Initiation of a cohort to define pathogenic Mechanisms, Precision diagnosis And Complications of Thrombotic Microangiopathies: The IMPACT Study

PROJECT SUMMARY - OVERALL The overall goal of this proposal is to create a Rare Disease Clinical Research Consortium (RDCRC) to facilitate collaborative clinical and translational research, patient advocacy and education, and training clinicians and researchers focused on thrombotic microangiopathies (TMAs). TMAs are a group of rare disorders characterized by thrombocytopenia, microangiopathic hemolysis, and ischemic organ injury due to microvascular thrombosis. They include immune-mediated thrombotic thrombocytopenic purpura (iTTP), congenital TTP (cTTP), complement-mediated TMA (CM-TMA or aHUS), and multiple causes of “secondary” TMA. iTTP is caused by autoantibody-mediated deficiency of ADAMTS13 (a key regulator of coagulation) and cTTP is caused by a genetic deficiency of ADAMTS13. Acute outcomes of TMA have improved dramatically with advances in pathogenesis and treatment. While it was previously believed that TMA survivors return to their baseline level of health after recovery from an acute episode, collaborative efforts from our group and others have established that iTTP and cTTP survivors experience increased rates of stroke and other cardiovascular events, cognitive impairment, depression, and earlier mortality that is attributable primarily to cardiovascular causes. There is little data on the long-term outcomes of CM-TMA, but our preliminary studies show high rates of hypertension and cardiac disease. We will leverage the existing United States TMA consortium with high volume clinical sites, experienced investigators, and close collaboration with patient advocacy groups to evaluate outcomes across the lifespan to define unmet treatment needs, answer pressing clinical questions, and to establish clinical trial readiness for interventional trials of novel treatment strategies. The RDCRC focused on collaborative clinical research in the TMAs will undertake prospective longitudinal registries of adults and children with cTTP, iTTP (Project 1), and CM-TMA (Project 2) with acute and remission clinical data, comorbidities, treatments, and outcomes including relapse, cardiovascular and cerebrovascular disease, and pregnancy outcomes. Project 1 will also prospectively evaluate cognitive function and silent cerebral infarction in cTTP and iTTP. In project 2, we will use a novel cell-based assay to evaluate the role of persistent complement dysregulation in clinical remission in CM-TMA sequelae including relapse, progressive renal impairment, and cardiovascular disease. We will develop a pilot core for evaluating and funding novel clinical research proposals, and a career enhancement core to provide training focused on TMAs to foster the development of future generations of TMA experts. Finally, we will collaborate with patient organizations, scientific and medical societies, and industry partners to provide information regarding diagnosis, treatment, clinical and basic research in TMAs to medical professionals, scientists, families, and other lay persons.