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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

基本信息

批准号：
10176180
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176180
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 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

项目摘要

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/文摘