Targeting silent cerebral infarction to improve long-term neurologic outcomes in immune thrombotic thrombocytopenic purpura (iTTP) - PROJECT SUMMARY/ABSTRACT Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder characterized by acute episodes of systemic microvascular thrombosis caused by deficiency of ADAMTS13, a von Willebrand factor cleaving protease. iTTP survivors remain at risk for multiple adverse neurologic outcomes including cognitive impairment and a five-fold increased risk of stroke. During the K99 award, Dr. Chaturvedi conducted a single- center prospective study and established that 50% of iTTP survivors have silent cerebral infarction (SCI), defined as magnetic resonance imaging evidence of brain ischemia in the absence of overt neurologic deficits, which is a much higher rate than reported in population-based cohorts. SCI is also independently associated with cognitive impairment in iTTP survivors. Critical unanswered questions that are addressed in this R00 proposal are: 1) do SCI occur during iTTP remission or are they only sequelae of acute iTTP, or both? 2) are SCI a risk factor for future stroke, and 3) how can we prevent SCI and their devastating neurologic sequelae (cognitive impairment and stroke)? The applicant will build upon the K99 study to conduct a multi-center observational study at three clinical sites with established prospective iTTP cohorts and a track record of research in iTTP (Johns Hopkins University, Ohio State University, and University of Minnesota). Aim 1 will elucidate the natural history of SCI and establish the incidence and risk factors for new SCI and stroke occurring during clinical remission of iTTP, with a focus on remission ADAMTS13 activity and other modifiable risk factors such as hypertension. Aim 2 will evaluate the impact of the novel anti-VWF therapy (caplacizumab), used in the treatment acute iTTP, on the prevalence of SCI and cognitive impairment by comparing with matched patients treated without caplacizumab, and adjusting for other acute iTTP specific variables such as neurologic involvement at presentation, and time to clinical response and ADAMTS13 activity recovery. Dr. Chaturvedi and her research team have established the infrastructure, expertise, protocols and have a record of accomplishment of successful clinical research in rare diseases. This R00 proposal will provide critical data that will directly impact clinical care in iTTP. Identifying whether early anti- VWF therapy or maintaining higher remission ADAMTS13 protect against SCI and cognitive impairment will change current paradigms of treatment where anti-VWF is not considered universally cost-effective, and only ADAMTS13 levels <20% are targeted to prevent relapse. if we establish that SCI are strongly associated with stroke, then SCI is an attractive shorter-term endpoint for an intervention to reduce the burden of cerebrovascular disease, potentially reducing the duration and expense of clinical trials. In addition to building infrastructure for and informing the design of a subsequent clinical trial of an intervention to alleviate the long- term neurologic morbidity of iTTP, this R00 proposal will also build a data and sample biorepository to investigate biomarkers and mechanisms of SCI in iTTP for a subsequent R01 application.
