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.

项目概要/摘要 标题：肝素诱导的血小板减少症体液免疫反应的分子基础 肝素诱导的血小板减少症（HIT）是影响血细胞的最常见的药物不良反应。 尽管肝素是一种重要的抗凝剂，在许多临床环境中广泛使用，但肝素暴露经常 导致产生针对血小板 α 表达的构象表位的特异性抗体 (Abs) 颗粒趋化因子、血小板因子 4 (PF4)，当它与肝素结合形成复合物 (PF4/H) 时。在一些 对于患者，特别是在手术后，这些 Abs 会引发 HIT，其特征是血小板减少，并且常常会导致生命危险。 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PF4依赖性抗体与血小板、单核细胞和可能的其他靶细胞的结合，导致细胞 通过 Fc 受体激活并产生促凝血活性。肝素诱导的机制 Abs 导致血小板减少和血栓形成的原因已被部分了解，但人们对 Abs 引起的血小板减少和血栓形成知之甚少。 潜在免疫反应本身的分子基础。 HIT 的一个独特特征是 25-50% 的患者 暴露于肝素会产生识别 PF4/H 的抗体，但只有 0.1-1.0% 经历经典 HIT 综合症。为什么一些肝素诱导的抗体是“良性的”或“非致病性的”，而另一些则是“致病性的” 不能仅根据抗体效力来解释。在此应用中，我们建议提供一个 分子解释为什么一些肝素诱导的抗体会引起病理，而另一些则可能识别 PF4/H 同样不会引起疾病。与临床医生的密切合作将促进我们的研究 转化科学家从事研究以提高对 HIT 发病机制的了解并改善 这种情况的诊断和治疗。