# Thrombotic microangiopathy (TMA) associated MODS after stem cell transplantation

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $690,967

## Abstract

ABSTRACT
Thrombotic microangiopathy (TMA) is an important cause of multi-organ dysfunction syndrome (MODS) and death after
hematopoietic cell transplantation (HCT). TMA with MODS occurs in about 11-15% of children after HCT. Mortality with
TMA and MODS is about 80%, both in the literature and in our own experience. We have shown that patients with TMA
develop MODS through endothelial damage mediated by activation of complement, and have identified complement
activation as a poor prognostic marker in TMA. Most importantly, we have shown in a single institution study that
complement blockade with eculizumab improves survival. We hypothesize that functional complement studies performed
prior to and during HCT will identify patients with increased susceptibility to severe TMA during HCT, and will provide
novel pre-transplant screening tools for TMA risk stratification. We also hypothesize that early intervention with eculizumab
will double survival in HCT recipients with high risk TMA and MODS, as compared to historical untreated controls. An
important goal of this proposal is to identify biological markers that define high-risk patients prior to proceeding to HCT.
Our published complement gene sequencing studies indicate that susceptibility to TMA is polygenic, with disease only
manifesting under the extreme stress of the HCT process. We found that multiple gene variants modify TMA susceptibility,
making pre-transplant genotyping in all patients an impractical approach to identifying high-risk children. In our first
specific aim we will test strategies using functional protein-based assays that will allow us to both identify highly susceptible
children prior to HCT, and identify the onset of TMA earlier than we currently do, to allow prophylactic and/or earliest
possible therapy in future clinical trials. Our first strategy is to test resting state complement activation in serum from 80
children (40 with and 40 without TMA) prior to starting transplant using an endothelial complement deposition assay and a
modified Ham’s test, to identify patients at high risk to activate complement during HCT. Our second strategy is to identify
endothelial injury occurring after HCT at the earliest possible time by measuring ST2 and NETS formation in 200 children
systematically phenotyped for TMA at weekly intervals after HCT. Early identification of endothelial injury will allow
intervention before organ damage occurs. In addition, we will perform RNAseq analysis of peripheral blood mononuclear
cells from 40 children with TMA at the time of disease, and after resolution of TMA, to identify undescribed dysregulated
pathways, and novel potentially druggable targets. In our second aim we will establish an eculizumab treatment regimen
that can be generalizable to multiple sites and does not require time-intensive individual pharmacokinetic and
pharmacodynamic (PK/PD) monitoring. In preparation for this study we established prospective TMA screening strategies,
determi...

## Key facts

- **NIH application ID:** 10001993
- **Project number:** 5R01HD093773-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Sonata Jodele
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $690,967
- **Award type:** 5
- **Project period:** 2018-08-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001993

## Citation

> US National Institutes of Health, RePORTER application 10001993, Thrombotic microangiopathy (TMA) associated MODS after stem cell transplantation (5R01HD093773-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10001993. Licensed CC0.

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