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.

项目总结/摘要 标题：肝素诱导的血小板减少症中体液免疫应答的分子基础 肝素诱导的血小板减少症（HIT）是影响血细胞的最常见药物不良反应。 尽管肝素是一种重要的抗凝剂，广泛应用于许多临床环境中，但肝素暴露通常 导致产生对血小板α表达的构象表位具有特异性的抗体（Ab） 颗粒趋化因子，血小板因子4（PF 4），当它结合肝素形成复合物（PF 4/H）。在一些 患者，特别是手术后，这些抗体引起HIT，其特征是血小板减少症，通常是终身的。 威胁动脉或静脉血栓形成/血栓栓塞。这种并发症被认为至少会导致 部分来自PF 4依赖性Ab与血小板、单核细胞和可能的其他靶细胞的结合，导致细胞凋亡。 通过Fc受体活化和产生促凝血活性。肝素诱导的细胞凋亡的机制 抗体引起的血小板减少症和血栓形成部分了解，但很少有人知道， 免疫反应的分子基础。HIT的一个独特特征是25-50%的患者 暴露于肝素产生识别PF 4/H的Ab，但只有0.1-1.0%经历经典HIT 综合征为什么有些肝素诱导的抗体是“良性”或“非致病性”，而另一些是“致病性” 不能仅根据抗体效价来解释。在本申请中，我们建议提供一种 分子解释为什么一些肝素诱导的抗体导致病理，而其他可能识别 PF 4/H同样不会引起疾病。我们的研究将通过与临床医生的密切合作来促进， 从事研究的转化科学家，以提高对HIT发病机制的理解， 这种情况的诊断和治疗。