The clinical presentation of pediatric venous thromboembolic (VTE) disease includes many manifestations, such as catheter-related thrombosis, pulmonary embolism (PE), deep vein thrombosis (DVT), and sinovenous thrombosis. The majority of pediatric subjects (>95%) with VTE have at least 1 clinical risk factor. Currently, the presence of a central venous catheter is the most important acquired trigger for the development of venous thromboembolic disease in pediatric subjects, contributing to >90% of all neonatal thrombi and more than half of all thrombi in the older children1, 2 3, 4. Several mechanisms play a role in the development of catheter related thrombosis, including vessel wall injury by the catheter or infused substances (especially parenteral nutrition), compromised blood flow, and thrombogenic effects of the catheter material5. Catheter-related thrombi develop in children with long-term venous access devices for diseases such as malignancy, intestinal failure, renal insufficiency, and cystic fibrosis and in children with short-term catheters on the intensive care unit or for cardiac catheterization6, 7, 8. Other important risk factors for pediatric thrombosis are congenital heart disease, surgery, immobilization, malignancy, nephrotic syndrome, sepsis, and estrogen treatment. The presence of congenital prothrombotic disorders contribute to the development of pediatric venous thrombosis, as well9. Increasing numbers of pediatric subjects with chronic diseases will require anticoagulation as the incidence of VTE events rises due to hypercoagulability and the use of central venous catheters1

The clinical presentation of pediatric venous thromboembolic (VTE) disease includes many manifestations, such as catheter-related thrombosis, pulmonary embolism (PE), deep vein thrombosis (DVT), and sinovenous thrombosis. The majority of pediatric subjects (> 95%) with VTE have at least 1 clinical risk factor. Currently, the presence of a central venous catheter is the most important acquired trigger for the development of venous thromboembolic disease in pediatric subjects, contributing to > 90% of all neonatal thrombi and more than half of all thrombi in the older children. Several mechanisms play a role in the development of catheter related thrombosis, including vessel wall injury by the catheter or infused substances (especially parenteral nutrition), compromised blood flow, and thrombogenic effects of the catheter material. Catheter-related thrombi develop in children with long-term venous access devices for diseases such as malignancy, intestinal failure, renal insufficiency, and cystic fibrosis and in children with short-term catheters on the intensive care unit or for cardiac catheterization. Other important risk factors for pediatric thrombosis are congenital heart disease, surgery, immobilization, malignancy, nephrotic syndrome, sepsis, and estrogen treatment. The presence of congenital prothrombotic disorders contribute to the development of pediatric venous thrombosis, as well. Increasing numbers of pediatric subjects with chronic diseases will require anticoagulation as the incidence of VTE events rises due to hypercoagulability and the use of central venous catheters. Currently, the majority of pediatric thrombi are treated with low molecular weight heparin (LMWH) or unfractionated heparin (UFH) followed by LMWH or vitamin K antagonists (VKAs) for a total of 3 to 6 months11. More recently, data exists for the use of fondaparinux in children. Subjects should receive LMWH, UFH, or fondaparinux for at least 5 days following diagnosis of VTE. Guidelines recommend starting VKA on the first treatment day because of slow onset of action. LMWH, UFH, or fondaparinux may be discontinued when the VKA has reached its therapeutic level, as indicated by an international normalized ratio (INR) ≥ 2.0 for 2 or more measurements at least 24 hours apart. Many pediatric subjects have severe underlying diseases which preclude early oral treatment and thus LMWH is continued. In children, the outcome of venous thromboembolic disease has been reported in several studies. The REVIVE trial, a randomized controlled trial comparing LMWH with UFH and VKAs showed a direct mortality rate of 0% in both groups after 3 months. In the Canadian outcome study mortality as result of thrombosis was 2.2%. In the REVIVE trial, recurrent thrombosis occurred in 12.5% of the subjects in the UFH/VKA group and 5.6% in the LMWH group after 3 months of treatment. The recurrence-free survival after 6 months was 93% in pediatric subjects of one center in the Netherlands. Most subjects were treated with LMWH or UFH followed by VKAs. Merkel et al followed 27 subjects treated with LMWH. After a mean time of 2.3 years (range: 0.5 – 6.25 years), 55.6% of the subjects showed complete resolution with radiographic tests, 29.6% partial resolution, and 14.8% no resolution. Newall et al studied radiographic outcome of 22 infants (< 6 months old) and 73 children (≥ 6 months old) after 5 days to 4.2 years. In infants and children, complete resolution occurred in 53% and 47%, partial resolution in 29% and 36%, and no resolution or extension in 18% and 17%, respectively. Post-thrombotic syndrome (PTS) is a manifestation of chronic venous insufficiency following DVT. Children with PTS must endure chronic sequelae for many decades. Goldenberg et al showed that PTS occurrence varied widely (< 10% to 70%) depending on the scoring system; the calculated mean frequency of PTS was 26% (95% confidence interval [CI]: 23% to 28%) among a total of nearly 1000 subjects with upper extremity (UE)/lower extremity (LE) DVT. In the cross-sectional study, multiple logistic regression analysis revealed that lack of thrombus resolution was associated with a statistically significant 4 fold increase in odds of PTS. Therefore we propose to evaluate edoxaban on the reduction of thrombotic burden defined by “no change and extension” of the thrombus at the month 3 visit. Edoxaban is an oral direct inhibitor of activated Factor X with predictable pharmacokinetics (PK) and pharmacodynamics (PD). As a result, anticoagulant effects are more likely to remain within the therapeutic range, thereby decreasing the likelihood of bleeding, and potentially removing the need for dose adjustment or frequent monitoring. These advantages may result in increased patient satisfaction and adherence compared with existing anticoagulants Edoxaban has been approved for the following indications in the US: • To reduce the risk of stroke and systemic embolism (SE) in subjects with nonvalvular atrial fibrillation (NVAF) with limitation of use in patients with CrCL > 95 mL/min. • Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant. In the EU and Japan, edoxaban has been approved for the following indications: • Prevention of stroke and systemic embolism in adult subjects with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack (TIA) with no limitation of use. • Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults . This study will evaluate the benefits and risks of edoxaban in pediatric subjects with thromboembolic disease.