Initiation of a cohort to define pathogenic mechanisms, precision diagnosis and complications of thrombotic microangiopathies: the impact study

The National Center for Advancing Translational Sciences (NCATS, CFDA 93.350) awarded a Cooperative Agreement totaling $622,077 to The Johns Hopkins University, with an award date of September 15, 2025, and completion date of June 30, 2030. The award funds the IMPACT Study (Initiation of a cohort to define pathogenic Mechanisms, Precision diagnosis And Complications of Thrombotic Microangiopathies), which establishes a Rare Disease Clinical Research Consortium (RDCRC) to facilitate collaborative clinical and translational research on thrombotic microangiopathies (TMAs)—a group of rare disorders characterized by thrombocytopenia, microangiopathic hemolysis, and microvascular thrombosis. The consortium will focus on immune-mediated thrombotic thrombocytopenic purpura (ITTP), congenital TTP (CTTP), and complement-mediated TMA (CM-TMA), including acute hemolytic uremic syndrome (AHUS).

The primary products and services include: establishing a collaborative research infrastructure leveraging existing U.S. TMA consortium sites and experienced investigators; evaluating long-term patient outcomes across the lifespan to identify unmet treatment needs and complications such as cardiovascular disease, cognitive impairment, and depression; conducting clinical research to answer pressing diagnostic and treatment questions; establishing clinical trial readiness for novel therapeutic interventions; and providing patient advocacy support and researcher training. The award includes a sub-award to The Washington University's Office of Sponsored Research Services, dated May 6, 2026, to support the cohort research and clinical investigations. Through this collaborative research network, the RDCRC will advance understanding of TMA pathogenic mechanisms and precision diagnosis while contributing to the translational science mission of accelerating discoveries into clinical solutions for rare disease patients.

Abstract

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.