TA-TMA and GVHD are distinct consequences of endothelial injury: a MIDAS consortium study

ABSTRACT: Graft-versus-host disease (GVHD) is a major risk factor for transplant-associated thrombotic microangiopathy (TA-TMA), and the 2 conditions often co-occur; therefore, we evaluated the biomarkers of endothelial injury to clarify their relationship. Our prospective Microangiopathy, Endothelial Damage in Adults Undergoing Stem Cell Transplantation cohort study of 368 adult (aged ≥18 years) patients measured biomarkers before and after their first allogeneic hematopoietic cell transplantation (HCT). We found that posttransplant cyclophosphamide significantly reduced acute GVHD incidence but had no impact on the reduction of TA-TMA incidence. Severe TA-TMA occurred in the absence of acute GVHD but also occurred more frequently with higher grades of acute GVHD. Pretransplant serum creatinine and detectable placental growth factor were associated with post-HCT TA-TMA. In sex-stratified multivariable models, a 1 mg/dL increase in pretransplant creatinine conferred a ∼40-fold higher TA-TMA risk in females vs approximately fivefold in males. Both landmark and association analyses identified day +28 creatinine and suppression of tumorigenicity 2 (ST2) as significant TA-TMA risk factors. Our study phenotyped TA-TMA and GVHD concurrently, and we show that ST2, previously linked to GVHD treatment response and nonrelapse mortality (NRM), also predicted TA-TMA. Day +28 levels of ST2, soluble FLT-1, and epidermal growth factor were associated with NRM and overall survival (OS), whereas baseline or day +28 soluble C5b-9 was not associated with TA-TMA. Post hoc analyses of Endothelial Activation and Stress Index composite score at day +28 after HCT found significant associations with severe TA-TMA, acute GVHD, NRM, and OS. Overall, our data highlight distinct risk factors and biomarker profiles for TA-TMA and GVHD and also identify differences between adults and reported biomarkers of TA-TMA in children.