A Pilot Multi-Pronged Approach to Measuring Endothelial Dysfunction and Predict the Development of Endothelial Disorders and Death Post Hematopoietic Cell Transplantation (HCT)

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Background Endothelial dysfunction is a key driver of transplant associated thrombotic microangiopathy (TA-TMA) and sinusoidal obstructive syndrome (SOS)- early syndromes post hematopoietic cell transplantation associated with non-relapse related mortality (NRM). The primary objective of this pilot study was to determine the feasibility of routine hyperemia arterial tonometry (RH-PAT) and obtaining circulating endothelial cells (CEC). Methods In this prospective IRB approved study, patients were serially enrolled from April 2020- December 2022. Imaging and blood were obtained pre-HCT, day 0, day 14 and day 30. All ages were eligible for the blood sample component, but the RH-PAT arm was restricted to those >10 years old. CEC were measured using flow cytometry (Farinacci et al. Res Pracr Thromb Haemost. 2019). RH-PAT is an FDA approved, non-invasive technique to measure endothelial health and calculates a reactive hyperemic index (lnRHI), lower lnRHI values are indicative or poor endothelial function . Descriptive statistics were used to compare groups. Results Fifty-one patients enrolled in the study, 21 participated in the RH-PAT arm, 43 in the blood sample arm, and 17 in both. The median age at HCT was 10.1 years, 24 (49%) were female and 47 (96%) underwent allogeneic HCT. Ten (25%) were Black and 13 (27%) Hispanic. Nineteen (37.2%) developed TA-TMA a median of 35 days post HCT (range 24.5 to 59). There were no significant differences in CEC at any time points in patients with TA-TMA compared to those without. LnRHI values were significantly lower pre-HCT in those who later developed TA-TMA compared to those who did not develop TA-TMA, though there were no differences on day 0, 14 nor at the time of TA-TMA diagnosis (Fig 1). Eleven patients developed SOS a median of 13 days post HCT (range 9.5 to 23). Seven patients experienced NRM a median of 134 days post HCT (range 69 to 353.5). CEC were not different among patients with SOS nor those who died of NRM at any time point. LnRHI was significantly lower on day 30 in those who ultimately died of NRM versus those who survived (Fig 2). Day 30 lnRHI predicted NRM with an AUC of 0.81 (95% CI 0.59 to 1). However, there were no differences in lnRHI at other time points, nor were there any differences in lnRHI in those with SOS compared to no SOS at any time points (Fig 3). Discussion CEC were low at all time points, difficult to isolate, and not different in those with endothelial disorders including SOS and TA-TMA. RH-PAT was poorly tolerated. Neither approach appear feasible in large cohorts. We found that those who developed TA-TMA had a significantly lower lnRHI pre-HCT, indicating poorer endothelial health prior to HCT. This supports the hypothesis that some patients come to HCT with more endothelial damage, perhaps predisposing them to developing TA-TMA. Additional studies are needed to identify alternative approaches of measuring endothelial dysfunction.

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