Endothelial injury, F-actin and vitamin-D binding protein after hematopoietic stem cell transplant and association with clinical outcomes.

Abstract

Endothelial injury after hematopoietic stem cell transplant is an important initiating factor for early transplant toxicities of thrombotic microangiopathy and acute graft versus host disease. We hypothesized that release of the angiopathic molecule filamentous actin (F-actin) from hematopoietic cells lysed during conditioning prior to stem cell transplant would be associated with clinical outcomes. We detected F-actin in the blood of 52% of stem cell transplant recipients in the first 14 days after transplant, and children with detectable F-actin had a significantly elevated risk of thrombotic microangiopathy (P=0.03) and non-relapse mortality (P=0.04). F-actin is cleared from the circulation by vitamin D binding protein (VDBP) so we expected that higher levels of VDBP would improve outcomes. In a cohort of 190 children receiving an allogeneic transplant, risk of thrombotic microangiopathy was reduced in those with serum concentrations of VDBP above the median at day 30 (10% vs. 31%, P=0.01), and graft versus host disease and non-relapse mortality were reduced in those with levels above the median at day 100 (3% vs. 18%, P=0.04 and 0% vs. 15%, P=0.002). Western blot analyses demonstrated actin-VDBP complexes in the blood, which cleared by day 21-28. Our data support modulation of cytokine secretion and macrophage phenotype by VDBP later after transplant. Taken together, our data identify an association between Factin, a mediator of endothelial damage, and VDBP, an actin scavenger, as modifiers of risk of clinical consequences of endothelial injury.