Early Echocardiographic and Serum Biomarkers Predict Thrombotic Microangiopathy, Endotheliopathy, and Survival After Pediatric Hematopoietic Stem Cell Transplant

Many life-threatening complications of hematopoietic stem cell transplantation (HSCT) develop secondary to endothelial injury and dysfunction, including transplant-associated thrombotic microangiopathy (TA-TMA), sinusoidal obstruction syndrome, idiopathic pneumonia syndrome, and engraftment syndrome. These endotheliopathies are often accompanied by cardiovascular compromise. Echocardiographic abnormalities including pericardial effusions and elevated right ventricular pressure have previously been identified as early indicators of TA-TMA. Additional echo-derived parameters and serologic metrics of ventricular function are yet to be evaluated as predictors of post-HSCT endotheliopathies and mortality among children. We sought to assess the utility of early post-HSCT echo and B-type natriuretic peptide (BNP) screening in predicting the development of TA-TMA, additional endotheliopathies, and death. A single-center, prospective cohort study was performed after the implementation of a uniform screening protocol at our pediatric hospital. Patients who received a HSCT from October 2021 to August 2023 were screened with echocardiography and serum BNP levels pre-HSCT, d +7 and d +30 from transplant. Changes from baseline in echocardiographic metrics of right and left ventricular function, pericardial effusions, and BNP levels were evaluated as predictors of post-HSCT TA-TMA, additional endotheliopathies, and death. Fifty-two patients underwent a first HSCT during the study period. The 1-yr cumulative incidence of TA-TMA was 13.8% ± 9.6%, of any endotheliopathy was 39.2% ± 13.7% and of death was 13.5% ± 9.4%. Several echocardiographic predictors were found to be associated with the later development of TA-TMA, including pericardial effusions (HR 7.59, 95% CI: 1.80 to 32.00, P = .006) and measures of increased right and left ventricular function, such as a 10% increase in longitudinal tricuspid annular systolic velocity (tricuspid s', HR 1.61, 95% CI: 1.08 to 2.38, P = .018), and a 10% increase in mitral s' (HR: 1.70, 95% CI: 1.05 to 2.75, P = .031) evaluated at d +30. Similarly, several echocardiographic metrics were associated with the later development of any endotheliopathy, including measures of increased ventricular function such as a 10% increase in tricuspid annular plane systolic excursion (HR 1.43, 95% CI: 1.08 to 1.90, P = .013) and a 10% increase in mitral s' (HR: 1.28, 95% CI: 1.05 to 1.57, P = .016) at d +30, as well as a BNP increase of 50pg/ml from baseline at d +7 (HR: 2.86, 95% CI: 1.15 to 7.08, P = .024). Mortality was significantly increased for patients with at least a 10% increase in left ventricular ejection fraction at d +7 (P = .035) and pericardial effusions (P = .002). Among pediatric HSCT recipients, acute cardiovascular injury associated with HSCT-related endotheliopathy develops at a subclinical level in the early post-transplant period. Subtle increases in right and left ventricular function, increases in BNP level, and pericardial effusions likely reflect an early response to endothelial injury and are associated with the later development of TA-TMA, other endotheliopathies, and death. Screening protocols and prophylactic and therapeutic interventions for pediatric HSCT recipients should consider these novel cardiovascular biomarkers.