Lipid dysregulation after hematopoietic stem cell transplant.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of allogeneic hematopoietic stem cell transplant (allo-HSCT), primarily driven by endothelial injury and complement activation. Statins, combined with other drugs, are commonly used as prophylaxis against endothelial injury in some parts of the world but their mechanism of action has not been clearly defined. We hypothesized that dysregulation of lipids, or their precursors, ceramides, might be an important mechanism of endothelial injury, and that statins might ameliorate that dysfunction. We measured plasma ceramide species at baseline and day 14 in pediatric and young adult allo-HSCT recipients. Ceramide species in general were increased in those who later developed endothelial injury, manifest as TA-TMA. These findings highlighted ceramides as markers of endothelial stress, prompting us to explore whether statin prophylaxis could favorably modulate lipid and ceramide pathways. A single-arm phase I trial of pravastatin prophylaxis was also performed in patients at elevated risk of endothelial injury due to high body mass index to assess lipid and ceramide modulation over time. Multiple ceramide species were elevated in patients who developed TA-TMA and showed strong correlations with ST2 but not with sC5b-9. While ceramides were associated with TA-TMA in univariate models, only ST2 remained significant in multivariable analysis. Addition of ceramide levels to ST2 only modestly improved prediction of later TA-TMA in Receiver Operating Characteristic (ROC) analysis. Pravastatin prophylaxis was associated with distinct shifts in lipoprotein and ceramide profiles, potentially reflecting modulation of endothelial function. Pravastatin may alter ceramide and lipoprotein pathways in a clinically meaningful way, contributing to their role in endothelial protection.