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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要本研究旨在更好地了解肝素诱导的病理生理学血小板减少症/血栓形成 (HIT)，一种常见且有时危及生命的肝素并发症治疗，并开发更好的早期诊断和管理工具。该候选人是医学博士、哲学博士 Anand Padmanabhan，是威斯康星州血液中心 (BCW) 的初级教员。 BCW坚定承诺保护申请人的研究时间在75%的水平，并提供必要的空间和人员支持。申请人将得到经验丰富的医师研究员理查德博士的指导。 Aster 医学博士在王德民博士和刘健博士的协助下，获得了免疫学和免疫学权威的认可分别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、统计学和临床免疫学，将促进 Padmanabhan 博士的专业成长为该研究计划基于 Padmanabhan 博士最近的发现，即肝素诱导的血小板减少。在没有肝素的情况下，激活（“致病性”）抗体与经过血小板因子 4 (PF4) 预处理的血小板结合，而非激活（“良性”）抗体则不然，Padmanabhan 博士指出了两者之间的区别。抗体类型的不同之处在于，当 PF4 发生变化时，致病性抗体会优先识别 PF4 中诱导的细微结构变化。与硫酸软骨素 (CS) 发生反应，该硫酸软骨素与构成主要血小板表面的未知核心蛋白相连他预计人们可以在生化、结构和功能水平上更好地了解蛋白多糖（PG）。 PF4“启动”血小板进行致病性抗体结合以及抗体本身的过程将导致对 HIT 发病机制的新认识以及改进的诊断工具以早期识别有 HIT 风险的患者 HIT 及其血栓并发症为了支持这一概念，他开发了一种新的检测方法，即 PF4 依赖性 p- 检测方法。选择素表达测定（PEA），在初步测试中发现更准确且技术含量较低 Padmanabhan 博士将进一步评估诊断结果。在一项针对疑似 HIT 患者的严格设计的前瞻性研究中，PEA 的实用性和治疗影响。 Padmanabhan 是一位有前途的初级医师研究员，在支持性和科学丰富的环境中提出了 K08 奖将使他能够专注于具有重要临床意义的明确且具有挑战性的项目。他的大部分时间都花在这项有希望的研究上，同时通过正规培训扩展他的科学能力他在申请中概述了该计划将为 Padmanabhan 博士的职业生涯提供理想的准备。血液学/输血医学独立研究者。