Characteristics and outcomes of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy: A retrospective single-center analysis

Abstract Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a heterogenous and life-threatening systemic complication of hematopoietic stem cell transplantation (HSCT), contributing significantly to transplant-related morbidity and mortality. Recent international efforts have proposed harmonization diagnostic criteria to facilitate early identification of patients with high-risk features for timely implementation of disease-directed therapies (Schoettler et al., 2023). Objective: To characterize the clinical features, retrospectively apply harmonization criteria, and evaluate clinical outcomes of TA-TMA at a large pediatric center. Methods: Data was abstracted from the electronic medical record for patients aged 0 – 22 years who underwent allogeneic or autologous HSCT at Texas Children's Hospital and were clinically and/or histologically diagnosed with TA-TMA between January 2011 and December 2024. TA-TMA was diagnosed by the treating physician using currently available diagnostic criteria. Harmonization criteria were retrospectively applied, including presence of high-risk features (hrTA-TMA) as defined by Schoettler et al., 2023. Treatment strategies, including therapeutic plasma exchange (TPE) and eculizumab (introduced in 2013), were made at physician discretion. Characteristics between subgroups were compared by t test for continuous variables and Fisher's exact test for categorical variables. Kaplan-Meier method was used to estimate overall survival (OS), calculated from the day of TA-TMA diagnosis until the date of last follow-up or death from any cause. Variables associated with outcome were evaluated in univariate analyses using a Cox proportional hazards model to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Statistical analyses were performed with STATA 18.0 (StataCorp). Results: During the study period, 110 patients out of 3128 HSCTs (3.5%) were diagnosed with TA-TMA, with a median onset of 110 days post-HSCT (interquartile range [IQR], 64-181). In this cohort, 103 patients (94%) retrospectively fulfilled harmonization criteria, and all 110 patients had one or more high-risk features. Pathologic confirmation was obtained in 30 patients by renal biopsy or post-mortem autopsy. Most underwent allogeneic HSCT (n=106), primarily from unrelated donors (60%) and 54% were fully HLA-matched. Median age at transplant was 8.8 years and 61% were male. Malignancy (65%) and immunodeficiency or immune dysregulation disorders (23%) were the most common underlying conditions. The study comprised 95 patients who had undergone one HSCT and 15 who had undergone a second HSCT. Initial treatment strategies included active monitoring, modification of calcineurin inhibitors, and/or treatment of presumed triggering infections or GVHD. TPE was performed in 51 patients (46%) and eculizumab was administered in 67 patients (61%); thirty patients received both therapies. Median time from hrTA-TMA diagnosis to the initiation of eculizumab was 15 days (IQR, -1 to 31), while median time to initiation of TPE was 22 days (IQR, -2 to 56). OS was 64% at 6 months and 55% at 1 year after diagnosis, with a mean follow-up of 2.9 years. OS at 1 year was 54% for eculizumab-only group, 43% for TPE + eculizumab, and 48% for TPE-only. In univariate analysis, predictors of poor survival included female sex (HR 1.84, P=0.025), cord blood grafts (HR 2.87, P=0.006), ICU admission (HR 10.33, P<0.001) and subsequent need for interventions. Most high-risk features correlated with decreased survival, except random urine protein-creatinine ratio, cardiovascular involvement, and infection. Among 54 survivors, long-term complications included chronic kidney disease (54%; 9 on long-term dialysis and 3 transplanted) and chronic lung disease (17%).Conclusion: TA-TMA remains a severe complication with poor long-term survival. We report a comprehensive analysis of patient outcomes at a large pediatric institution. All patients demonstrated high risk features, limiting stratification utility of the harmonized diagnostic criteria when applied retrospectively to this cohort. Outcomes for those treated with eculizumab, TPE, or both were poor. Organ injury strongly predicted mortality, underscoring the need for earlier diagnosis and improved therapeutic intervention. These findings highlight the need for novel treatment strategies and prospective studies to refine risk stratification and improve early detection.