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

项目概要/摘要 本研究旨在更好地了解肝素诱导的肝硬化的病理生理学。 血小板减少/血栓形成（HIT），肝素的常见并发症，有时危及生命 治疗和开发更好的早期诊断和管理工具。 候选人阿南德·帕德马纳班医学博士博士，是威斯康星州血液中心（BCW）的初级教员。 BCW已作出坚定的承诺，以保护申请人的研究时间在75%的水平，并提供必要的 空间和人员支助。申请人将由一位经验丰富的医生兼调查员理查德博士指导 Aster医学博士在Demin Wang博士和Jian Liu博士的帮助下，获得了免疫学领域公认的权威， 糖生物学。描述了一个雄心勃勃的职业发展计划，其中包括以下方面的基本培训： 糖生物学，统计学和临床免疫学，并将促进博士Padmanabhan的专业成长为一个 独立调查员这项研究计划是基于Padmanabhan博士最近的发现，肝素诱导的血小板- 活化（“病原性”）抗体与在没有肝素的情况下用血小板因子4（PF 4）预处理的血小板结合， 而非活化（“良性”）抗体则不是。Padmanabhan博士假设， 致病性抗体优先识别PF 4中诱导的细微结构变化， 与硫酸软骨素（CS）反应，硫酸软骨素连接到一个未识别的核心蛋白，构成主要的血小板表面 蛋白聚糖（PG）。他预计，在生物化学，结构和功能水平的更好的理解， PF 4“引发”血小板与病原性抗体结合的过程和抗体本身将导致 对HIT发病机制的新认识，以及用于早期识别有HIT风险的患者的改进的诊断工具， HIT及其血栓性并发症。为了支持这一概念，他开发了一种新的检测方法，PF 4依赖性p- 选择素表达测定（PEA），在初步测试中发现它更准确，技术上更少 比金标准血清素释放测定（SRA）更苛刻。Padmanabhan博士将进一步评估 在一项针对疑似HIT患者的严格设计的前瞻性研究中，评估PEA的效用和治疗影响。博士 Padmanabhan是一位有前途的初级医生，在一个支持和科学丰富的环境中进行调查， 定义明确且具有挑战性的项目，具有重要的临床意义。K 08奖将使他能够专注于 他的大部分时间都花在这项有前途的研究上，同时通过正规的培训来扩大他的科学能力， 在他的申请中。所描述的计划将为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。

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.