There has been a dramatic increase in the rate of pediatric venous thromboembolism (VTE). The concept of VTE in children has now evolved from that of an acute event to one of chronic disease. VTE leads to tremendous burdens, especially on physical functioning, due either to antithrombotic therapy or the development of poor outcomes over time. The major poor outcomes after VTE include a chronic, life-long syndrome of pain, cramping and swelling of the affected extremity called the postthrombotic syndrome (PTS), recurrent VTE and other debilitating post thrombotic sequelae including, but not limited to pulmonary hypertension. Although early diagnosis of VTE complications can improve health outcomes, it is not known currently how to identify children at risk of these outcomes. The capacity of a given individual to generate thrombin called thrombin generation potential (TGP) and, dissolve the clot called fibrinolysis can be measured in plasma by global coagulation assays. Global coagulation assays capture coagulation in its entirety and provide information from clot initiation through clot dissolution. These assays may help identify children at risk of poor outcomes after VTE. Even if global coagulation assessment is more likely to identify those at risk of poor outcomes, it is unlikely that biomarker profiling or pharmacology alone will be sufficient to eradicate post VTE disease. Indeed, decreased exercise and activity levels are already known to contribute to the risk for PTS in adults. Maintaining adherence to a post VTE-activity regimen is likely to be a problem, though. Emerging technological tools might be leveraged to more carefully track activity and increase incentive for such activity in children. The paucity of data and the poor understanding of the biology behind these outcomes holds several important implications: 1) providers caring for pediatric patients with VTE (pediatric hematologists/oncologists) and those following them after diagnosis (pediatricians and family physicians) are poorly informed about the gravity of these complications; 2) standardized approaches to testing and long term follow-up are missing; and 3) expertise and/or resources to carry out well-conceived prospective studies to define robust, predictive biomarkers and effective treatment strategies are rare. This proposal describes a career development plan that will prepare the candidate to become a successful independent investigator and attain her long-term career goal of becoming a national leader in pediatric thrombosis. Her immediate goals include testing the conceptual innovation of looking at coagulation globally to predict poor VTE outcomes in children. She will also investigate the feasibility of using a fitness tracker to facilitate adherence to an activity regimen in children with deep venous thrombosis (DVT. To meet these goals, she has proposed a career development plan that integrates didactic coursework, participation in local and national conferences and workshops, and a progression of mentored research studies within the supportive research environment at University of Texas Southwestern Medical Center and Children's Hospital in Dallas, TX. This environment includes a NIH-funded CTSA and Clinical and Translational Research Center and a state- funded Hemostasis Thrombosis Center, an entity that is the only referral center for children with thrombosis in the entire North Texas.
The research aims of this project are to: 1) To prospectively evaluate TGP and fibrinolysis, using global coagulation assays as biomarkers to identify children likely to develop adverse outcomes after an initial VTE and 2) demonstrate the feasibility and potential effectiveness of a personal fitness tracker to improve adherence to an activity regimen following an initial VTE in children.
These research aims will serve as the platform for the career development plan and training aims which include: 1) training to enhance knowledge and understanding of clinical research, statistics and epidemiology by pursuing a Masters in Clinical Science; 2) develop and refine skills in clinical research design and implementation, and 3) transition into an independent investigator. Together, the research studies and training aims of the K23 proposal will provide the training, experience, and preliminary data for two R01 applications. One R01 will be a larger screening study to test and develop risk prediction tools for poor VTE outcomes incorporating conventional thrombophilia and the global coagulation biomarkers. The other R01 will be a fully powered, multisite RCT to determine efficacy of an activity/exercise regimen to prevent and treat PTS in high risk groups as identified from Aim 1. The proposed research and training aims will strategically position the PI to become a leader in pediatric thrombosis and its long-term outcomes. The innovative approach to study coagulation globally to predict poor outcomes and target the most frequent complication, PTS, as outlined in this K23 proposal has the potential for very high impact on clinical care for this very common, serious, and costly disease.
Venous thromboembolism (VTE) is a major and growing problem in children. Alarmingly, VTE has increased by 70% in hospitalized children in the past decade. Accompanying this startling increase in VTE is the attendant increase in chronic complications of VTE, the most frequent of which is the post thrombotic syndrome (PTS). Although evidence for treatment of acute VTE exists, the best strategies to identify children at high risk of developing poor outcomes after VTE are unclear. Moreover, no preventive or treatment strategies exist for PTS. The proposed research will assess thrombin generating capacity and fibrinolysis- 'the global coagulation assessment'- and harness it to identify patients at risk of poor outcomes of VTE. Moreover, as a first step toward prevention and treatment of PTS, it will also determine the feasibility of an activity tracker to adhere to an activity regimen post VTE. These novels approaches, which leverage global assays and commonly available technological tools, have the potential for wide dissemination and implementation if successful.
