International Network and Registry for TMA

描述(由申请人提供)： 以血栓性微血管病(TMA)为特征的一组罕见疾病，是一种以原发内皮损伤为特征的独特组织病理学实体，是儿科患者发病率和死亡率的重要原因。TMA有两种主要的临床表型--溶血性尿毒症综合征和血栓性血小板减少性紫癜。这些孤儿疾病可由感染源、药物、潜在的医疗条件、器官移植或各种循环或膜结合蛋白中的遗传异常引发。不幸的是，对于这些实体的合适的病理生理分类和诊断标准存在争议。此外，由于这些疾病是罕见的，关于它们的发病机制、发病率、自然病史和最佳治疗方法的数据很少。最后，这些疾病的低发病率阻碍了开发新疗法和在精心设计的随机对照临床试验中评估疗效的努力。在这个完全独立的R21应用中，我们建议组成一个由临床站点和专用实验室组成的联盟，长期目标是研究发生在儿科患者中的所有形式的TMA。这项合作工作的具体目标是：(1)建立参与中心的国际网络；(2)建立登记和基于网络的数据库，创建TMA患者的生物信息库；(3)描述所有形式的TMA的流行病学和临床特征，并对重症患者进行纵向观察性研究；(4)澄清TMA(非典型HUS)亚组的潜在遗传原因。TMA国际网络和注册中心的意义有两方面：(1)它将增进对这些罕见疾病的了解，并提供机会及时测试潜在的治疗方法；(2)通过增加对TMA中内皮损伤以及凝血和补体级联调节的了解，该项目可能对以内皮功能障碍、无序血栓形成和补体激活为特征的一些疾病具有更广泛的相关性。这些疾病包括高血压、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.