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，与轻度的血小板减少有关，但危及肢体和生命的血栓形成。这一修订计划项目的主题仍然是了解HIT潜在的分子机制，并利用这些知识为其治疗开发新的治疗方法。我们认为，这是一个及时的提议，将几种不同但高度互动的努力结合在一起，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：在费城儿童医院(CHOP)莫蒂默·庞茨的领导下，HIT中潜在的血小板减少和血栓形成的细胞事件将检查体内发生的导致血小板减少和血栓前状态的事件。项目2：宾夕法尼亚大学(UPenn)道格拉斯·B·凯恩(Douglas B.Cines)领导下的HIT中的致病抗体将更好地了解致病和非致病抗血小板因子4(PF4)/肝素抗体的区别。项目3：杜克大学Gowthami Aepally下HIT的免疫发病机制将研究PF4/肝素复合体的物理特性和HIT致病免疫反应的细胞学基础。项目4：在托马斯·杰斐逊大学史蒂文·麦肯齐和宾夕法尼亚大学布鲁斯·萨查伊斯的领导下，HIT中的新疗法将研究两种新的早期干预策略，以单独或与目前的标准疗法结合使用，以改善这种毁灭性的疾病。除了管理核心外，还涉及两个核心。Lubica Rauova(CHOP)下的核心B蛋白，将提供大量的人、小鼠和特定的突变体PF4，以及大量的类HLT和对照单抗。该核心还将从由Cines博士领导的临床样本核心C分离和处理的血浆中分离出批量的大规模HIT免疫球蛋白以及单个HIT免疫球蛋白样本。Core C将负责在所有三个主要的成人项目中识别高可能性的Hit患者，同意这些人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。我们相信，拟议的项目具有很强的互动性。在每个项目中开发的进步和技术将对其他项目具有重大价值。此外，这些堆芯将以高标准提供大量独特的材料，使科学进步迅速，项目之间容易相互干扰。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.