International Network and Registry for TMA

描述（由申请人提供）： 一组以血栓性微血管病（TMA）为特征的罕见疾病，一种以原发性内皮损伤为特征的独特组织病理学实体，是儿科患者发病和死亡的重要原因。有两种主要的临床表型与TMA相关-溶血性尿毒症综合征和血栓性血小板减少性紫癜。这些孤儿疾病可以由传染性病原体、药物、潜在的医学状况、器官移植或各种循环或膜结合蛋白的遗传异常触发。不幸的是，有争议的适当的病理生理分类和诊断标准，这些实体。此外，由于这些疾病很罕见，关于其发病机制、发病率、自然史和最佳治疗方法的数据也很缺乏。最后，这些疾病的低发病率阻碍了开发新疗法和在设计良好的随机对照临床试验中评估疗效的努力。在这项完全独立的R21申请中，我们建议成立一个由临床研究中心和专门实验室组成的联盟，其长期目标是研究儿科患者中发生的所有形式的TMA。这项合作努力的具体目标是：（1）建立一个参与中心的国际网络;（2）建立一个登记和基于网络的数据库，并为TMA患者创建一个生物储存库;（3）描述所有形式的TMA的流行病学和临床特征，并对严重疾病患者进行纵向观察研究;（4）阐明TMA的一个亚组--非典型HUS的潜在遗传原因。TMA的国际网络和注册的意义是双重的：（1）它将提高对这些罕见疾病的理解，并提供及时测试潜在疗法的机会;和（2）通过增加对TMA中内皮损伤和凝血和补体级联调节的认识，该项目可能与许多以内皮功能障碍、紊乱性血栓形成和补体激活为特征的疾病具有更广泛的相关性。这些疾病包括原发性高血压、糖尿病、高脂血症、心肌梗死和慢性肾脏疾病。

DESCRIPTION (provided by applicant): A diverse group of rare disorders characterized by thrombotic microangiopathy (TMA), a distinctive histopathologic entity characterized by primary endothelial injury, represents an important cause of morbidity and mortality in pediatric patients. There are two major clinical phenotypes associated with TMA - hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. These orphan diseases can be triggered by infectious agents, drugs, underlying medical conditions, organ transplantation, or genetic abnormalities in various circulating or membrane bound proteins. Unfortunately, there is controversy about the appropriate pathophysiological categorization and diagnostic criteria for these entities. Moreover, because these illnesses are rare, there is a paucity of data about their disease mechanism, incidence, natural history, and optimal treatment. Finally, the low incidence of these diseases has hampered efforts to develop novel therapies and to evaluate efficacy in well designed randomized controlled clinical trials. In this fully independent R21 application, we propose to form a consortium of clinical sites and dedicated laboratories with the long-term objective of studying all forms of TMA that occur in pediatric patients. The specific aims of this collaborative effort will be to: (1) establish an international network of participating centers; (2) establish a registry and web-based database and create a biorepository for patients with TMA; (3) describe the epidemiology and clinical features of all forms of TMA and perform a longitudinal observational study of patients with severe disease; and (4) clarify the underlying genetic causes in a subgroup of TMA, atypical HUS. The significance of an International Network and Registry for TMA is two-fold: (1) it will enhance understanding of these rare diseases and provide an opportunity to test potential therapies in a timely manner; and (2) by increasing knowledge about the endothelial injury and the regulation of the coagulation and complement cascades in TMA, this project is likely to have much broader relevance to a number of diseases characterized by endothelial dysfunction, disordered thrombosis, and complement activation. These include essential hypertension, diabetes, hyperlipidemia, myocardial infarction, and chronic kidney disease.