Clinically relevant bleeding and heavy menstrual bleeding among patients <21 years old with provoked VTE: Findings from the multinational kids-DOTT trial

Abstract Introduction Clinically relevant bleeding (CRB) remains an adverse outcome of anticoagulation for treatment of venous thromboembolism (VTE), with occurrence ranging from 2 to 3% in recent randomized clinical trials (RCT) of pediatric VTE treatment with direct oral anticoagulants and the Kids-DOTT trial on duration of therapy. Heavy menstrual bleeding (HMB) not otherwise meeting criteria for major bleeding was not included in the definition of CRB historically, but its importance has become recognized more recently. Factors associated with risk of CRB and HMB in pediatric VTE patients remain undefined. Accordingly, the objective of this work was to characterize, as well as investigate factors associated with, CRB and HMB in children treated with anticoagulation for VTE, via an analysis of the multinational Kids-DOTT RCT. Methods The Kids-DOTT trial was an NIH-sponsored multinational randomized RCT comparing 6 weeks vs. 3 months of anticoagulation for provoked acute VTE treatment in patients <21 years, whose primary RCT findings were published in 2022. Data analyzed in the present work were limited to Kids-DOTT participants without persistent antiphospholipid antibodies (APA) and included: patient demographics; VTE anatomic site; VTE provoking factors; anticoagulant treatment during acute (within 1 week) and subacute (>1 week) periods post-diagnosis of index VTE; and occurrence and features of CRB and HMB. Findings in children with persistent APA have been separately published. Data were summarized as counts (with percentages) for categorical variables and medians (with interquartile ranges (IQR)) for continuous variables. Statistical analyses were performed using SAS version 9.4 (Cary, NC: SAS Institute Inc.). Results Clinically relevant bleeding (CRB) and HMB occurred in 9 of 286 patients (3.1%; CRB) and 7 of 80 females >11 years old (8.8%; HMB), respectively, who were without persistent APA and followed through 1 year. Median age of those with CRB, was 8.7 years (IQR 3.5-16.2 years), and of those without CRB or HMB was 7.6 years (IQR 0.9-14.7 years). CRB occurred in 4 (2.4%) and 5 (2.2%) patients who received shortened (6 weeks) and conventional (3 months) durations of anticoagulation. Among patients with CRB, all bleeding events occurred during the subacute treatment period post-diagnosis of index VTE. Among patients undergoing clinical laboratory investigation for contributors to CRB or HMB, none had supratherapeutic anticoagulant levels or occult coagulopathy. Conclusions In patients enrolled in the Kids-DOTT trial, CRB occurred at a similar frequency to other recent anticoagulation randomized control trials, while HMB occurred in a relatively high proportion of females >11 years old. Given the latter novel finding, future studies of pediatric VTE treatment must continue to prospectively assess HMB occurrence. Further research is also needed to elucidate risk factors for CRB and HMB in children receiving anticoagulation for the treatment of VTE.