Critical Link Discovered for Dangerous Complication of Stem Cell Transplants

Published September 7, 2017 | Blood

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and poorly recognized complication that can occur in about 30 percent of people receiving hematopoietic stem cell transplantation (HSCT). In severe cases, mortality can exceed 80 percent.

However, a study led by Nicholas Gloude, MD, and Stella Davies, MBBS, PhD, reveals an important mechanistic link that appears to drive the emergence of TA-TMA and may serve as a target for improving outcomes.

The team reviewed medical records and biosamples from 103 children who received allogeneic HSCT for non-malignant disorders. Then they tracked outcomes of complications from chemotherapy, radiation or infections.

They found that injured endothelium releases IL-8, causing neutrophil activation. This, in turn, releases granule proteins and double-stranded DNA (dsDNA) that form extracellular fibers known as neutrophil extracellular traps (NETs). These NETs trigger complement activation with deposition of complement factor P and C5b-9, and result in microthrombi formation. The result: TA-TMA, which often can be difficult to distinguish from graft-versus-host disease (GVHD).

“Our study results demonstrate a strong association between the presence of higher levels of circulating dsDNA following stem cell transplantation and transplant outcomes, including overall survival, TA-TMA, and acute GVHD,” the co-authors wrote. “Our data offer a mechanistic insight … that might allow development of targeted therapies that would reduce injury and improve survival.”

The good news: complement-blocking therapy using eculizumab can clear away NETs and resolve TMA in patients without acute GVHD. Patients with acute GVHD, however, require further treatment.

The team also notes that circulating levels of dsDNA can serve as a rapid proxy test to measure NET levels. Such a test should be further explored in clinical trials, the authors say.