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）：儿科静脉血栓栓塞（VTE）的发生率急剧增加。儿童静脉血栓栓塞的概念已从急性事件演变为慢性疾病。由于抗血栓治疗或随着时间的推移发生不良结局，静脉血栓栓塞导致巨大负担，特别是对身体功能。VTE后的主要不良结局包括被称为血栓形成后综合征（PTS）的受影响肢体疼痛、痉挛和肿胀的慢性终身综合征、复发性VTE和其他使人衰弱的血栓形成后后遗症，包括但不限于肺动脉高压。虽然早期诊断静脉血栓栓塞并发症可以改善健康状况，但目前尚不清楚如何识别有这些风险的儿童。给定个体产生凝血酶的能力（称为凝血酶生成潜力（TGP））和溶解凝块的能力（称为纤维蛋白溶解）可以通过整体凝血测定在血浆中测量。整体凝血测定可完整捕获凝血，并提供从凝块启动到凝块溶解的信息。这些检测可能有助于识别VTE后有不良结局风险的儿童。即使总体凝血评估更有可能识别出那些有不良结局风险的患者，但仅生物标志物分析或药理学不太可能足以根除VTE后疾病。事实上，已经知道运动和活动水平的降低会增加成年人的PTS风险。然而，保持对职业教育后活动方案的依从性可能是一个问题。可以利用新兴的技术工具，更仔细地跟踪儿童的活动，并增加对儿童进行这种活动的激励。 数据的缺乏和对这些结果背后的生物学的理解不足有几个重要的意义：1）照顾患有VTE的儿科患者的提供者（儿科血液科医生/肿瘤科医生）和诊断后随访的患者（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;和3）很少有专门知识和/或资源来进行构思良好的前瞻性研究，以确定稳健的、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，将准备候选人成为一个成功的独立研究者，并实现她的长期职业目标，成为全国领先的儿科血栓形成。她的近期目标包括测试在全球范围内观察凝血的概念创新，以预测儿童的不良VTE结果。她还将研究使用健身追踪器来促进深静脉血栓形成（DVT）儿童坚持活动方案的可行性。为了实现这些目标，她提出了一个职业发展计划，整合教学课程，参加地方和国家会议和研讨会，并在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性研究。该环境包括NIH资助的CTSA和临床与转化研究中心以及国家资助的止血血栓形成中心，该中心是整个北德克萨斯州唯一的血栓形成儿童转诊中心。该项目的研究目的是：1）前瞻性评估TGP和纤维蛋白溶解，使用全球凝血测定作为生物标志物，以识别儿童可能在初始VTE后发生不良结局; 2）证明个人“健身跟踪器”的可行性和潜在有效性，以改善儿童初始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，其中包括：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的培训; 2）发展和完善临床研究设计和实施的技能，以及3）过渡到独立研究者。K23项目的研究和培训目标将为两个R 01应用提供培训、经验和初步数据。其中一项R 01将是一项更大规模的筛选研究，旨在测试和开发不良VTE结局的风险预测工具，包括传统血栓形成倾向和全球凝血生物标志物。另一项R 01将是一项充分把握度的多中心RCT，旨在确定活动/运动方案预防和治疗目标1中确定的高危人群PTS的疗效。拟议的研究和培训目标将战略性地定位PI，使其成为儿科血栓形成及其长期结局的领导者。如本K23提案所述，在全球范围内研究凝血以预测不良结局并针对最常见的并发症PTS的创新方法有可能对这种非常常见、严重和昂贵的疾病的临床护理产生非常大的影响。