Impact of Obesity on Anticoagulation Dosing and Clinical Outcomes in Pediatric Patients with Venous Thrombo-Embolism

Background: Venous thromboembolism (VTE) and obesity are both dramatically increasing among all pediatric age groups. Dosing guidance for anticoagulation in children with obesity remains uncertain even though nearly 20% of Canadian children are deemed obese, despite possible pharmacokinetics differences.

Aims: Between obese and non-obese children receiving anticoagulation for VTE, compare the number of dose adjustments required to obtain a therapeutic dosage, required doses of anticoagulants, and rates of bleeding and thrombotic progression/recurrence.

Methods: This retrospective cohort study included children aged 0-<18 years old who received anticoagulation for VTE at therapeutic doses, hospitalized at the CHU de Québec (2000-2023). Data were collected for all anticoagulants used by included patients, except direct oral anticoagulants as they do not require monitoring. As per institutional standards, anticoagulation was resumed using standard doses without dose capping. Whether the dose of unfractionated heparin (UFH), low molecular weight heparin (LMWH), or vitamin K antagonist (VKA) was within therapeutic range was verified after 4-6 hours of UFH infusion or 2 to 3 doses of LMWH or VKA using anti-factor Xa (anti-Xa) or international normalized ratio, as appropriate, with target of 0.3-0.7 U/ml, 0.5-1.0 U/ml, or 2.0-3.0, respectively.

The outcomes were: 1) number of dose adjustments to reach therapeutic values, 2) increase or decrease from the initial dose, in %, 3) thrombotic progression or recurrence, defined using pediatric standardized ISTH criteria (Mitchell et al, 2011) and 4) clinically relevant bleeding (combining major bleeding and clinically relevant non-major bleeding, as per ISTH criteria).

Pearson Chi-square, Fisher exact, and Wilcoxon-Mann Whitney tests were used to compare characteristics of obese and non-obese children. Kaplan-Meier estimator was performed to assess the cumulative incidence of thrombotic recurrence/progression and of major bleeding. We performed a secondary stratified analysis excluding young children <2 years of age, in whom the definition of obesity has not been validated.

Results: We included 212 children, having 259 anticoagulation encounters (median age: 6.2 years, 49.1% male). Most frequent VTE locations included lower limb (31.6%), cerebral sinus venous thrombosis (21.2%), and upper limb (20.3%). Most children had associated comorbidities, infectious/inflammatory condition (63.7%), cancer (14.6%), and cardiac disease (13.2%), and being the more common. Overall, 23.6% of children were obese, with similar distribution in males and females. Obese children tended to be older (median age: 14.9 vs. 3.4 years, p<0.001). Prothrombotic risk factors varied, with higher rates of combined hormonal contraception (44.0 vs 9.9%, p<0.001), family history of thrombosis (30.0 vs 8.0%, p<0.001) and lower rates of central venous catheter (22.0 vs 46.9%, p<0.002) in obese vs. non-obese children.

Anticoagulants used included LMWHs (enoxaparin [78.4%], dalteparin [n=1.9%], and tinzaparin [n=1.9%]) followed by UFH (17.4%) and were comparable between obese and non-obese children (p=0.797). Most children had therapeutic anti-Xa levels following one dosage (66.7% in obese vs 51.5% in non-obese, p=0.181). Dosing requirements significantly differed between obese and non-obese children, with average increase from initial dose of 3.2 vs. 11.4% (p<0.001). In obese children, 11.1% of patients required reduction of ≥10% in anticoagulation dose compared to 2.0% in non-obese children (p<0.001).

The cumulative incidence of thrombotic progression/recurrence was comparable between groups (overall, over study duration: 10.8%, obese: 12.0%, non-obese: 10.5%, Log rank test p=0.786). Similarly, clinically significant bleeding was rare for both groups during the study (overall: 2.8%, obese: 2.0%, non-obese: 3.1%, Log rank test p=0.610).

Results were comparable when younger children (<2 years old) were excluded from analysis.

Conclusion: In children receiving therapeutic anticoagulation for VTE, mostly treated with enoxaparin, obesity was associated with lower anticoagulation requirements. Further prospective work is urgently needed to explore alternate dosing regimens in obese pediatric patients, such as dose capping, reduced initial dosing, or the use of fat-free mass.