Thrombosis in Pediatric Cardiology and Congenital Heart Disease: Perspectives and Unique Challenges

Children and adults with congenital heart disease and children with acquired heart disease are patients at risk for clinically significant thrombosis. These include intracardiac, intravascular, and coronary thrombosis; thrombosis of implanted devices and shunts; and thromboembolic stroke. Thrombosis and its management and complications are now increasingly recognized as important factors contributing to their morbidity and mortality.

The prevalence and clinical relevance of thrombosis in these populations are influenced by developmental, acquired, and hemodynamic factors. The interplay between these various factors is complex and poorly understood. First, studies in developmental hemostasis demonstrate that there are quantitative as well as qualitative differences of the coagulation system with age.¹ For example, neonates and young children have decreased levels of Factors II, VII, IX, X, XI, XII; protein C; protein S; antithrombin; tPA; and plasminogen but increased levels of alpha 2 macroglobulin and PAI-I. Platelets from neonates display a decreased responsiveness to platelet agonists such as collagen, thrombin, ADP, and epinephrine. In addition, children with congenital heart disease can have abnormalities in coagulation proteins, inhibitors of coagulation and fibrinolytic proteins, and prothrombotic genetic polymorphisms.

Secondly, acquired factors contribute to thrombosis in children with heart disease and adults with congenital heart disease and include the use of aggressive life-saving therapies such as cardiopulmonary bypass and ventricular assist devices. Blood coagulation and inflammatory systems can be activated upon contact with these foreign surfaces.^2,3 Devices of extended duration such as pacemakers, artificial heart valves, intracardiac occlusion devices, stents, and intravascular catheters are also being used increasingly in this patient population. Although biomedical device technology has made progress, a surface that is completely biocompatible for long-term use has not been achieved.

Thirdly, hemodynamic factors related to abnormal ventricular function, arrhythmias, and complex cardiac anatomy are additional contributors to the risk of thrombosis. The highest risk groups include children with single ventricle in which all three of these hemodynamic factors may co-exist. The incidence of thrombotic complications is 40% and 28% after initial palliation and superior cavopulmonary connection (SCPC), respectively, while the 5-year freedom from thrombotic complications after Fontan procedure is 79%.⁴

Unfortunately, despite a better understanding of some of these developmental, acquired, and hemodynamic factors, there continues to be sparse data regarding the optimal strategies for prevention, detection/surveillance, and management of thrombosis in pediatric heart disease and adult congenital heart disease. The AHA Scientific Statement entitled “Prevention and Treatment of Thrombosis in Children and Adults with Congenital Heart Disease and in Children with Acquired Heart Disease”⁵ is an invaluable contribution to the literature. It is a comprehensive summary of the pathophysiology, clinical course, monitoring, prevention, management, and needed research in heart disease in children as well as adults with congenital heart disease. The American College of Chest Physicians has recently published another valuable clinical practice guideline for pediatric thrombosis.⁶ The Chest 2012 guidelines additionally covered other childhood conditions beyond heart disease, including stroke, thrombophilias, renal disease, and cancer. Expert panels of clinicians and scientists developed both of these guidelines and comprehensive literature searches were performed to compile relevant data.

Yet, it is noteworthy that the majority of recommendations in the current statement5 (including those Class I) and those in the Chest 2012 guidelines6 refer to level C (consensus opinion) evidence. Remarkably, there are no Level of Evidence A recommendations out of the more than 140 total provided in the current AHA statement.⁵

Why is the evidence base weak and why are randomized trials so difficult to accomplish in this area? There are several factors that make controlled studies challenging in this patient population:

• The patient population is very heterogeneous. The ages and sizes of the patients are variable and the types of diseases with risk of thrombosis are multiple (i.e., patients with single ventricle physiology, intracardiac devices, ventricular assist devices, cardiomyopathy, Kawasaki disease, arrhythmia, and pulmonary hypertension).
• The overall patient population is relatively rare as compared with adults with atherosclerotic cardiovascular disease and thrombosis.
• Endpoints for a thrombosis clinical trial in children are difficult to establish. Fortunately, death and stroke are rare in this population. Surrogate endpoints utilizing cardiac or vascular imaging can be difficult, requiring sedation in younger children. Moreover, few studies have evaluated diagnostic efficacy of imaging modalities for thromboembolism in the setting of pediatric cardiovascular disease.
• There is a large amount of clinical practice variation with respect to thrombosis in children and adults with congenital heart disease and children with acquired heart disease. Many of the standard drugs (e.g., aspirin, warfarin, enoxaparin, and heparin) are used variably at different doses making control groups difficult to establish due to lack of equipoise among practitioners.
• Parents and guardians are often unwilling to consent for their child to be randomized to placebo therapy, particularly if painful procedures (e.g., frequent blood draws) are involved.

Despite these hurdles, it is increasingly important to perform controlled trials and research in thrombosis in children. The Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 strengthened requirements and incentives for the pharmaceutical industry to perform trials to demonstrate efficacy and safety of drugs in children.⁷ Direct thrombin inhibitors (dabigatran) and direct factor Xa inhibitors (rivaroxaban, apixaban) have been developed and approved to prevent venous thrombosis and thromboembolism in adults, and to prevent stroke in patients with atrial fibrillation.⁸ The acquisition of pediatric-specific pharmacokinetic and pharmacodynamic data and clinical trials evaluating the efficacy and safety of these compounds, as well as other drugs, is essential. Innovative study designs, adaptive analytic approaches, multicenter collaborative efforts, and creative composite endpoints will enhance these studies, and will provide new information that will likely result in long-term health benefits for these vulnerable and unique patients.