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.

项目摘要 镰状细胞病（SCD）是一种多系统、危及生命的遗传性血液疾病， 美国低收入弱势群体。在大约10万名患有这种疾病的人中 在这个国家，非洲后裔占病人的90%。这种疾病的一个特点是 血管内皮功能障碍的发展，促进慢性血栓前状态，增加风险 静脉血栓栓塞症（VTE）。患有SCD的住院儿科患者的 与住院的普通儿科人群相比，但尽管 高凝状态和SCD之间的已知关联，VTE仍然是一个认识不足的， 未充分研究的并发症，特别是在儿科SCD人群中。具体而言，生物标志物和 儿童SCD发生VTE的机制在研究中很少受到关注， 迫切需要开展工作，以确定干预性试验中未来调查的可改变因素。 该提案旨在通过系统分析来自以下方面的VTE数据， 一项多中心混合前瞻性-回顾性队列研究，对SCD儿童患者进行平行生物样本库， 没有VTE。具体目的是：1）识别VTE事件（1a）和复发（1b）的临床风险因素 在儿科SCD中; 2）鉴定凝血激活、炎症、内皮损伤的血浆标志物， 无偏蛋白质组学谱预测儿童偶发（2a）和复发（2b）VTE的发展 SCD;和3）开发一种新的生物标志物告知的儿科SCD VTE临床预后模型。 申请人的长期目标是成为具有专业知识的独立临床和翻译研究者 在儿科SCD中开发生物标志物告知的VTE临床预后模型。她设计 个人职业发展计划，总体目标是获得生物标志物发现方面的专业知识， 儿童VTE的验证，以及生物标志物和临床风险因素的应用， 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）获得指导，先进的教学和经验教育和培训， 在儿童VTE和SCD人群中开展多中心观察性和干预性研究; 2）获得 在蛋白质组学方法和生物标志物发现，验证和 在儿科血液病中的实施;和3）获得指导，先进的教育和培训 儿科血液病预后模型的发展和应用。