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.

项目总结 镰状细胞病(SCD)是一种多系统的、危及生命的遗传性血液疾病，它不成比例地影响 美国的低收入弱势少数民族。在大约10万名患有这种疾病的人中 在该国的情况下，非洲人后裔占患者的90%。这种疾病的一个特点是 促进慢性血栓前状态的血管内皮细胞功能障碍增加风险 静脉血栓栓塞症(VTE)。住院的儿童SCD患者有更高的发病率 与住院的普通儿科人群相比，发生和复发的VTE。然而，尽管 已知的高凝状态与SCD之间的联系，VTE仍然是一个未被充分认识的 研究不足的并发症，特别是在儿童SCD人群中。具体地说，生物标志物和 尽管如此，儿童SCD中VTE的发生机制在研究中受到的关注很少 迫切需要开展工作，以便为今后的干预试验研究确定可修改的因素。 该提案旨在通过系统分析VTE数据来解决知识中的这一关键差距 儿童SCD患者的多中心前瞻性-回顾性队列平行生物分组研究 而且没有VTE。具体目标是：1)确定发生(1a)和复发(1b)静脉血栓栓塞症的临床危险因素 在儿童SCD中；2)确定凝血激活、炎症、内皮损伤的血浆标志物，以及 无偏倚蛋白质组学特征对儿科患者发生(2a)和复发(2b)VTE的预测 以及3)开发一种新的儿童SCD的VTE的临床预后模型。 申请者的长期目标是成为一名具有专业知识的独立临床和翻译研究员 在儿科SCD的VTE临床预后模型的开发中。她设计了 个人职业发展计划，首要目标是获得生物标志物发现和开发方面的专业知识 儿科静脉血栓栓塞术的验证，以及在生物标记物和临床危险因素的发展中的应用 静脉血栓栓塞术预后模型及风险分层预防试验设计。她职业生涯的具体目标 发展计划是：1)在以下方面获得指导、先进的教学和体验式教育和培训 在儿童VTE和SCD人群中进行多中心观察性和干预性研究；2)获得 指导蛋白质组学方法和生物标记物发现、验证和实践方面的专业知识 在儿科血液病中实施；以及3)获得指导、高级教育和培训 儿科血液病预后模型的建立与应用。