Current practices of anticoagulant utilization in pediatric patients with acute myeloid leukemia (AML)

Abstract

Abstract Introduction: Management of thromboembolism (TE) in pediatric acute myeloid leukemia (AML) is challenging due to prolonged periods of thrombocytopenia and associated bleeding. There are no guidelines for prophylactic or therapeutic anticoagulation for children with AML. This study aims to understand anticoagulation utilization and association with bleeding events in hospitalized children with AML, both with and without thromboses. Methods: We performed a retrospective cohort study using the Pediatric Health Information System (PHIS) administrative database of index hospitalizations for patients 1-21 years of age upon admission and discharge in 2016-2024 with the diagnosis of AML across 49 hospitals. Patients with primary bleeding disorders or thrombophilia were excluded. Patients with acute promyelocytic leukemia were excluded due to risk of coagulopathy at diagnosis. Demographic data, diagnosis of TE, anticoagulation use, and bleeding events (BE) were extracted. Any ICD-10 code corresponding to clinically significant TE was included, such as deep venous thrombosis, arterial thrombosis, pulmonary embolism, and thrombosis of the central nervous system; any ICD-10 code corresponding to bleeding was categorized as a BE. Evaluated anticoagulants included low molecular weight heparins, the oral thrombin inhibitors, oral factor Xa inhibitors, and the vitamin K antagonist warfarin. Continuous anticoagulants, such as unfractionated heparin and bivalirudin, were excluded due to their role in complex critical care outside of the management of thrombosis. While dosing information was unavailable, use for presumed prophylaxis was defined as patients receiving anticoagulation in the absence of a TE. Comparisons were made using Chi-squared tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. Results: A total of 3,768 patients with AML were included from 49 PHIS hospitals with 167 (4.4%) experiencing a TE. Patients with TEs tended to be older than those without TEs (median [IQR]: 13 years [7, 17] vs. 10 [3, 15]; p<0.001). Among the 167 patients with TEs, 62.3% experienced an extremity venous thromboembolism, which was the most frequent site for a TE. The presence of a TE was associated with longer hospital stays (36 days [25, 60] vs. 28 [6, 37]), more ICU days (1 [0, 9] vs. 0 [0, 1]), greater hospital costs ($819,104 [$423,747, $1.4 million] vs. $414,980 [$126,701, $770,730]), and higher in-hospital mortality (13.8% vs. 3.4%) (all p<0.001). Of the cohort, 171 patients (4.5%) received anticoagulation. Almost half of these patients received anticoagulation for presumed prophylaxis (83/171; 48.5%). Of patients with a TE, 88 (52.3%) received anticoagulation, with the remainder receiving no anticoagulation. Enoxaparin was the most frequently utilized anticoagulant (150/171; 87.7%) followed by rivaroxaban (22 patients; 12.9%). Wide institutional variation was observed in anticoagulation use, with percentages of patients receiving any anticoagulation ranging from 0 to 12.2% (median [IQR]: 3.57, [1.47, 5.91]). A total of 750 patients (20% of cohort) experienced ≥1 BE. Most patients with BE received no anticoagulation (705/750; 94%). The occurrence of a BE was not found to be related to whether the patient was on no anticoagulation, on presumed prophylaxis, or receiving anticoagulation in the setting of a TE (p=0.055). The most common BE was ear, nose, and throat (ENT) bleeding, which was diagnosed for 58.3% of patients with a BE. Approximately 20% of patients with bleeding experienced ≥ 1 BE type with ENT and gastrointestinal BEs most frequently reported concurrently. Conclusions: Anticoagulation practices for pediatric patients with AML vary widely by institution. Bleeding prevalence was not found to be greater among patients receiving presumed prophylaxis compared to patients who received anticoagulation to treat TE, and those who did not receive anticoagulation. This suggests there may be a role for safe utilization of prophylaxis in high-risk patients. Prospective research is needed to determine the most safe and effective use for prophylactic and therapeutic anticoagulation in this high-risk patient population.