# Effective Treatment of Allogeneic Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy in Pediatric Patients Using Defibrotide: A Report from a Single Center in China
## Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for various hematologic malignancies, bone marrow failure syndromes, and certain genetic disorders. However, allo-HSCT is associated with several complications, one of which is thrombotic microangiopathy (TMA). TMA is a severe and life-threatening condition characterized by endothelial injury, microvascular thrombosis, hemolysis, and organ dysfunction. In pediatric patients, the incidence of TMA following allo-HSCT ranges from 10% to 30%, and it is associated with significant morbidity and mortality.
The pathophysiology of TMA in the context of allo-HSCT is complex and multifactorial, involving endothelial damage due to conditioning regimens, immunosuppressive drugs (e.g., calcineurin inhibitors), infections, and graft-versus-host disease (GVHD). The management of TMA is challenging, and there is no consensus on the optimal treatment. Traditional therapeutic approaches include discontinuation of calcineurin inhibitors, plasma exchange, and supportive care. However, these strategies often yield suboptimal outcomes.
Defibrotide, a polydisperse oligonucleotide with anti-inflammatory, anti-thrombotic, and endothelial-protective properties, has emerged as a promising therapeutic option for TMA. Initially approved for the treatment of hepatic veno-occlusive disease (VOD) following HSCT, defibrotide has shown potential in treating TMA due to its ability to protect and repair endothelial cells. This article presents a report from a single center in China on the effective use of defibrotide in pediatric patients with allo-HSCT-associated TMA.
## Case Series Overview
### Study Design and Patient Population
This retrospective study was conducted at a single pediatric hematology center in China. The study included pediatric patients (aged 1-18 years) who developed TMA following allo-HSCT between January 2018 and December 2022. TMA was diagnosed based on clinical and laboratory criteria, including the presence of microangiopathic hemolytic anemia, thrombocytopenia, elevated lactate dehydrogenase (LDH), schistocytes on peripheral blood smear, and evidence of organ dysfunction (e.g., renal impairment, neurological symptoms).
All patients received defibrotide as part of their treatment regimen for TMA. The primary objective of the study was to evaluate the efficacy and safety of defibrotide in this patient population. Secondary objectives included assessing the resolution of TMA-related symptoms, improvement in laboratory parameters, and overall survival.
### Defibrotide Administration
Defibrotide was administered intravenously at a dose of 25 mg/kg/day, divided into four doses, for a minimum of 14 days. The duration of treatment was individualized based on the patient’s clinical response and resolution of TMA-related symptoms. In addition to defibrotide, supportive care measures such as red blood cell and platelet transfusions, renal support, and discontinuation of calcineurin inhibitors were implemented as needed.
### Results
#### Patient Characteristics
A total of 15 pediatric patients with allo-HSCT-associated TMA were included in the study. The median age of the patients was 9 years (range: 2-17 years), and the underlying conditions for which allo-HSCT was performed included acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), aplastic anemia, and thalassemia major. The median time to TMA onset following allo-HSCT was 45 days (range: 20-90 days).
#### Clinical and Laboratory Outcomes
All patients demonstrated significant clinical improvement following defibrotide treatment. Key findings included:
– **Resolution of Hemolysis**: Hemolysis, as evidenced by a decrease in LDH levels and the disappearance of schistocytes on peripheral blood smear, resolved in 13 out of 15 patients (87%) within 14 days of initiating defibrotide.
– **Platelet Recovery**: Thrombocytopenia improved in 12 out of 15 patients (80%), with platelet counts returning to normal or near-normal levels by the end of the treatment course.
– **Renal Function**: Renal impairment, which was present in 10 patients (67%) at the time of TMA diagnosis, improved in 8 patients (80%) following defibrotide therapy. Two patients required temporary dialysis, but both were able to discontinue dialysis after treatment.
– **Neurological Symptoms**: Three patients presented with neurological symptoms (e.g., seizures, altered mental status) at the time of TMA diagnosis. All three