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

Graft-versus-host disease (GVHD) is a major risk factor for transplant-associated thrombotic microangiopathy (TA-TMA), and the two conditions often co-occur; therefore, we evaluated biomarkers of endothelial injury to clarify their relationship. Our prospective MIDAS cohort study of 368 adult (>18 years) patients measured biomarkers before and after first allogeneic HCT. We found post-transplant cyclophosphamide (PTCy) significantly reduced acute GVHD incidence but had no impact on 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. Pre-transplant serum creatinine and detectable placental growth factor (PlGF) were associated with post-HCT TA-TMA. In sex-stratified multivariable models, a 1 mg/dL increase in pre-transplant creatinine conferred a ~40-fold higher TA-TMA risk in females versus ~5-fold 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 non-relapse mortality (NRM), also predicts TA-TMA. Day+28 levels of ST2, soluble Fms-like tyrosine kinase-1 (sFLT-1), and epidermal growth factor (EGF) were associated with NRM and overall survival, whereas baseline or day+28 soluble C5b-9 (sC5b-9) was not associated with TA-TMA. Post-hoc analyses of the EASIX composite score at day+28 post-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.