ADAMTS13 in Human Health and Disease

About This Grant

PROJECT SUMMARY This application proposes to study thrombotic disorders linked by the common thread of ADAMTS13 deficiency. The metalloprotease ADAMTS13 is responsible for cleaving ultra-large von Willebrand factor (VWF) multimers into smaller units, thereby regulating the thrombogenicity of this important circulating coagulation factor. Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening autoimmune hematologic disorder characterized by severe acquired ADAMTS13 deficiency (<10% activity, normal range: 50-150%) and diffuse microvascular thrombosis, end-organ damage, and death if left untreated. Beyond iTTP, moderately low ADAMTS13 (10-70% activity) has been hypothesized to contribute to common forms of macrovascular thrombosis, including stroke and myocardial infarction. We plan to study both iTTP and less severe ADAMTS13 deficiency. We organized the Harvard TMA Research Collaborative (HTRC), one of the world’s largest single- center registries for iTTP, to fuel innovative clinical and translational research of this understudied disease. Our group has pioneered the application of robust statistical modeling approaches to key questions in iTTP as well as the use of population-scale multidimensional datasets in hemostasis and thrombosis research. In Aim 1, we will leverage the HTRC registry to identify upfront predictors of negative outcomes in ITTP, including relapse and the composite of mortality, refractoriness, and need for critical care. Models developed in this Aim will facilitate risk stratification of iTTP patients and help guide therapeutic decision-making. In Aim 2, common germline genetic variants will be evaluated via the first genome-wide association and admixture mapping studies in iTTP with a view to understanding the disproportionate disease risk borne by some populations. Project results will provide avenues to develop novel screening, prevention, and intervention strategies for iTTP and serve as a model for the study of other classical hematologic disorders. In Aim 3, we will analyze genomic and proteomic data from nearly 800,000 individuals in the UK Biobank and NIH All of Us datasets to define the contribution of moderate ADAMTS13 deficiency to widespread thrombotic conditions, including stroke, myocardial infarction, peripheral artery disease, and venous thromboembolism. Our findings will have direct implications for clinical practice due to the recent FDA approval of recombinant ADAMTS13 and the hypothesis that ADAMTS13 supplementation could potentially aid the many patients suffering from these forms of thrombosis.