Improving the diagnosis of heparin-induced thrombocytopenia

改善肝素诱导的血小板减少症的诊断

• 批准号: 8656424
• 负责人: Adam Cuker
• 金额: $ 13.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656424
• 关键词: Address; Adopted; Advisory Committees; Agreement; American Society of Hematology; Antibodies; B-Lymphocytes; Biological Assay; Blood Platelets; Caring; Cell Line; Characteristics; Climate; Clinical; Clinical Research; Cohort Studies; Community Hospitals; Complication; Consensus; Coupled; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Drug Costs; Educational process of instructing; Environment; Epidemiologist; Event; Expert Opinion; Faculty; Fostering; Frequencies; Fright; Funding; Health system; Hemorrhage; Hemostatic function; Heparin; Human; Immune; Immunology procedure; Incidence; Institutes; Institution; International; Investigation; Laboratories; Luciferases; Master' s Degree; Measures; Mediating; Medicine; Mentors; Modeling; Mus; Outcome; Paper; Pathology; Patients; Pennsylvania; Performance; Population; Prevention; Probability; Prospective Studies; Publishing; Radioactivity; Recruitment Activity; Reporter; Research Methodology; Research Personnel; Research Training; Rest; Retrospective Studies; Risk; Scientist; Serotonin; Specificity; Testing; Thrombin; Thrombocytopenia; Thrombosis; Training; Translational Research; United States National Institutes of Health; Universities; Work; authority; base; career development; cohort; common treatment; cost; design; experience; improved; inhibitor/antagonist; innovation; interest; lectures; meetings; member; novel; novel diagnostics; patient oriented; prevent; primary outcome; professor; prospective; tertiary care; tool

DESCRIPTION (provided by applicant): Heparin-induced thrombocytopenia (HIT) is a potentially fatal prothrombotic complication of heparin therapy. Management involves immediate discontinuation of heparin and initiation of a direct thrombin inhibitor (DTI). In practice, the diagnosis of HIT is often challenging. The cardinal clinical manifestation of the disorder - thrombocytopenia in the setting of a proximate heparin exposure - is a common finding among hospitalized patients for which plausible alternative explanations often exist. Immunologic assays, the most widely used laboratory tests for HIT, are highly sensitive but are limited by false-positive rates as high as 100%. More specific functional assays such as the serotonin release assay (SRA) are available only at select reference laboratories, owing t technical barriers including need for donor platelets and radioactivity. The frequency of thrombocytopenia among heparinized patients, the poor specificity of widely available laboratory tests, and clinicians' fears of missing a case of true HIT conspire to foster a climate of frequen overdiagnosis and overtreament. As a result, a substantial number of thrombocytopenic patients are unnecessarily exposed to costly DTIs and their attendant 10-20% risk of major hemorrhage. The overarching objective of this proposal is to better understand the magnitude of this problem and to develop improved diagnostic tools to address it. Specifically, we propose to determine the frequency and consequences of unnecessary DTI use in a prospective cohort of patients with suspected HIT (Aim 2). In this same cohort, we aim to evaluate the performance of and potential for two novel diagnostic tests to reduce unnecessary DTI use. The first of these tests, the HIT Expert Probability (HEP) Score (Aim 1), is a novel clinical decision rule developed by Dr. Cuker that showed the potential to safely reduce DTI use by 41% in a recently published retrospective study. The second is an innovative functional laboratory assay that utilizes a DT40 cell line transfected with human Fc?RIIA and a luciferase reporter (Aim 3). In preliminary studies, this assay has proven simple-to-perform and highly reproducible and holds promise as a replacement for the more technically cumbersome SRA. Dr. Cuker, the primary investigator on this application, is an Assistant Professor of Medicine and of Pathology & Laboratory Medicine at the University of Pennsylvania and has a clinical and research interest in immune-mediated thrombocytopenic disorders. He has pursued formal training in patient-oriented investigation through completion of a Masters Degree in Translational Research as well as participation in the American Society of Hematology Clinical Research Training Institute. He has also published original first-author papers and reviews and delivered several lectures at national meetings in his field. Dr. Cuker has chosen an ideal academic environment for completion of the proposed studies and his career development. He will continue to work with his primary mentor of the last 4 years, Dr. Douglas Cines, an international authority on HIT and an experienced mentor with a reputation for fostering the development of junior faculty into independent, NIH-funded, investigators. In addition, he has assembled a team of renowned basic scientists, clinicians, and clinical epidemiologists to serve as co-mentors and members of his advisory committee. His training experience under the current proposal will be augmented through advanced coursework in clinical research methods, participation in campus seminars, teaching, and the care f patients with disorders of hemostasis and thrombosis.

描述（由申请人提供）：肝素诱导的血小板减少症（HIT）是肝素疗法的潜在致命性血栓性并发症。管理涉及立即中断肝素和直接凝血酶抑制剂（DTI）的启动。实际上，诊断命中通常具有挑战性。该疾病的基本临床表现 - 在接近肝素接触的情况下，血小板减少症 - 在住院患者中常见的常见发现，通常存在合理的替代解释。免疫学测定是最广泛使用的HIT实验室测试，具有高度敏感，但受到假阳性率高达100％的限制。更具体的功能分析（例如5-羟色胺释放测定法（SRA））仅在选定的参考实验室中可用，造成技术障碍，包括对供体血小板和放射性的需求。 肝素化患者中血小板减少症的频率，广泛可用的实验室测试的特异性差，以及临床医生担心缺少真正的命中案的案例，以促进过度诊断和过度交流的气候。 结果，大量的血小板减少症患者不必要地暴露于昂贵的DTI及其随之而来的10-20％重大出血风险。该提案的总体目的是更好地了解此问题的幅度，并开发改进的诊断工具来解决该问题。具体而言，我们建议确定未经疑似命中患者的前瞻性DTI使用的频率和后果（AIM 2）。 在同一队列中，我们旨在评估两种新型诊断测试的性能和潜力，以减少不必要的DTI使用。这些测试中的第一个是热门专家概率（HEP）得分（AIM 1），是Cuker博士制定的新型临床决策规则，该规则显示了在最近发表的一项回顾性研究中，有可能将DTI使用将41％安全地减少41％。 第二是使用人类FC riia和荧光素酶报告基因转染的DT40细胞系的创新功能实验室测定（AIM 3）。 在初步研究中，该测定法已被证明是简单的，并且高度可重现，并有望替代技术上更繁琐的SRA。 该应用程序的主要研究人员Cuker博士是宾夕法尼亚大学医学和病理与实验室医学助理教授，对免疫介导的血小板细胞减少症具有临床和研究兴趣。 他通过完成翻译研究硕士学位以及参与美国血液学临床研究培训研究所的硕士学位，从事面向患者的调查的正式培训。他还发表了原始的第一名论文和评论，并在该领域的全国会议上发表了几次演讲。 Cuker博士选择了一个理想的学术环境，以完成拟议的研究及其职业发展。他将继续与过去四年的主要导师合作，道格拉斯·西恩斯（Douglas Cines）博士，他是一名受击中的国际机构，也是一位经验丰富的导师，以促进初级教职员工发展成独立，NIH资助，资助， 调查人员。此外，他还召集了由著名的基础科学家，临床医生和临床流行病学家组成的团队，担任其咨询委员会的联合体和成员。他在当前建议下的培训经验将通过临床研究方法的高级课程，参与校园研讨会，教学以及患有止血和血栓形成障碍的护理患者的培训经验。