Most children who develop VTE have complex chronic conditions, multiple risk factors, and are hospitalized. Advantages of DOACs, including no monitoring and oral administration, are potential disadvantages in hospitalized children whose clinical status may change quickly, necessitating unplanned procedures or discontinuation of oral intake. The DOAC trials required that children with acute VTE receive a parenteral anticoagulant (UFH or LMWH) for at least 5 days prior to initiating the DOAC (4, 5). This is different from adult regimens, where DOACs (apixaban and rivaroxaban) can be used as initial treatment for acute VTE at a higher dose intensity for 1–3 weeks (12–14). Initial DOAC therapy for pediatric VTE may be desired in some situations, such as clinically stable, older adolescents with low likelihood of antiphospholipid antibody syndrome (APS), and can be considered (off label) in patients > 50 kg, based on adult regimens. Whether initial DOAC therapy is safe and effective for acute VTE in clinically stable younger children, and if higher intensity is needed, remains unknown.

The bimodal age peaks of VTE in children < 1 year of age and adolescents have been long recognized (1, 15, 16). Children < 1 year are underrepresented in the DOAC pediatric investigational programs due to inclusion/exclusion criteria and the challenges of enrolling young children on interventional trials. Trials restricted enrollment to neonates with gestational age > 37 weeks and/or body weight of at least 2.6 kg (4, 5). Oral formulations appropriate for infants are not available and limit their current use outside of clinical trials. Additional data on infants from prospective observational studies will be important to confirm the results observed in the small cohorts included in the clinical trials.

While the majority (80–90%) of pediatric VTE is related to a central venous catheter (CVC), patients with CVC-VTE represent a minority (15–27%) in pediatric DOAC trials (4, 5, 17). This may be because children who develop CVC-VTE are often acutely ill and may not be good candidates for a DOAC. However, sub analysis of 126 children with CVC-VTE in the EINSTEIN-Jr trial (90 rivaroxaban, 36 SOC) identified no recurrent VTE or major bleeding in either study arm, suggesting that DOACs are safe and effective for patients who met inclusion criteria (18).

CVT is often associated with risk factors such as cancer, head and neck infections, thrombophilia, and hormonal contraception (19, 20). Although use of anticoagulants in CVT must be balanced with the risk of intracranial hemorrhage, therapeutic anticoagulation is generally recommended in patients without hemorrhage (2). In a sub analysis of 114 children with CVT in the EINSTEIN-Jr trial (73 rivaroxaban, 41 SOC), symptomatic recurrent VTE at 3 months was rare (none in the rivaroxaban group, 1 in SOC group) (21). There were no major bleeding events in either cohort; clinically relevant non-major bleeding (CRNM) was observed in 5/73 (6.8%) of the rivaroxaban recipients compared to 1/41 in the SOC group (21). All patients were treated with LMWH or UFH for 5–9 days prior to randomization (21).

Children with cancer have multiple risk factors for VTE, including the cancer itself, CVCs, and prothrombotic medications including asparaginase and steroids (22). Anticoagulation can be challenging in oncology patients as they are frequently thrombocytopenic, require repeated procedures, have variable oral intake, and require medications that cause drug–drug interactions. The published pediatric DOAC trials did include children with cancer although excluded those with thrombocytopenia (platelet count <50–80 × 10⁹/L) or considered to be at a high risk of bleeding (4, 5). EINSTEIN-Jr included 40 patients with active cancer in the rivaroxaban arm and 16 patients in the SOC arm (5). DIVERSITY included 1 patient with active or previous cancer in the SOC arm and 18 in the dabigatran arm (4). These patients were not analyzed separately, yet overall rates of recurrent VTE and bleeding were low in both trials.

Meta-analysis of several large clinical trials comparing DOACs to LMWH in adults with cancer has concluded that DOACs are an effective treatment option for adults with cancer but should be used with caution in patients at high risk of bleeding (23). 2021 ASH guidelines suggest DOACs over LMWH for adults with cancer (24). Use of DOACs in children with cancer and VTE is reasonable, although there is limited data on management around procedures and thrombocytopenia, and drug interactions may be more frequent in this population.

Children with congenital and acquired heart disease often have unique risk factors for thrombosis including abnormal vascular flow, surgery, venous and arterial catheters, coagulation factor imbalances, and intracardiac devices. EINSTEIN-Jr included 35 children with cardiac disease in the rivaroxaban arm and 14 patients in the SOC arm (5). In the DIVERSITY study, 21 patients with congenital heart disease and VTE were included in the dabigatran arm and 27 patients in the SOC arm (4).

Current International Society of Thrombosis and Hemostasis guidelines for adults with VTE who are >120 kg or BMI > 40 kg/m² suggest that standard doses of rivaroxaban or apixaban are appropriate options regardless of high BMI and weight but suggest the other DOACs continue to be avoided in this population due to the lack of data (25). Although patients > 120 kg were not included in the pediatric clinical trials, it is reasonable to extrapolate adult data to patients < 18 years of age who are >120 kg and are otherwise acceptable candidates for DOACs.

