Predicting and Preventing Poor Outcomes of Venous Thromboembolism in Children

 描述(申请人提供)：儿科静脉血栓栓塞症(VTE)的发病率急剧增加。儿童静脉血栓栓塞症的概念现已从急性事件演变为慢性病。静脉血栓栓塞术导致巨大的负担，特别是对身体功能的影响，要么是由于抗血栓治疗，要么是随着时间的推移结果不佳。VTE后的主要不良结局包括被称为血栓后综合征(PTS)的受影响肢体的慢性终身疼痛、抽筋和肿胀综合征、复发的VTE和其他使人衰弱的血栓后后遗症，包括但不限于肺动脉高压。虽然早期诊断静脉血栓栓塞症并发症可以改善健康结局，但目前还不知道如何识别有这些后果风险的儿童。特定个体产生凝血酶的能力称为凝血酶生成潜力(TGP)，溶解凝块的能力称为纤溶，可以通过整体凝血试验在血浆中进行测量。整体凝血试验捕获凝血的全部过程，并提供从凝块形成到凝块溶解的信息。这些检测可能有助于确定VTE术后预后不良的风险儿童。即使全球凝血评估更有可能确定那些有不良预后风险的人，仅靠生物标记物分析或药理学也不太可能足以根除VTE后疾病。事实上，运动和活动水平的减少已经被认为是成年人PTS风险的原因之一。然而，维持VTE活动后养生法的坚持很可能是一个问题。可以利用新兴的技术工具更仔细地跟踪儿童的活动，并增加对儿童这类活动的激励。 缺乏数据和对这些结果背后的生物学缺乏了解有几个重要的影响：1)照顾患有VTE的儿童患者的提供者(儿科血液学家/肿瘤学家)和那些在诊断后跟踪他们的人(儿科医生和家庭医生)对这些并发症的严重性知之甚少；2)缺乏标准化的检测方法和长期随访；以及3)开展精心设计的前瞻性研究以确定强有力的、可预测的生物标志物和有效的治疗策略的专业知识和/或资源很少。这份提案描述了一项职业发展计划，该计划将使候选人为成为一名成功的独立调查员做好准备，并实现她成为儿科血栓形成国家领导者的长期职业目标。她的近期目标包括测试概念创新，即在全球范围内观察凝血以预测儿童VTE的不良结局。她还将研究在患有深静脉血栓(DVT)的儿童中使用健身跟踪器来促进坚持活动方案的可行性。为了实现这些目标，她提出了一项职业发展计划，其中包括教学课程、参加地方和国家会议和研讨会，以及在德克萨斯州达拉斯的德克萨斯大学西南医学中心和儿童医院的支持性研究环境中进行指导研究的进展。这一环境包括由NIH资助的CTSA和临床与翻译研究中心，以及州政府资助的止血血栓中心，这是整个德克萨斯州北部唯一的血栓儿童转诊中心。该项目的研究目标是：1)前瞻性地评估TGP和纤溶，使用全球凝血试验作为生物标记物，以确定儿童在首次VTE后可能出现不良结果的可能性和潜在有效性；以及2)证明个人“健康跟踪器”的可行性和潜在有效性，以提高儿童在首次VTE后对活动方案的依从性。这些研究目标将作为职业发展计划和培训目标的平台，包括：1)通过攻读临床科学硕士学位，加强对临床研究、统计学和流行病学的知识和理解；2)发展和完善临床研究设计和实施方面的技能；以及3)过渡到独立研究人员。K23提案的研究研究和培训目标将共同为两个R01应用提供培训、经验和初步数据。One R01将是一项更大的筛查研究，以测试和开发结合传统亲血栓和全球凝血生物标记物的不良VTE结果的风险预测工具。另一个R01将是一个全功率、多部位的随机对照试验，以确定活动/运动方案的有效性，以预防和治疗目标1中确定的高危人群的PTS。拟议的研究和培训目标将战略性地使PI成为儿科血栓形成及其长期结果的领导者。在全球范围内研究凝血以预测不良结果并针对最常见的并发症PTS的创新方法，如K23提案中所概述的，可能会对这种非常常见、严重和昂贵的疾病的临床护理产生非常大的影响。

 DESCRIPTION (provided by applicant): 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.