Clinical and Molecular based prognostic factors for Venous Thromboembolism (VTE) in Children with Sickle Cell Disease

镰状细胞病儿童静脉血栓栓塞 (VTE) 的临床和分子预后因素

• 批准号: 10739524
• 负责人: Marisol Betensky
• 金额: $ 19.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739524
• 关键词: Accounting; Achievement; Address; Adult; Affect; African; Anti-Inflammatory Agents; Anticoagulants; Area; Area Under Curve; Attention; Award; Biological; Biological Assay; Biological Markers; Biological Specimen Banks; Black race; Case/Control Studies; Catheters; Cell Adhesion; Cell Adhesion Molecules; Cessation of life; Child; Childhood; Chronic; Clinical; Clinical Data; Clinical Investigator; Coagulation Process; Cohort Studies; Complication; Computerized Medical Record; Country; Coupled; Cytolysis; Data; Databases; Development; Development Plans; Disease; Endothelium; Event; Frequencies; Future; Genotype; Goals; Hematological Disease; Hemoglobin SS; Hospitalization; Incidence; Individual; Inflammation; Inflammatory; Inherited; Interleukin-6; Interleukins; Intervention Studies; Intervention Trial; Investigation; Knowledge; Life; Logistic Regressions; Low income; Mass Spectrum Analysis; Mentors; Methods; Minority; Modeling; Molecular; Observational Study; Organ; Outcome; P-Selectin; Packed Red Blood Cell Transfusion; Pathogenesis; Pathway interactions; Patients; Pediatric Hematology; Persons; Pharmaceutical Preparations; Plasma; Population; Prevention trial; Primary Prevention; Prognostic Factor; Proteomics; Recording of previous events; Recurrence; Regression Analysis; Research; Research Personnel; Research Priority; Retrospective cohort; Retrospective cohort study; Risk; Risk Factors; Secondary Prevention; Secondary to; Sickle Cell Anemia; Specimen; Splenectomy; System; Thrombophilia; Thromboplastin; Training; Training and Education; United States; United States National Institutes of Health; Validation; Venous; Work; acute chest syndrome; antithrombin III-protease complex; biobank; biomarker development; biomarker discovery; biomarker validation; career; career development; clinical prognostic; clinical risk; design; early onset; high risk; improved outcome; interest; novel; novel marker; pediatric patients; prognostic model; prognostic signature; prospective; risk stratification; translational scientist; vascular endothelial dysfunction; venous thromboembolism

PROJECT SUMMARY Sickle cell disease (SCD) is a multi-system, life-threatening, inherited blood disorder that disproportionally affects low-income vulnerable minorities in the United States. Of the approximately 100,000 individuals living with this condition in the country, people of African descend account for 90% of patients. A hallmark of the disease is the development of vascular-endothelial dysfunction that promotes a chronic prothrombotic state increasing the risk of venous thromboembolism (VTE). Hospitalized pediatric patients with SCD have substantively higher rates of incident and recurrent VTE compared to the hospitalized general pediatric population. However, despite the known association between hypercoagulability and SCD, VTE has remained an underrecognized and understudied complication, particularly in the pediatric SCD population. Specifically, biomarkers and mechanisms for the development of VTE in pediatric SCD have received little attention in research despite such work being urgently needed in order to identify modifiable factors for future investigation in interventional trials. This proposal aims to address this critical gap in knowledge by systematically analyzing VTE data derived from a multicenter mixed prospective-retrospective cohort with parallel biobanking of pediatric patients with SCD with- and without VTE. The Specific Aims are to: 1) Identify clinical risk factors for incident (1a) and recurrent (1b) VTE in pediatric SCD; 2) identify plasma markers of coagulation activation, inflammation, endothelial damage, and unbiased proteomic profiles prognostic of the development of incident (2a) and recurrent (2b) VTE in pediatric SCD; and 3) to develop a novel biomarker-informed clinical prognostic model for VTE in pediatric SCD. The applicant’s long-term goal is to become an independent clinical and translational investigator with expertise in the development of biomarker-informed VTE clinical prognostic models in pediatric SCD. She has designed an individual career development plan with the overarching goal of gaining expertise in biomarker discovery and validation for pediatric VTE, and in the application of biomarkers and clinical risk factors for the development of VTE prognostic models and the design of risk-stratified VTE prevention trials. The specific aims of her career development plan are: 1) to obtain mentored, advanced didactic and experiential education and training in conducting multicenter observational and interventional studies in pediatric VTE and SCD populations; 2) to gain mentored didactic and hands-on expertise on proteomics methods and biomarker discovery, validation and implementation in pediatric hematologic diseases; and 3) to obtain mentored, advanced education and training on the development and application of prognostic models for pediatric hematologic diseases.

项目概要 镰状细胞病 (SCD) 是一种多系统、危及生命的遗传性血液疾病，对患者的影响尤为严重 美国的低收入弱势少数群体。在大约 100,000 名患有这种疾病的人中 在该国的病情中，非洲人后裔占患者的90%。该病的一个特点是 血管内皮功能障碍的发展促进慢性血栓形成状态，增加风险 静脉血栓栓塞（VTE）。住院的 SCD 儿科患者的发生率明显更高 与住院的一般儿科人群相比，事件和复发性 VTE 的情况。然而，尽管 尽管高凝状态与 SCD 之间存在已知关联，但 VTE 仍然是一个未被充分认识和认识的问题。 并发症尚未得到充分研究，特别是在儿科 SCD 人群中。具体来说，生物标志物和 尽管存在这样的问题，但儿科 SCD 中 VTE 发生的机制在研究中却很少受到关注。 迫切需要开展工作，以确定未来干预试验研究中可改变的因素。 该提案旨在通过系统分析源自以下内容的 VTE 数据来解决这一关键知识差距： 一项多中心混合前瞻性回顾性队列，对患有 SCD 的儿科患者进行平行生物样本库分析，其中： 并且没有 VTE。具体目标是： 1) 确定事件 (1a) 和复发 (1b) VTE 的临床风险因素 儿科 SCD； 2) 识别凝血激活、炎症、内皮损伤的血浆标志物，以及 儿科静脉血栓栓塞事件 (2a) 和复发性 (2b) VTE 发生的无偏蛋白质组学特征预测 SCD； 3) 开发一种新型的基于生物标志物的儿科 SCD 静脉血栓栓塞临床预后模型。 申请人的长期目标是成为一名具有专业知识的独立临床和转化研究者 开发基于生物标志物的儿科 SCD VTE 临床预后模型。她设计过 个人职业发展计划，其总体目标是获得生物标志物发现和 儿科 VTE 的验证，以及生物标志物和临床风险因素在发展中的应用 VTE 预后模型和风险分层 VTE 预防试验的设计。她职业生涯的具体目标 发展计划是： 1) 获得以下方面的指导、高级教学和体验式教育和培训： 对儿科 VTE 和 SCD 人群进行多中心观察和介入研究； 2）获得 指导蛋白质组学方法和生物标志物发现、验证和实践方面的专业知识 在儿科血液病中的实施； 3) 获得指导、先进的教育和培训 儿科血液病预后模型的开发和应用。