Improving the diagnosis of heparin-induced thrombocytopenia

改善肝素诱导的血小板减少症的诊断

基本信息

批准号：
8278801
负责人：
Adam Cuker
金额：
$ 13.84万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/8278801
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&apos 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

项目摘要

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）是肝素治疗的一种潜在致命的血栓前并发症。治疗包括立即停用肝素并开始使用直接凝血酶抑制剂（DTI）。在实践中，HIT 的诊断通常具有挑战性。这种疾病的主要临床表现——在接近肝素暴露的情况下出现血小板减少——是住院患者中的常见发现，对此通常存在合理的替代解释。免疫检测是最广泛使用的 HIT 实验室检测，其灵敏度很高，但受到高达 100% 的假阳性率的限制。由于需要供体血小板和放射性等技术障碍，诸如血清素释放测定 (SRA) 等更具体的功能测定仅在选定的参考实验室提供。肝素化患者中血小板减少症的发生率、广泛使用的实验室检测的特异性较差以及临床医生担心错过真正的 HIT 病例，这些因素共同助长了频繁的过度诊断和过度治疗的风气。结果，大量血小板减少症患者不必要地接受昂贵的 DTI 治疗，并伴随着 10-20% 的大出血风险。该提案的总体目标是更好地了解该问题的严重性并开发改进的诊断工具来解决该问题。具体来说，我们建议在疑似 HIT 患者的前瞻性队列中确定不必要的 DTI 使用频率和后果（目标 2）。在同一队列中，我们的目标是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。其中第一个测试是 HIT 专家概率 (HEP) 评分（目标 1），是 Cuker 博士开发的一种新颖的临床决策规则，在最近发表的一项回顾性研究中显示了可以安全地将 DTI 使用量减少 41% 的潜力。第二种是创新的功能实验室测定，利用转染人 Fc?RIIA 和荧光素酶报告基因的 DT40 细胞系（目标 3）。在初步研究中，这种检测方法已被证明操作简单且可重复性高，有望替代技术上更为繁琐的 SRA。 Cuker 博士是本申请的主要研究者，是宾夕法尼亚大学医学以及病理学和实验医学助理教授，对免疫介导的血小板减少性疾病有临床和研究兴趣。他通过完成转化研究硕士学位并参加美国血液学会临床研究培训机构，接受了以患者为导向的调查的正式培训。他还发表了第一作者的原创论文和评论，并在该领域的全国会议上发表了多次演讲。 Cuker 博士选择了一个理想的学术环境来完成拟议的研究和职业发展。他将继续与他过去 4 年的主要导师 Douglas Cines 博士合作，Douglas Cines 博士是 HIT 领域的国际权威，也是一位经验丰富的导师，在促进初级教师发展成为独立的、由 NIH 资助的、调查人员。此外，他还组建了一支由著名基础科学家、临床医生和临床流行病学家组成的团队，作为他的顾问委员会的共同导师和成员。他在当前提案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、教学以及止血和血栓形成疾病患者的护理来增强。