Initiators of thrombotic microangiopathy

PROJECT SUMMARY/ABSTRACT Thrombotic microangiopathy (TMA) occurs in 20% of children after hematopoietic stem cell transplant (HCT) and can cause multi-organ dysfunction and death. Over the last decade, our research team has advanced understanding of the diagnosis and management of TMA. Standardized diagnostic criteria for TMA, developed by our group, were recently adopted by international consensus (Transplantation and Cellular Therapy, 2022). Our published data demonstrate that dysregulation of complement and interferon are associated with endothelial injury and a high-risk TMA phenotype. Complement blockade has been associated with improved outcomes in children with TMA (70% versus 16% historical survival), but is not effective in all patients. Furthermore, we still do not fully understand the specific initiators or triggers for TMA. Our preliminary proteomic data demonstrate increased phosphatidylinositol 4-kinase (PI4K) expression – which regulates viral replication – in HCT recipients. In our published prospective natural history study of BK polyomavirus (BKPyV), we observed that ~20% of children had BKPyV in their blood within the first few months after HCT and BKPyV viremia was associated with a seven-fold increased risk of TMA, making BKPyV a good model of a viral trigger in TMA. Finally, we have sequenced over 150 clinical BKPyV samples and have identified high levels of genomic diversity after HCT. Our established collaborations across Cincinnati Children’s Hospital, the Children’s Hospital of Philadelphia, and the University of Cincinnati make us uniquely qualified to perform the proposed studies. The objective of the current proposal is to examine initiators and mechanisms of TMA in an established cohort of children and young adults (N=300) undergoing HCT. We hypothesize that exogenous and endogenous mechanisms both initiate TMA, mediated by complement and interferon. Our hypothesis focuses on complement and interferon because this hypothesis is supported by our published and preliminary data, and because these initiators can be targeted in future interventional studies. Specifically, available therapeutic options now include inhibitors of the complement and interferon systems and virus-specific T cells to eradicate BKPyV. To test our hypothesis, we propose two Specific Aims. Specific Aim 1 will systematically evaluate complement and interferon as triggers for TMA in children undergoing allogeneic HCT. We will test for complement and interferon activation pre-HCT and then weekly after HCT. Aim 2 will evaluate host susceptibility and viral exposure as novel triggers for TMA in children undergoing allogeneic HCT. We will evaluate susceptibility to TMA in children with BKPyV viremia by testing samples for BKPyV diversity and PI4K after HCT. Finally, the knowledge gained from Aim 1 and Aim 2 will be applied to a new performance cohort (N=100), to be enrolled in the final years of the award period. The performance cohort will test, during clinical care, how the identified triggers can predict TMA and its severity after HCT. This approach will inform the design of future interventional trials to prevent, treat, or decrease the severity of TMA after HCT and improve patient survival for this high-risk population.