Predicting and Preventing Poor Outcomes of Venous Thromboembolism in Children

预测和预防儿童静脉血栓栓塞的不良后果

• 批准号: 9088833
• 负责人: Ayesha Zia
• 金额: $ 18.39万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9088833
• 关键词: Accelerometer; Acute; Adherence; Adult; Adverse effects; Affect; Anticoagulation; Assessment tool; Biological Assay; Biological Markers; Biology; Caring; Center for Translational Science Activities; Child; Childhood; Chronic; Chronic Disease; Clinical; Clinical Research; Clinical Sciences; Coagulation Process; Cohort Studies; Complication; Consent; Data; Deep Vein Thrombosis; Development; Development Plans; Diagnosis; Disease; Early Diagnosis; Educational workshop; Effectiveness; Eligibility Determination; Environment; Epidemiology; Event; Exercise; Family Physicians; Fibrinolysis; Force of Gravity; Fostering; Frequencies; Funding; Future; Generations; Goals; Health; Hemostatic function; Hospitalized Child; Incentives; Individual; Intervention; Investigation; Knowledge; Lead; Left; Life; Limb structure; Measures; Medical center; Mentors; Muscle Cramp; Oncologist; Outcome; Pain; Patients; Pediatric Hematologist; Pediatric Hospitals; Pharmacology; Physical Function; Physical activity; Plasma; Positioning Attribute; Postphlebitic Syndrome; Prevention; Prevention strategy; Preventive; Prognostic Marker; Prospective Studies; Provider; Pulmonary Hypertension; Quality of life; Quality-of-Life Assessment; Randomized Clinical Trials; Randomized Controlled Trials; Recurrence; Regimen; Research; Research Design; Research Personnel; Research Training; Resources; Risk; Signs and Symptoms; Swelling; Syndrome; Testing; Texas; Therapeutic; Thrombin; Thromboembolism; Thrombophilia; Thrombosis; Time; Training; United States National Institutes of Health; Universities; Varicose Ulcer; Veins; Venous; Work; adverse outcome; career; career development; chronic pain; clinical care; comparison group; design; effective therapy; exercise program; exercise regimen; experience; fitbit; fitness; follow-up; group intervention; high risk; improved; innovation; meetings; novel strategies; pediatric patients; pediatrician; predictive marker; prevent; primary outcome; prospective; public health relevance; research study; screening; secondary outcome; skills; standard of care; statistics; symposium; tool; treatment strategy

 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.

 描述（由申请人提供）：儿童静脉血栓栓塞（VTE）的发病率急剧增加。儿童 VTE 的概念现已从一种急性事件演变为一种导致巨大负担的慢性疾病。 ，特别是在身体功能方面，由于抗血栓治疗或随着时间的推移出现不良后果，VTE 后的主要不良后果包括受累肢体的慢性、终生疼痛、痉挛和肿胀综合征，称为“静脉血栓栓塞症”。血栓后综合征 (PTS)、复发性 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，尽管早期诊断 VTE 并发症可以改善健康结果，但目前尚不清楚如何识别有这些结果风险的儿童。特定个体产生称为凝血酶生成潜能 (TGP) 的凝血酶，并溶解称为纤维蛋白溶解的凝块，可以通过整体凝血测定在血浆中测量整体凝血测定捕获其中的凝血。完整并提供从凝块开始到凝块溶解的信息，这些可能有助于识别 VTE 后有不良结果风险的儿童。事实上，人们已经知道，运动和活动水平的降低会增加成人患 PTS 的风险，但新兴技术可能会导致坚持 VTE 后的治疗方案。可以利用工具来更仔细地跟踪儿童的活动并增加对此类活动的激励。 数据的匮乏和对这些结果背后的生物学了解不足带来了几个重要的影响：1) 照顾 VTE 儿科患者的提供者（儿科血液学家/肿瘤学家）以及诊断后跟随他们的人（儿科医生和家庭医生）对这些结果知之甚少。这些并发症的严重性；2) 缺乏标准化的检测方法和长期随访；3) 缺乏专门知识和/或资源来开展周密的前瞻性研究来确定稳健的、预测性的生物标志物和有效的治疗策略。该提案描述了一个职业发展计划，该计划将使候选人成为一名成功的独立研究者，并实现成为儿科血栓形成领域国家领导者的长期职业目标。她的近期目标包括测试全球凝血预测的概念创新。她还将研究使用健身追踪器促进深静脉血栓 (DVT) 儿童遵守活动方案的可行性。为了实现这些目标，她提出了一项职业发展计划，其中整合了教学课程、参与地方和国家会议和研讨会，以及在德克萨斯大学西南医学中心和德克萨斯州达拉斯儿童医院的支持性研究环境中进行的一系列指导研究。该环境包括 NIH 资助的 CTSA 和临床和转化研究中心以及国家资助的一个。止血血栓中心，是整个北德克萨斯州唯一的血栓儿童转诊中心。该项目的研究目的是： 1) 使用整体凝血技术前瞻性评估 TGP 和纤溶。 2）证明个人“健身追踪器”的可行性和潜在有效性，以提高儿童初次 VTE 后对活动方案的依从性。作为职业发展计划和培训目标的平台，其中包括：1）通过攻读临床科学硕士学位来增强对临床研究、统计学和流行病学的知识和理解的培训；2）发展和完善临床研究设计和实施的技能， 3) 过渡K23 提案的研究和培训目标将为两个 R01 应用提供培训、经验和初步数据，其中一个 R01 将是一项更大规模的筛选研究，用于测试和开发不良 VTE 的风险预测工具。另一个 R01 将是一项功能齐全的多部位随机对照试验，旨在确定目标 1 中确定的活动/运动方案预防和治疗高危人群 PTS 的功效。研究和培训目标将从战略上使 PI 成为儿科血栓形成及其长期结果领域的领导者，如本 K23 提案中所述，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 的创新方法已得到证实。对于这种非常常见、严重且昂贵的疾病的临床护理可能会产生很大的影响。