MIDAS: Microangiopathy, endothelial Damage in Adults undergoing Stem cell transplantation ABSTRACT Hematopoietic cell transplant-associated thrombotic microangiopathy (HCT-TMA) is a clinical diagnosis based on consensus criteria and associated with high mortality rates (80%). Approximately 9,000 hematopoietic cell transplant (HCT) procedures are performed in the U.S. annually, and reported frequencies of HCT-TMA are highly variable due to lack of routine screening. HCT-TMA is a morbid and potentially life-threatening complication of HCT including microangiopathic hemolytic anemia, renal dysfunction and neurological symptoms. The initiating event of HCT-TMA appears to be endothelial injury, and extensive data indicate decline in endothelial health as people age suggesting that HCT-TMA might be more frequent or severe in older persons. Preliminary data indicate a bimodal distribution of HCT-TMA in adults, with a peak early after transplantation, which is well described in children, but a second later peak 3-6 months after transplant, sometimes associated with a flare of graft versus host disease (GVHD) during taper of immune suppression. There is no reported prospective study of HCT-TMA in adults thus risk factors and outcomes are currently unknown. This is a key gap in current knowledge and we plan to address this gap in our proposal. The need for a prospective adult cohort study of HCT-TMA is urgent as older patients are increasingly eligible for HCT. This study will define clinical phenotypes, risk factors, and possible therapeutic strategies for HCT-TMA. Our overarching hypothesis is that ?The etiology and risk factors for HCT-TMA are different in adults than children, and that these differences importantly modify potential diagnostic and therapeutic strategies?. We propose to identify strategies that will define HCT recipients with increased susceptibility to HCT-TMA occurring early after transplantation, and later after establishment of GVHD. Identifying endothelial injury occurring post-HCT at the earliest possible time will allow for prompt clinical intervention and interruption of the cycle of endothelial injury and complement activation. The centers participating in this study are ideal for this work because they are large transplant centers with a strong track record of successful clinical research and study enrollment with a long-standing interest in HCT- TMA, evidenced by previous publications in the area. We will use our prospectively generated, well-annotated clinical database to test hypotheses regarding pathophysiology, for example, that GVHD is a major contributor to HCT-TMA by examining clinical risk factors and biomarkers of endothelial injury. We will measure the financial cost of HCT-TMA, late organ toxicity and will formulate and test a predictive index for HCT-TMA to target monitoring and treatment to highest-risk individuals. In summary, this study will provide essential data to identify persons at highest risk of HCT-TMA to allow testing of future clinical interventions such as studies of endothelial protecting agents and complement or interferon inhibitors for HCT-TMA and development of evidence-based guidelines for screening and diagnosis of HCT-TMA in adults.
We are proposing a multi-institution study to address a severe hematopoietic stem cell transplant (HCT) complication called thrombotic microangiopathy or ?TMA?. In our first aim we will define incidence, risk factors, phenotypic diversity, temporality between Graft-versus-host disease and TMA and role of markers of complement activation in diagnosis of HCT-TMA. In our second aim, we will identify key mechanisms of endothelial injury and complement activation after HCT that will result in identification of novel therapeutic targets.
