Treatment and Prevention of Venous Thromboembolism in Children: Current State and Future Directions

Venous thromboembolism (VTE), predominantly composed of deep vein thrombosis (DVT) and pulmonary embolism (PE), is recognized as the second most common complication of hospitalization in children.¹  PE can be life-threatening, and DVT poses a risk for long-term sequelae pertaining to chronic venous insufficiency. Further, pediatric VTE carries a significant financial burden by increasing health care costs and length of hospitalization for affected children.²  VTE in young patients is a global concern, though evidence for its continued rise in incidence over the past few decades has been best established in the United States, where a recent analysis of the Pediatric Health Information System database demonstrated a 130 percent increase in the rate of pediatric hospital-acquired VTE from 2008 to 2019.³ 

Anticoagulation is the mainstay of care for patients with VTE, based on evidence for efficacy in reducing the risk of recurrent VTE dating back to an early randomized clinical trial (RCT) conducted in the 1960s on the use of vitamin K antagonists versus placebo in adults with proximal limb DVT.⁴  Since that time, most trials in adults have evaluated various treatment regimens for VTE through either head-to-head trials of newer anticoagulants versus conventional ones (most trials) or varying durations of anticoagulation (a smaller number of trials). Additionally, anticoagulation as primary VTE prevention has been studied in several settings in adults, from orthopedic surgery to hospitalization for nonsurgical conditions, across multiple drug development programs.

Evidence in support of the standards of care for VTE treatment and primary prevention among patients younger than 21 years has remained a critical unmet need in the VTE field for more than two decades, despite VTE becoming increasingly recognized as an important pediatric concern. The extrapolation of adult data on anticoagulation to pediatric use in VTE treatment and prevention is limited by important differences in disease epidemiology and pathophysiology and in pharmacodynamic response to anticoagulants among children when compared to adults, some of which are driven by changes that occur in the hemostatic system throughout childhood.⁵ 

Few RCTs of VTE treatment were conducted in pediatric populations prior to the present decade, most of which were terminated early due to suboptimal accrual.⁶  Recently, the direct oral anticoagulant (DOAC) development programs have seen the successful completion of RCTs of pediatric VTE treatment and have provided high-quality evidence in support of the safety and efficacy of these anticoagulants when compared to the historical conventional anticoagulants (predominantly low-molecular-weight heparins and vitamin K antagonists).^7,8  Additionally, for patients younger than 21 years with acute provoked VTE, the National Institutes of Health–sponsored Kids-DOTT RCT recently demonstrated that a six-week duration of anticoagulation is noninferior to the historical conventional duration of three months; notable exclusions from enrollment or randomization in Kids-DOTT were prior VTE, severe anticoagulant deficiencies, proximal PE, active cancer, lupus, persistent antiphospholipid antibodies at six weeks post-VTE, or complete veno-occlusion at six weeks post-VTE.⁹ 

Currently, rivaroxaban and dabigatran have been approved by regulatory agencies in the United States, European Union, and United Kingdom for the treatment and secondary prevention of VTE in children. Additionally, rivaroxaban has been approved by the U.S. Food and Drug Administration for thromboprophylaxis in children with congenital heart disease following the Fontan procedure.^10,11 

The evidence basis for primary VTE (or all-TE) prevention in children has also grown rapidly in recent years. In particular, the recent DOAC development programs have included RCTs in pediatric cancer–associated primary VTE prevention (specifically, patients with hematologic malignancies and central venous catheters [CVCs] receiving chemotherapy regimens containing L-asparaginase)¹²  and primary thromboembolism prevention in children with cardiac disease (post-Fontan procedure, Kawasaki disease, and other settings).^13,14  At the same time, many common scenarios for heightened VTE risk (particularly critically ill and non-critically ill hospitalized patients) have yet to be addressed by RCTs or are currently undergoing such studies.

Critically ill children in particular exhibit a multitude of VTE risk factors such as the presence of a CVC, prolonged hospitalization, acute immobility, underlying inflammatory conditions, and invasive mechanical ventilation, that place them at an especially heightened risk for VTE when compared to non-critically ill children.^15–17  Although lower in prevalence, VTE among non-critically ill hospitalized children remains a leading cause of morbidity.¹⁸  Similar to the VTE risk profile of the critically ill patient, the presence of a CVC, systemic inflammation or infection, and prolonged hospitalization are independent risk factors for VTE among non-critically ill hospitalized children.^19–21 

Multicenter efforts to derive and validate risk models for hospital-acquired VTE among the critically ill and non-critically ill pediatric populations have been conducted, including via the Children's Hospital Acquired Thrombosis Consortium in the United States,^17,22  and recently through a nonrandomized phase II multicenter trial on enoxaparin as primary VTE prevention in children hospitalized for COVID-19–related illness, including the multisystem inflammatory syndrome of childhood.²³  The identification of such pediatric subpopulations at greatest risk for hospital-acquired VTE is essential to the design of risk-stratified thromboprophylaxis trials that optimize the inherent tradeoff between thromboprophylaxis efficacy (i.e., VTE risk reduction) and safety (i.e., clinically relevant bleeding risk increase) related to anticoagulant administration.

Although great advances have been made in the past few decades in the understanding of the epidemiology, natural history, management, and prevention of pediatric VTE, there are still considerable knowledge gaps to be addressed. Long-term post-thrombotic sequelae, as well as clinical and biologic prognostic markers thereof,^24,26  remain suboptimally defined but offer promise toward tailoring future therapeutic regimens to not only safely prevent VTE but also optimize long-term functional outcomes. Future work in the field of pediatric VTE must also continue to evaluate special populations at heightened risk for VTE as well as pursue rare “indications,” and must address facilitators and barriers for access and adherence to evidence-based treatment and prevention modalities, including efforts to elucidate and ameliorate inequities in outcomes across race,^27,28  ethnicity, and socioeconomic groups. The increasing depth and diversity of talented early-career interdisciplinary investigators from multiple disciplines who are passionately pursuing collaborative clinical and translational research in pediatric VTE must continue to be fostered and will ensure that the recent acceleration in the rate of advancement in the field of pediatric VTE will be sustained long into the future.