New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy

Abstract

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is an understudied complication of HSCT that significantly affects transplant-related morbidity and mortality. Over the past several decades, the cause of TA-TMA has remained unknown, limiting treatment options to non-specific therapies adapted from other diseases. Recent prospective studies dedicated to the study of TA-TMA have provided new insights into the pathogenesis of, and genetic susceptibility to TA-TMA, raising awareness of this important transplant complication and allowing for the identification of potentially novel therapeutic targets. Specifically, many patients with TA-TMA develop multi-organ tissue injury through endothelial damage mediated by the activation of the complement pathway, leading to rational therapeutic strategies including complement blockade. This new knowledge has the potential to favorably influence clinical practice and change the standard of care for how patients with TA-TMA are managed. In this review, we summarize novel approaches to the recognition and management of TA-TMA, using case examples to illustrate key clinical points that hopefully lead to improved short and long-term outcomes for these complex HSCT patients, who remain at significant risk for treatment-related morbidity and mortality.

Safety and effectiveness of eculizumab for pediatric patients with atypical hemolytic–uremic syndrome in Japan: interim analysis of post-marketing surveillance

“…Most of these patients had underlying HSCT-TMA or malignancies: 4 of 10 patients with HSCT-TMA (40%) survived and 3 showed evidence of TMA improvement. A previous prospective observational study of HSCT-TMA showed that overall survival was significantly longer for pediatric patients treated with eculizumab than for those who did not receive eculizumab (62 vs. 9%, respectively, at 1 year after TMA diagnosis) [19,20]. However, in that study eculizumab dose was increased significantly, which was not the case in this PMS study.…”

Thrombotic Microangiopathy and the Kidney

“…The optimal treatment strategy remains controversial; favorable outcomes with eculizumab have been described in uncontrolled retrospective analyses (101) and there is some evidence to suggest that complement is activated (13), but prospective trials are likely needed in order to establish a consensus.…”

In vitro evidence of complement activation in transplantation-associated thrombotic microangiopathy

“…Recent data demonstrating remission of TA-TMA after use of the anti-C5 monoclonal antibody eculizumab suggest a central pathophysiologic role of the complement cascade. [8][9][10] The modified Ham test uses PIGA-null TF-1 cells, which lack expression of the complement regulatory proteins CD55 and CD59, rendering them increasingly vulnerable to complement-mediated cell death. 11 This test has been used in the research setting to distinguish microangiopathic diseases based on the degree of complement activation.…”