? 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. ? ?
