Prophylaxis and Treatment Strategy for Endothelial Cell Damages after Hematopoietic Cell Transplantation in Children

Abstract

Introduction Sinusoidal obstruction syndrome (hSOS) and thrombotic microangiopathy (TMA) are life-threatening complications caused by endothelial cell damage (ECD) associated with hematopoietic cell transplantation (HCT). Danaparoid sodium (DS) is a heparinoid comprising a mixture of low molecular weight glycosaminoglycans with anti-Xa and anti-IIa effects, which prevent fibrin formation. Recombinant thrombomodulin (rTM) comprises the active extracellular domain of thrombomodulin and inactivates coagulation by binding to thrombin. Both of them were expected to play crucial roles in the management of disseminated intravascular coagulation (DIC) and ECD after HCT. Objectives We aimed to evaluate the efficacy and feasibility of DS for prophylaxis and rTM for the treatment of hSOS and TMA after HCT in children. Methods Between January 2011 and December 2017, 91 children (median age 7.6 years, range 0.6–18.2; with hematologic malignancies [n = 54], solid tumors [n = 9], or benign diseases [n = 28]) underwent 118 consecutive HCTs (9 autologous and 109 allogeneic settings; busulfan-based myeloablative conditioning [n = 23], total body irradiation-based myeloablative conditioning [n = 35], or reduced intensity [n = 60]) at our institution. All of them were treated prophylactically with DS (intravenously injection, 30 international units [IU] per kg of body weight, twice a day from the initiation of the conditioning regimen to day 50 after HCT) to prevent ECD. Any patient who developed ECD despite prophylaxis were treated with rTM (intravenous drip infusion, 380 IU per kg, once a day). We reviewed their clinical records and evaluated the efficacy and feasibility of rTM for these children. Results Nine patients developed SOS (severe 5, moderate 1, and mild 3) at a median of 19 days after HCT (range, 6–173), and 6 patients developed TMA at median day 38 (range, 27–106). The cumulative incidences of SOS and TMA at 100 days were 6.8% and 4.4%, respectively. A total of 17 patients received 18 courses of rTM for complications after HCT. The median dose and duration of rTM treatments were 367 IU/kg/day (range, 189–404) and 7 days (range, 3–22), repectively. rTM treatments initiated at a median of 30 days after HCT (range, 6–173). The cause of rTM administration included SOS (n = 9), infection with DIC (n = 4), TMA (n = 3), or engraftment syndrome with DIC (n = 2). All these complications were resolved or improved by rTM treatment along with supportive care. Among the 17 patients receiving rTM treatment, no hemorrhagic events or deaths due to HCT-related toxicity were observed; however, 7 died of their underlying disease. Multivariate analysis revealed that neither SOS nor TMA had a negative impact for transplant outcome. Conclusion DS and rTM are effective and safe for the management of ECD after HCT in children. A larger multicenter prospective study is warranted to confirm these findings.