Molecular Basis of the Humoral Immune Response in Heparin-Induced Thrombocytopenia

肝素诱导的血小板减少症体液免疫反应的分子基础

• 批准号: 10491676
• 负责人: Renren Wen
• 金额: $ 58.3万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491676
• 关键词: Affect; Alpha Granule; American; Antibodies; Antibody Activation; Antibody Formation; Anticoagulants; Aspartic Acid; B-Lymphocytes; Basic Amino Acids; Behavior; Benign; Binding; Biological Assay; Blood; Blood Cells; Blood Platelets; Cell Culture Techniques; Cells; Clinic; Clone Cells; Collaborations; Complex; Complication; Data; Diagnosis; Disease; Enzyme-Linked Immunosorbent Assay; Epitopes; Exposure to; Fc Receptor; Frequencies; Future; Generations; Heparin; Immune response; Immunoglobulin G; Immunoglobulin M; Individual; Investigation; Life; Light; Light-Chain Immunoglobulins; Minority; Molecular; Molecular Conformation; Molecular Genetics; Molecular Profiling; Operative Surgical Procedures; PF4 Gene; Pathogenesis; Pathogenicity; Pathology; Patients; Persons; Phase; Platelet Activation; Prevalence; Prevention; Reporting; Research; Risk; Serotonin; Solid; Structure; Syndrome; Testing; Thrombocytopenia; Thromboembolism; Thrombosis; Venous Thrombosis; adverse drug reaction; chemokine; complementarity-determining region 3; experience; heparin-induced thrombocytopenia; high risk; improved; monocyte; novel strategies; patient screening; patient subsets; tool; translational scientist

Project Summary/Abstract Title: Molecular basis of the humoral immune response in heparin-induced thrombocytopenia Heparin induced thrombocytopenia (HIT) is the most common adverse drug reaction affecting blood cells. Although heparin is an important anticoagulant widely used in many clinic settings, heparin exposure often leads to production of antibodies (Abs) specific for conformational epitopes expressed by the platelet alpha granule chemokine, platelet factor 4 (PF4) when it binds to heparin to form a complex (PF4/H). In some patients, particularly after surgery, these Abs provoke HIT, characterized by thrombocytopenia and often life- threatening arterial or venous thrombosis/thromboembolism. This complication is thought to result, at least in part, from PF4-dependent Ab binding to platelets, monocytes and possibly other target cells, leading to cell activation via Fc receptors and generation of procoagulant activity. The mechanisms by which heparin-induced Abs cause thrombocytopenia and thrombosis are partially understood, but very little is known about the molecular basis of the underlying immune response itself. One unique feature of HIT is that 25-50% of patients exposed to heparin produce Abs that recognize PF4/H but only 0.1-1.0% experience the classical HIT syndrome. Why some heparin-induced Ab are “benign” or “non-pathogenic” and others are “pathogenic” cannot be accounted for on the basis of Ab potency alone. In this application, we propose to provide a molecular explanation for why some heparin-induced Abs cause pathology whereas others that may recognize PF4/H equally well fail to cause disease. Our studies will be facilitated by close collaboration with clinicians and translational scientists engaged in research to improve understanding of HIT pathogenesis and improve diagnosis and treatment of this condition.

项目摘要/摘要 标题：肝素引起的血小板减少症中体液免疫调节的分子基础 肝素诱导的血小板减少症（HIT）是影响血细胞的最常见不良药物反应。 尽管肝素是在许多诊所中广泛使用的重要抗凝剂，但肝素暴露经常暴露 导致产生针对血小板α表达的会议表位的抗体（ABS） 颗粒趋化因子，血小板因子4（PF4）与肝素结合以形成复合物（PF4/H）。在某些人中 患者，尤其是手术后，这些ABS引起的命中，其特征是血小板减少症，通常是寿命 威胁动脉或静脉血栓形成/血栓症。人们认为这种并发症至少在 部分，从依赖PF4的AB结合到血小板，单核细胞和可能的其他靶细胞，导致细胞 通过FC受体和引发活性的生成激活。肝素引起的机制 ABS引起血小板减少症和血栓形成是部分理解的，但对此知之甚少 潜在免疫反应本身的分子基础。 HIT的一个独特功能是25-50％的患者 暴露于肝素产生的ABS识别PF4/H但只有0.1-1.0％的经验经验 综合征。为什么某些肝素引起的AB是“良性”或“非致病性”，而另一些则是“致病性” 不能仅仅基于AB效力来解释。在此应用程序中，我们建议提供 分子解释说明为什么某些肝素诱导的ABS会导致病理，而其他可能识别 PF4/H同样良好地引起疾病。我们的研究将通过与临床医生的密切合作和 转化科学家从事研究以提高对命中发病机理的理解并改善 诊断和治疗此疾病。