Inhibitor development in patients with hemophilia A undergoing surgery

描述(由申请人提供)：中和抗第八因子(FVIII)抗体的发展，抑制剂，是影响治疗的血友病A(HA)患者的最重要的并发症。一旦开发出一种抑制剂，治疗就不那么有效，成本也就更高。尽管抑制剂最常见于重度HA患者，但25%的新抑制剂出现在轻度和中度HA患者中。到目前为止，试图了解轻度和中度HA患者中抑制物形成的危险因素的研究仅限于回顾分析，并将强化FVIII治疗和手术确定为危险因素。在一些但不是所有的研究中，通过持续输注接受FVIII与轻、中度HA的抑制剂的发展有关。因此，评估抑制剂开发风险的下一个合乎逻辑的步骤是一项前瞻性的观察性队列研究。如果持续的FVIII输注与抑制剂的发展有关，部分原因可能是促进了更强大的促炎反应。我的长期目标是减少HA中新的抑制剂的发生率，这项应用的目标是确定轻中度HA患者对FVIII的免疫反应如何以及为什么在那些形成和抑制的患者和那些没有形成和抑制的患者之间存在差异。具体目标1将检验轻中度HA受试者围手术期FVIII分娩方法与抑制物形成相关的假设。为了验证这一点，我们将进行一项多中心前瞻性队列研究，招募140名轻中度HA患者接受外科手术。持续输注FVIII和抑制剂开发之间的关系将根据混杂变量进行调整，如手术类型、手术时间、FVIII水平和先前FVIII暴露的程度。我们预计，接受FVIII持续输注的受试者中会有更大比例的抑制剂形成。我们还预计，FVIII提供的剂量和手术的类型将是减弱这种关系的中介因素。特殊目的2将验证这样的假设，即接受手术的轻中度HA患者的抑制物发展与以下因素有关：1)术后炎性细胞因子增加；2)偏离T辅助(TH)2适应性免疫反应。我们预计术后第7天促炎细胞因子升高的受试者与致炎细胞因子几乎没有增加的受试者相比，对FVIII有主要的TH2反应和更高比例的抑制物形成。这些实验的结果将对手术中对FVIII的免疫反应提供重要的洞察，并为设计减少HA患者抑制物发展的治疗策略提供重要的基础免疫学背景。除了完成具体目标外，拟议的职业发展活动还将在埃默里大学进行，这是一个强大和富有成效的研究环境，包括：1)指导课程工作，2)参与会议，3)实践实验室技能发展，以及3)Lollar、Zimring和Merten博士的密切指导。这些活动将建立在我目前实验室和临床研究的基础上，并极大地促进我向独立临床研究员的发展。

DESCRIPTION (provided by applicant): The development of neutralizing anti-factor VIII (fVIII) antibodies, inhibitors, is the most significant complication affecting treated patients with hemophilia A (HA). Once an inhibitor develops, treatment is less effective and costly. Although inhibitors occur most commonly in those with severe HA, 25% of new inhibitors occur in patients with mild and moderate HA. To date, studies that seek to understand risk factors for inhibitor development in those with mild and moderate HA have been limited to retrospective analyses and have identified intensive fVIII treatment and surgery as risk factors. Receiving fVIII by continuous infusion has been associated with inhibitor development in mild and moderate HA in some but not all studies. Accordingly, the next logical step to evaluate the risk of inhibitor development is a prospective observational cohort study. If continuous fVIII infusion is associated with inhibitor development, it may be due in part to the promotion a more robust pro-inflammatory response. Toward my long-term goal of reducing the incidence of new inhibitors in HA, the objective of this application is to identify how and why the immune response to fVIII in patients with mild and moderate HA varies between those that develop and inhibitor and those that do not. Specific Aim 1 will test the hypothesis that the method of peri-operative fVIII delivery in subjects with mild and moderate HA is associated with inhibitor development. To test this we will perform a multicenter prospective observational cohort study enrolling 140 subjects with mild and moderate HA undergoing a surgical procedure. The association between fVIII delivery by continuous infusion and inhibitor development will adjusted for confounding variables such as type of surgery, operative time, fVIII level, and extent of prior fVIII exposure. We anticipate that there will be a greater proportion of inhibitors formed in subjects who receive fVIII delivered by continuous infusion. We also anticipate that the dose fVIII delivered and the type of surgery performed will be mediating factors that attenuate this relationship. Specific Aim 2 will test the hypothesis that inhibitor development in patients with mild and moderate HA undergoing surgery is associated with: 1) post-operative increases in inflammatory cytokines and 2) deviation toward a T helper (TH) 2 adaptive immune response. We anticipate that subjects with increased in proinflammatory cytokines on post-operative day 7 will have a predominantly TH2 response to fVIII and a higher proportion of inhibitor development compared with subjects with little or no increase in proinflammatory cytokines. The results of these experiments will provide significant insight into the immune response to fVIII in the setting of surgery and provide important basic immunologic background to facilitate the design of treatment strategies to reduce inhibitor development in patients with HA. In addition to completion of the Specific Aims, the proposed career development activities will take place at Emory University, a robust and productive research environment, and include: 1) directed course work, 2) conference participation; 3) hands-on laboratory skill development, and 3) close mentorship by Drs. Lollar, Zimring and Mertens. These activities will build on my current foundation in laboratory and clinical research and greatly enhance my development toward an independent clinical investigator.