Pathogenesis and management of heparin-induced thrombocytopeneia

肝素诱导的血小板减少症（HIT）是一种与轻度血小板减少症相关的医源性并发症，但会导致肢体和危及生命的血栓形成。本修订项目的主题仍然是了解HIT的分子机制，并利用这些知识开发新的治疗方法。我们相信这是一个及时的建议，将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。项目1:HIT中血小板减少和血栓形成的细胞事件，由费城儿童医院（CHOP）的Mortimer Poncz领导，将研究体内发生的导致血小板减少和血栓形成前状态的事件。宾夕法尼亚大学（UPENN） Douglas B. Cines领导的项目2:HIT中的致病性抗体将更好地了解致病性与非致病性抗血小板因子4 (PF4)/肝素Ab的区别。杜克大学（Duke） Gowthami Arepally领导的项目3:HIT的免疫发病机制将研究PF4/肝素复合物的物理特性和HIT致病性免疫反应的细胞基础。项目4：由Thomas Jefferson大学的Steven McKenzie和UPENN的Bruce Sachais领导的HIT的新疗法将研究两种早期干预的新策略，以改善这种毁灭性的疾病，或者与目前的标准疗法相结合。除了管理核心之外，还涉及两个核心。Lubica Rauova （CHOP）公司的蛋白质核心B将提供大量的人、小鼠和特定突变型pf4，以及大量的几种hlt样和对照单克隆抗体。该核心还将从Cines博士的临床样本核心C分离和处理的血浆中分离出批量大规模的HIT IgG和单个HIT IgG样品。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，同意个人并从他们那里获取血浆，并记录他们的临床和血清学数据。我们认为拟议的项目具有高度的互动性。在每个项目中开发的先进技术将对其他项目具有重大价值。此外，这些核心将提供大量和高标准的独特材料，这将使科学进步迅速，并使项目之间容易相互交流。在5年的支持结束时，我们相信将产生重要的基础和临床有用的信息，这一疾病仍然具有高度的临床相关性。

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.