Pathogenesis and management of heparin-induced thrombocytopeneia

肝素诱导的血小板减少症（HIT）是一种医源性并发症，与轻度血小板减少症相关，但可导致危及肢体和生命的血栓形成。这个修订后的计划项目的主题仍然是了解HIT的分子机制，并利用这些知识来开发新的治疗方法。我们相信，这是一个及时的建议，将联合收割机几种不同但高度互动的努力结合起来，以促进我们对HIT患者的理解和护理。有四个拟议的项目：项目1：血小板减少症和血栓形成的细胞事件在HIT下，由费城儿童医院（CHOP）的Mortimer Poncz将检查体内发生的导致血小板减少症和血栓形成前状态的事件。项目2：道格拉斯B下HIT中的病原性抗体。宾夕法尼亚大学（UPENN）的电影将更好地了解致病性与非致病性抗血小板因子4（PF 4）/肝素抗体的区别。项目三：杜克的Gowthami Arepally下的HIT的免疫发病机制将研究PF 4/肝素复合物的物理特性和HIT中致病性免疫应答的细胞基础。项目四：托马斯杰斐逊大学的Steven McKenzie和宾夕法尼亚大学的布鲁斯萨切斯将研究两种新的早期干预策略，以改善这种毁灭性的疾病，或与目前的标准疗法结合。除了一个行政核心外，还有两个核心。Lubica Rauova（CHOP）下的蛋白质核心B将提供大量的人、小鼠和特异性突变型PF 4以及大量的几种HlT样和对照单克隆Ab。该核心还将从由Dr. Cines领导的临床样本核心C分离和处理的血浆中分离批量大规模HIT IgG以及单个HIT IgG样本。核心C将负责在所有三个主要成人项目中识别高可能性的HIT患者，同意个体并从他们那里获得血浆，以及记录他们的临床和血清学数据。我们认为，拟议的项目是高度互动的。每个项目中开发的先进技术将对其他项目产生巨大价值。此外，核心将提供大量和高标准的独特材料，这将允许快速的科学进步和项目之间的容易串扰。在5年的支持结束时，我们相信，对于一种仍然具有高度临床相关性的疾病，将产生重要的基础和临床有用的信息。

Heparin-induced thrombocytopenia (HIT) is an iatrogenic complication associated with mild thrombocytopenia, but limb- and life-threatening thrombosis. The theme of this revised Program Project remains to understand the molecular mechanisms underlying HIT and to use that knowledge to develop new therapeutic approaches for its treatment. We believe that this is a timely proposal to combine several different, but highly interactive, efforts to advance our understanding and care of patients with HIT. There are four proposed Projects: Project 1: Cellular Events Underlying Thrombocytopenia and Thrombosis in HIT under Mortimer Poncz at the Children's Hospital of Philadelphia (CHOP) will examine the events that occur in vivo that lead to both the thrombocytopenia and prothrombotic state. Project 2: Pathogenic Antibodies in HIT under Douglas B. Cines at the University of Pennsylvania (UPENN) will better understand what distinguishes a pathogenic from a non-pathogenic anti-platelet factor 4 (PF4)/heparin Ab. Project 3: Immune Pathogenesis of HIT under Gowthami Arepally at Duke will study the physical characteristics of the PF4/heparin complex and the cellular basis of the pathogenic immune response in HIT. Project 4: Novel Therapeutics in HIT under Steven McKenzie at Thomas Jefferson University and Bruce Sachais at UPENN will study two novel strategies for early intervention to ameliorate this devastating disease on their own or in conjunction with present standard therapies. In addition to an administrative core, there are two cores involved. A Protein Core B under Lubica Rauova (CHOP) that will provide large quantities of human, mouse and specific mutant PF4s as well as large quantities of several HlT-like and control monoclonal Abs. This Core will also isolate batched large-scale HIT IgGs as well as individual HIT IgG samples from plasma isolated and processed by the Clinical Sample Core C under Dr. Cines. Core C will be responsible for identifying high likelihood of HIT patients at all three major adult programs, consent the individuals and obtain plasma from them as well as record their clinical and serological data. We believe that the proposed Projects are highly interactive. Advances and technologies developed within each will have great value to other Projects. Moreover the Cores will provide unique materials in large amounts and to high standards that will allow rapid scientific progress and easy crosstalk between projects. At the end of the 5 years of support, we believe that important fundamental and clinically useful information will have been generated for a disease that remains highly clinically relevant.