New Approaches to Pathogenesis and Diagnosis of Heparin-Induced Thrombocytopenia (HIT)

肝素引起的血小板减少症 (HIT) 发病机制和诊断的新方法

• 批准号: 9314829
• 负责人: Anand Padmanabhan
• 金额: $ 17.28万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314829
• 关键词: Academic Medical Centers; Antibodies; Anticoagulant therapy; Anticoagulants; Argatroban; Award; Behavior; Benign; Binding; Biochemical; Biological Assay; Blood Coagulation Disorders; Blood Platelets; Charge; Chondroitin Sulfates; Clinical; Clinical Immunology; Clinical Research; Collaborations; Complex; Complication; Core Protein; Dangerousness; Detection; Development; Development Plans; Diagnosis; Diagnostic; Diagnostic Specificity; Disease; Doctor of Medicine; Doctor of Philosophy; Early Diagnosis; Early identification; Environment; Epitopes; Faculty; Functional disorder; Future; Glycobiology; Glycosaminoglycans; Goals; Gold; Growth; Hematology; Heparin; Human Resources; Immunoassay; Immunology; In Vitro; Ion-Exchange Chromatography Procedure; Junior Physician; Laboratories; Lead; Life; Link; Mass Spectrum Analysis; Medicine; Membrane; Mentors; Modification; Molecular; Molecular Conformation; Morbidity - disease rate; P-Selectin; Pathogenesis; Pathogenicity; Patient-Focused Outcomes; Patients; Phase; Physicians; Platelet Activation; Platelet Factor 4; Preparation; Process; Prospective Studies; Proteoglycan; Reaction; Research; Research Personnel; Risk; Role; Sampling Studies; Savings; Serotonin; Site; Solid; Specificity; Surface; Techniques; Testing; Therapeutic; Thrombin; Thrombocytopenia; Thrombosis; Time; Training; Transfusion; Unspecified or Sulfate Ion Sulfates; Wisconsin; Work; accurate diagnosis; authority; base; bivalirudin; career; career development; clinically relevant; density; design; experience; improved; inhibitor/antagonist; insight; member; mortality; novel; novel strategies; physical property; programs; prospective; proteoglycan core protein; research study; skills; statistics; tool

PROJECT SUMMARY/ABSTRACT This research is aimed at gaining a better understanding of the pathophysiology of heparin-induced thrombocytopenia/thrombosis (HIT), a common and sometimes life-threatening complication of heparin treatment, and developing better tools for early diagnosis and management. The candidate, Anand Padmanabhan M.D., Ph.D, is a junior faculty member at the BloodCenter of Wisconsin (BCW). BCW has made a firm commitment to protect the applicant's research time at the 75% level and to provide necessary space and personnel support. The applicant will be mentored by a highly experienced physician-investigator, Dr. Richard Aster, MD aided by Dr. Demin Wang, PhD and Dr. Jian Liu, PhD, recognized authorities in immunology and glycobiology, respectively. An ambitious career development plan is described that includes basic training in glycobiology, statistics and clinical immunology and will facilitate Dr. Padmanabhan's professional growth into an independent investigator. The research plan is based on Dr. Padmanabhan's recent finding that heparin-induced, platelet- activating (“pathogenic”) antibodies bind to platelets pre-treated with platelet factor 4 (PF4) in the absence of heparin, whereas non-activating (“benign”) antibodies do not. Dr. Padmanabhan hypothesizes that the distinction between the two types of antibodies is that pathogenic antibodies preferentially recognize subtle structural changes induced in PF4 when it reacts with chondroitin sulfate (CS) linked to an unidentified core protein that makes up the dominant platelet surface proteoglycan (PG). He anticipates that a better understanding at biochemical, structural and functional levels of the process by which PF4 “primes” platelets for pathogenic antibody binding and of the antibodies themselves will lead to new understanding of HIT pathogenesis and to improved diagnostic tools for early identification of patients at risk for HIT and its thrombotic complications. In support of this concept, he has developed a novel assay, the PF4-dependent p- selectin expression assay (PEA), which in preliminary testing was found to be more accurate and less technically demanding than the gold standard serotonin release assay (SRA). Dr. Padmanabhan will further assess the diagnostic utility and treatment impact of the PEA in a rigorously-designed prospective study in patients suspected of HIT. Dr. Padmanabhan is a promising junior physician-investigator in a supportive and scientifically-rich environment proposing a well defined and challenging project that has important clinical implications. The K08 award will enable him to focus the majority of his time on this promising research while expanding his scientific capabilities through formal training as outlined in his application. The program described will provide Dr. Padmanabhan ideal preparation for a career as an independent investigator in hematology/transfusion medicine.

项目摘要/摘要 这项研究旨在更好地了解肝素引起的病理生理 血小板减少症/血栓形成（HIT），这是一种常见的肝素并发症的常见并发症 治疗，并为早期诊断和管理开发更好的工具。 候选人Anand Padmanabhan M.D.博士是威斯康星州血液中心（BCW）的初级教师。 BCW做出了坚定的承诺，以保护申请人在75％的水平上的研究时间，并提供必要 空间和人员支持。申请人将由经验丰富的物理评估者Richard博士考虑 Aster，MD由Demin Wang博士，博士和Jian Liu博士博士的协助，公认的免疫学当局和 分别是糖生物学。描述了一个雄心勃勃的职业发展计划，其中包括基础培训 糖生物学，统计和临床免疫学，并将促进Padmanabhan博士的专业发展 独立研究者。该研究计划基于Padmanabhan博士最近的发现，即肝素引起的血小板 - 在没有肝素的情况下，激活（“致病”）抗体与血小板因子4（PF4）预处理的血小板结合， 而非激活（“良性”）抗体却没有。 Padmanabhan博士假设两者之间的区别 抗体类型是，病原抗体优先识别出PF4中引起的细微结构变化 与硫酸软骨素（CS）反应，与构成主要血小板表面的未识别核心蛋白相关 蛋白聚糖（PG）。他预计，对生化，结构和功能水平的更好理解 PF4的PF4“ Primes”血小板用于致病性抗体结合和抗体本身将导致 对命中发病机理的新了解和改善诊断工具，以早日识别有风险的患者 命中及其血栓形成并发症。为了支持这个概念，他开发了一种新颖的测定法，依赖PF4的P- Selectin表达测定（PEA），在初步测试中发现更准确，在技术上更少 比黄金标准5-羟色胺释放测定法（SRA）的要求。 Padmanabhan博士将进一步评估诊断 豌豆在严格设计的前瞻性研究中对涉嫌命中的患者的实用性和治疗影响。博士 Padmanabhan是一个有前途的初级物理评估者 具有重要临床意义的良好定义和挑战项目。 K08奖将使他能够集中精力 他在这项承诺研究上的大部分时间，同时通过正式培训扩大了科学能力 在他的申请中概述了。所描述的计划将为Padmanabhan博士提供理想的准备，作为职业的理想准备 血液学/输血医学的独立研究者。