Trend, Risk Factors and Outcome of Thrombotic Microangiopathy in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Multi-Institutional Review

Introduction: Thrombotic microangiopathy (TMA) is a rare but serious complication of hematopoietic stem cell transplantation (HSCT). Review of literature shows variable incidence of TMA following HSCT with high mortality but its true incidence and outcome in the pediatric population is not known.  The purpose of our study is to estimate the incidence, prevalence and analyze the risk factors and outcome of TMA in children receiving HSCT.

Methods: We used the Pediatric Health Information System (PHIS), an electronic database of children's hospitals in the US. Patients under the age of 21 who underwent HSCT at one of the 42 PHIS hospitals from 2000-2012 were analyzed. We abstracted data on demographics, hospitalizations, TMA and other HSCT related complications. 

Results: From 2000 to 2012, a total of 12369 unique pediatric patients who received HSCT were identified. Among these 93 (0.8%) children were identified to have the diagnosis of TMA. Overall, there was an increasing trend of TMA diagnosis seen in our cohort (Figure 1). The demographic characteristics, risk factors and outcome of these children with and without TMA are shown in Figure 2.  TMA was significantly associated with allogeneic HSCT (p=<0.001), PBSCT (p=0.045), CMV (p=<0.001), HHV6 (p=<0.001), fungal infection (p=<0.001), GVHD (p=<0.001) and VOD (p=0.01). The mortality was significantly higher in patients with TMA compared to those without (30.1% vs. 12.2%, p=<0.001, Figure 3A). Also, median time (days) to mortality following HSCT was shorter in patients with TMA than those without (754 [365, 1614] vs. 1439 [552, 2847], p=<0.0001). Multivariate logistic regression analysis of mortality using age, gender, HSCT type, CMV, HHV6, fungal infection and plasmapheresis showed only HHV6 was an independent risk factor  associated with increased mortality in patients with TMA (Hazard Ratio: 2.86 [1.01, 8.39], p=0.05) (Figure 3B).

Conclusions: Ours is the largest cohort of TMA following HSCT in children. The prevalence of TMA in our study is 0.8% with an increasing trend in recent years. The mortality in our pediatric TMA cohort is 30% which is in contrast to the higher mortality reported in previously published small case series. HHV6 emerged as not only a risk factor for TMA but also associated with increased mortality in these patients. Plasmapheresis was not associated with improved survival in our study. Studies exploring the pathophysiology of TMA and its relationship to other complications of HSCT are needed to optimize the outcome.