Each of the DOACs requires some degree of renal excretion which is highly variable across drugs. Dabigatran is the most reliant on renal excretion and apixaban is the least (renal excretion by drug: apixaban 27%, rivaroxaban 36%, dabigatran 80%, and edoxaban 50%) (26). Patients with renal dysfunction may have decreased clearance and increased risk of bleeding complications. The DIVERSITY and EINSTEIN-Jr studies excluded children with severe renal dysfunction. Patients with estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m² (Schwartz formula) or on dialysis were excluded from DIVERSITY while children with eGFR <30 mL/min/1.73 m² and children <1 year old with serum creatinine > 97.5th percentile were excluded from EINSTEIN-Jr (4, 5).

Use of DOACs in adults with various degrees of renal insufficiency and renal failure continues to evolve as more data are available (27). Dose reductions and recommendations based on renal clearance for adults are provided in the package insert for each drug.

Children with abnormal liver function studies were also excluded from the DOAC trials. In EINSTEIN-Jr, exclusion criteria included ALT > 5× upper limit of normal (ULN) or bilirubin > 2× ULN; in DIVERSITY, those with ALT, AST or alkaline phosphatase >3× ULN were excluded (4, 5). In general, DOACs are not recommended for adults with moderate or severe hepatic impairment due to associated coagulation abnormalities and should also be avoided in children who would have been excluded based on above criteria until further data is available.

Adult data show inferiority of factor Xa inhibitors compared to VKA in patients with APS, particularly those with triple positive antiphospholipid antibodies (APA) (28–30). The ASH 2020 guidelines for management of VTE in adults exclude APS in their suggestion for DOACs over VKAs (31). Currently, the FDA labels for all DOACs exclude patients with triple positive APA. Most of the data leading to these recommendations is from studies evaluating rivaroxaban compared to VKAs, although one meta-analysis did include 144 patients treated with dabigatran (30). The DIVERSITY trial included 11 children with APA, 7 in the SOC arm and 4 in the dabigatran arm (4). Detailed information about these patients or their APA titers was not provided. Given the current literature, we would not recommend using DOACs in children with APS. Whether or not to test children with VTE for APA prior to use of a DOAC depends on the clinical scenario, recognizing that DOACs often cause a false positive dilute Russel Viper Venom Time (32).

Emerging data evaluating menstrual bleeding in adults indicates increased rates of AUB in women on rivaroxaban compared to VKAs and apixaban (33, 34). EINSTEIN-Jr reported menorrhagia in 7% of the rivaroxaban arm and 3% of SOC arm, none of which met criteria for major or CRNM bleeding (5). AUB was not separately described in the DIVERSITY study (4). These data are limited by variable definitions of AUB and denominators that may include all participants instead of only menstruating participants. This area deserves further investigation, particularly in female adolescents with VTE.

The UNIVERSE study was a randomized trial comparing rivaroxaban to aspirin for thromboprophylaxis in 112 children aged 2–8 years, within 4 months after a Fontan procedure (6). Rivaroxaban dosing in this study was targeted to achieve equivalent to 10 mg daily dosing in adults (6). The rate of thrombotic events was 3% (2/76) of the rivaroxaban group and 9% (3/34) in the aspirin group, with low rates of bleeding in both groups (6). Based on these data, rivaroxaban received FDA approval for thromboprophylaxis in children >2 years old with Fontan physiology.

ENNOBLE-ATE is a randomized trial to evaluate the safety of edoxaban compared to LMWH or VKA for thromboprophylaxis in children with cardiac diseases at risk for thromboembolism including patients with Fontan physiology, Kawasaki disease, heart failure, or other cardiac indication for thromboprophylaxis (7). The SAXOPHONE trial is a randomized trial comparing apixaban to LMWH or VKA to prevent thrombosis in children and infants with congenital and acquired heart disease (8). ENNOBLE-ATE and SAXOPHONE target therapeutic dose intensity DOACs which differs from UNIVERSE, which targeted prophylactic intensity rivaroxaban (6–8). These studies will inform thromboprophylaxis strategies in children with cardiac disease.

Current guidelines do not recommend routine thromboprophylaxis for children with cancer, although some hospitalized children and adolescents with multiple VTE risk factors may be started on prophylaxis. The PREVAPIX-ALL trial is a recently completed randomized trial designed to evaluate the efficacy and safety of apixaban for thromboprophylaxis in children with acute lymphoblastic leukemia or T or B cell lymphoblastic lymphoma and a CVC receiving asparaginase therapy (9). Apixaban, at equivalent dose intensity used for adult VTE prophylaxis (2.5 mg twice daily) was compared to no anticoagulation (9). Patients at high risk for bleeding were excluded, including those requiring multiple lumbar punctures (LPs), known bleeding disorder or coagulopathy, uncontrolled hypertension, hyperleukocytosis, or major surgery within 7 days of enrollment (9). Patients were required to have a platelet count ≥20,000/uL within 24 h of starting treatment and apixaban was held when the platelet count was <20,000/uL (9). The anticipated result of this study, which includes 512 children, will inform future thromboprophylaxis strategies for children with leukemia and a CVC.

DOACs are routinely used and approved to prevent AIS in adults with atrial fibrillation. There have not been any pediatric studies investigating the role of DOACs for primary or secondary AIS prevention. The etiology of AIS in children is multifactorial, however up to 45% have intracranial arteriopathy which is associated with a high risk of recurrent stroke (35). While both antiplatelet therapy and anticoagulants are used to prevent recurrent stroke in children, it is not always clear which approach is best and therapy is individualized by pediatric stroke experts (35).