Project 1 - Longitudinal study of thrombotic thrombocytopenic purpura

Johns Hopkins University, Baltimore MD

Investigators

Abstract

PROJECT SUMMARY – PROJECT 1 The overarching goal of this project is to develop the first multicenter, prospective, longitudinal study of immune-mediated thrombotic thrombocytopenic purpura (iTTP) and the extremely rare congenital TTP (cTTP). In survivors of both diseases, long-term complications include relapses, cognitive dysfunction, mental health disorders, and stroke. It is also likely that cognitive dysfunction is progressive, but the mechanism and tempo of this sinister but subtle phase of these diseases is not well understood. Similarly, relapse can be unpredictable, creating stress and poor quality of life, and likely contributes to mental health disorders. Rituximab, the current standard of care for immunosuppression in iTTP, is far less effective than once thought, suggesting a critical need for more tailored approaches for iTTP. Two advances in the acute treatment of iTTP and cTTP include caplacizumab and recombinant ADAMTS13, respectively, but how these shifting treatment paradigms will impact the natural history of these complications is unknown and will be critical to establish. This project will address these important questions for the long-term health and quality of life of survivors by creating the first longitudinal study of iTTP and cTTP to evaluate long term risk of cardiovascular disease, relapse, and cognitive dysfunction, as well as a sub-study of annual MRI scans of the brain and cognitive testing to evaluate the incidence of silent cerebral infarcts and progression of cognitive dysfunction. We aim to enroll 500 participants, including both adults and children in our longitudinal study of iTTP, collecting clinical data on relapses, ADAMTS13 activity, treatment, comorbidities (including vascular diseases in particular), patient-reported outcomes and quality of life measures. We will also enroll 100 participants with cTTP from participating centers and from around the country by recruiting participants in the International hereditary TTP registry living in the US. In aim 2, we will study subpopulations of subjects with iTTP and cTTP to establish the incidence and risk factors for incident silent cerebral infarct occurring during clinical remission and identify whether this is a risk factor for stroke in participants with iTTP and cTTP. We stand at the precipice of what we expect to be a highly innovative next decade in these diseases, with the recognition that current therapies are inadequate to protect against relapse and likely against progressive neurological dysfunction, but also where novel therapies are in development and their impact on short- and long-term outcomes needs to be established.