Inhibitor development in patients with hemophilia A undergoing surgery

接受手术的 A 型血友病患者的抑制剂开发

• 批准号: 8431402
• 负责人: Christine Luise Kempton
• 金额: $ 15.44万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-08 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431402
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigens; Attenuated; Biological; Clinical Investigator; Clinical Research; Clinical Trials; Cohort Studies; Collaborations; Complication; Confounding Factors (Epidemiology); Continuous Infusion; Development; Disease; Dose; Education; Enrollment; Environment; Factor VIII; Foundations; Future; Goals; Hemophilia A; Hemorrhage; Hemostatic function; Immune response; Immunologics; Immunology; Incidence; Inflammatory; Inflammatory Response; Infusion procedures; Interleukin-10; Interleukin-6; Interleukins; Knowledge; Laboratories; Laboratory Research; Life; Logistic Regressions; Measures; Mediating; Mentorship; Methods; Operative Surgical Procedures; Patients; Peripheral Blood Mononuclear Cell; Plasma; Postoperative Period; Recording of previous events; Research; Resources; Risk; Risk Factors; Scientist; Study Subject; T cell response; T-Lymphocyte; Techniques; Testing; Time; Time Factors; Training; Tumor Necrosis Factor-alpha; Universities; Work; antibody inhibitor; career development; cost; cytokine; design; experience; high risk; immune activation; inhibitor/antagonist; insight; prevent; prospective; public health relevance; research study; response; skills; symposium; treatment center; treatment strategy

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.

描述（由申请方提供）：中和抗因子VIII（fVIII）抗体（抑制剂）的形成是影响血友病A（HA）治疗患者的最显著并发症。一旦出现抑制剂，治疗效果就会降低，而且成本也会降低。虽然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。迄今为止，旨在了解轻度和中度HA患者抑制物形成风险因素的研究仅限于回顾性分析，并已将强化fVIII治疗和手术确定为风险因素。在一些但不是所有研究中，通过连续输注接受fVIII与轻度和中度HA中的抑制物形成相关。因此，评价抑制物形成风险的下一个合乎逻辑的步骤是前瞻性观察性队列研究。如果连续FVIII输注与抑制物形成相关，则可能部分是由于促进了更稳健的促炎反应。为了实现我降低HA中新抑制剂发生率的长期目标，本申请的目的是确定轻度和中度HA患者对fVIII的免疫应答在产生抑制剂和不产生抑制剂的患者之间如何以及为什么不同。具体目标1将检验轻度和中度HA受试者的围手术期fVIII输送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观察性队列研究，入组140例接受外科手术的轻度和中度HA受试者。将根据混淆变量（如手术类型、手术时间、fVIII水平和既往fVIII暴露程度）调整通过连续输注进行的fVIII递送与抑制物形成之间的相关性。我们预计，接受连续输注给予FVIII的受试者中形成的抑制物比例更高。我们还预计，FVIII的剂量和手术类型将是减弱这种关系的中介因素。具体目标2将检验以下假设：接受手术的轻度和中度HA患者中抑制物的形成与以下因素相关：1）术后炎性细胞因子增加和2）T辅助细胞（TH）2适应性免疫应答偏离。我们预计，与促炎细胞因子很少或没有增加的受试者相比，术后第7天促炎细胞因子增加的受试者将主要对FVIII产生TH 2反应，并且抑制物形成的比例更高。这些实验的结果将提供对手术环境中对FVIII的免疫应答的重要见解，并提供重要的基础免疫学背景，以促进治疗策略的设计，以减少HA患者中抑制物的产生。除了完成具体目标外，拟议的职业发展活动将在埃默里大学进行，这是一个强大而富有成效的研究环境，包括：1）指导课程工作，2）参加会议; 3）动手实验室技能发展，以及3）Lollar，Zimring和Mertens博士的密切指导。这些活动将建立在我目前在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者的发展。