy. However, the frequency of infusions required to deliver prophylactic therapy frequently results in poor compliance. As a result, many individuals with hemophilia A in the United States are treated with on-demand therapy. Prophylactic therapy is very expensive, creating an economic burden to society. Severe hemophilia A, which is defined by a fVIII activity assay in which the level is less than 1% of normal, usually is diagnosed in the first year of life. Individuals with severe hemophilia A often have spontaneous bleeding, i.e., bleeding in the absence of overt trauma. However, there is considerable variability in the bleeding diathesis within the severe hemophilia A population. Currently, there are no diagnostic tests that can predict variability of bleeding. Identification of such diagnostics would guide the management of individuals with severe hemophilia A in early life, e.g., by identifying individuals in whom prophylaxis should be aggressively pursued to protect target joints. Even the best current situation, namely successful prophylactic therapy in an individual with congenital hemophilia A who is not inhibitor prone, does not represent a cure. Gene therapy continues to represent the best chance for cure of hemophilia A. Advances in hematopoietic stem cell (HSC)-based gene therapy for other congenital disorders, including adrenoleukodystrophy and severe combined immunodeficiency disease, and preclinical studies in a murine hemophilia A model at Emory University, suggest that a cure for hemophilia A, including inhibitor patients, is imminent. State-of-the-art management of hemophilia occurs in multidisciplinary treatment centers. The care of individuals with hemophilia from infancy through adult life requires a team of physicians and allied personnel to manage the evolution of issues that arise. Additionally, a hemophilia treatment center ideally includes an integrated basic, translational and clinical research program to provide ongoing advances in the management of hemophilia. There is an unmet need for more physician scientists to provide the specialized care and conduct research in hemophilia treatment centers. The investigators in this project are physician-scientists, clinical investigatos and molecular biologists in the Hemostasis/Thrombosis Program in the Aflac Cancer Center & Blood Disorders Service at Emory University who have broad expertise in hemophilia care and hemophilia research. The program represents a fertile environment for training the next generation of physician-scientists, clinical, and basic researcher in the management and research of hemostatic disorders