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

项目摘要/摘要 这项研究的目的是为了更好地了解肝素诱导的病理生理。 血小板减少/血栓形成(HIT)，肝素的常见并发症，有时甚至危及生命 治疗，并开发更好的早期诊断和管理工具。 候选人Anand Padmanabhan医学博士是威斯康星州血液中心(BCW)的初级教员。 BCW已经做出了坚定的承诺，在75%的水平上保护申请者的研究时间，并提供必要的 空间和人员支持。申请者将由一位经验丰富的内科研究员理查德博士指导。 在王德民博士和刘健博士的帮助下，ASTER医学博士承认免疫学和 分别是糖生物学。描述了一项雄心勃勃的职业发展计划，其中包括 糖生物学、统计学和临床免疫学，并将促进Padmanabhan博士的职业成长为 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- 在没有肝素的情况下，激活的(致病的)抗体结合到用血小板因子4(PF4)预处理的血小板上， 而非激活(“良性”)抗体则不起作用。Padmanabhan博士假设两者之间的区别 抗体的类型是，致病抗体优先识别在PF4诱导的细微结构变化 与硫酸软骨素(CS)反应，该蛋白与一种未知的核心蛋白相连，该核心蛋白构成主导的血小板表面 蛋白多糖(PG)。他预计，在生物化学、结构和功能水平上更好地理解 PF4与致病抗体结合和抗体本身结合的过程将导致 对HIT发病机制的新认识和改进的诊断工具，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，即依赖于PF4的p- 选择素表达分析(PEA)，在初步测试中被发现更准确，技术含量更低 比黄金标准的5-羟色胺释放试验(SRA)要求更高。Padmanabhan博士将进一步评估诊断 在一项对疑似HIT患者进行的严格设计的前瞻性研究中，PEA的效用和治疗影响。Dr。 Padmanabhan是一名有前途的初级医生兼研究员，在一个支持性和科学丰富的环境中提出了一个 定义明确且具有挑战性的项目，具有重要的临床意义。K08奖将使他能够专注于 他的大部分时间都花在了这项有希望的研究上，同时通过正规的培训来扩大他的科学能力 在他的申请表中概述了。所描述的项目将为Padmanabhan博士的职业生涯提供理想的准备 血液学/输血医学独立研究员。

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.