Biological Variation in Hemophilia

FVIII（fVIII）替代治疗是发达国家先天性血友病A治疗的主要手段。这项TRC-THD U 54申请名为《血友病生物变异》，旨在提高我们对抑制剂形成的理解，以及严重血友病A人群表型异质性的基础。此外，它提出了新的方法，将基本发现转化为抑制剂治疗的临床前模型和临床研究，以测试预测重度血友病A出血素质的新诊断。fVIII替代治疗最可怕的并发症是产生fVIII抑制性抗体（抑制剂），约30%的重度和中重度血友病A患者发生这种情况。此外，fVIII抑制剂可发生在非血友病患者中，产生称为获得性血友病A的自身免疫性疾病。获得性血友病A是最常见的涉及凝血系统的自身免疫性出血性疾病。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，难以控制。血友病A患者接受按需治疗以控制出血发作或接受预防性治疗以防止出血。为了限制致残性关节病发展的可能性，大多数患者接受预防性治疗。然而，递送预防性治疗所需的输注频率经常导致依从性差。因此，在美国，许多血友病A患者接受按需治疗。预防性治疗非常昂贵，给社会造成经济负担。重度血友病A，其定义为FVIII活性测定，其中水平低于正常值的1%，通常在 生命的第一年。患有重度血友病A的个体通常有自发性出血，即，在没有明显外伤的情况下出血然而，重度血友病A人群中的出血素质存在相当大的变异性。目前，没有诊断测试可以预测出血的变异性。此类诊断的确定将指导早期重度血友病A患者的管理，例如，通过识别应积极进行预防以保护目标关节的个体。即使是目前最好的情况，即在先天性血友病A患者中成功的预防性治疗，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）的基因疗法在其他先天性疾病（包括肾上腺脑白质营养不良和严重联合免疫缺陷病）方面的进展，以及埃默里大学在小鼠血友病A模型中的临床前研究表明，血友病A（包括抑制剂患者）的治愈迫在眉睫。血友病的最新管理发生在多学科治疗中心。血友病患者从婴儿期到成人期的护理需要一个医生和专职人员团队来管理出现的问题的演变。此外，血友病治疗中心理想地包括一个综合的基础，转化和临床研究计划，以提供血友病管理的持续进展。有一个未满足的需要，更多的医生科学家提供专门的护理和血友病治疗中心进行研究。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/血栓形成项目的医生科学家，临床医生和分子生物学家，他们在血友病护理和血友病研究方面具有广泛的专业知识。该计划代表了一个肥沃的环境，培养下一代的医生，科学家，临床和基础研究人员在止血疾病的管理和研究

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