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(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的致命性血栓前并发症。治疗包括立即停用肝素和开始使用直接凝血酶抑制物(DTI)。在实践中，HIT的诊断往往是具有挑战性的。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，对此往往有看似合理的替代解释。免疫分析是最广泛使用的HIT实验室检测方法，具有高度的敏感性，但假阳性率高达100%。更具体的功能分析，如5-羟色胺释放试验(SRA)，仅在选定的参考实验室可用，原因是技术障碍，包括对捐赠者血小板和放射性的需求。肝素化患者中血小板减少的频率，广泛可用的实验室测试的糟糕的特异性，以及临床医生对错过真正成功病例的恐惧，共同促成了一种经常过度诊断和过度治疗的氛围。因此，相当数量的血小板减少患者不必要地暴露在昂贵的DTI中，并伴随着10%-20%的大出血风险。这项建议的首要目标是更好地了解这一问题的严重性，并开发改进的诊断工具来解决这一问题。具体地说，我们建议在一组疑似HIT的患者中确定不必要的DTI使用的频率和后果(目标2)。在相同的队列中，我们的目标是评估两种新的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命中专家概率(HEP)评分(AIM 1)，这是Cuker博士开发的一种新的临床决策规则，在最近发表的一项回顾研究中显示了将DTI使用安全地减少41%的潜力。第二种是一种创新的功能实验室检测方法，该方法利用转染人Fc？RIIA和荧光素酶报告基因的DT40细胞系(Aim 3)。在初步研究中，这种方法已被证明操作简单，重复性高，有望取代技术上更为繁琐的SRA。Cuker博士是这一应用的主要研究员，是宾夕法尼亚大学的医学和病理学与实验室医学助理教授，对免疫介导的血小板减少性疾病有临床和研究兴趣。他通过完成翻译研究硕士学位以及参加美国血液学会临床研究培训研究所，在以患者为导向的调查方面进行了正式培训。他还发表了第一作者的原创论文和评论，并在他所在领域的全国会议上发表了几次演讲。库克博士为完成拟议的研究和他的职业发展选择了一个理想的学术环境。他将继续与他过去4年的主要导师道格拉斯·辛斯博士合作，道格拉斯·辛斯博士是HIT领域的国际权威，也是一位经验丰富的导师，以将初级教师培养成独立的、由NIH资助的、 调查人员。此外，他还组建了一支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，作为他的咨询委员会的共同导师和成员。根据目前的提议，他的培训经验将通过临床研究方法方面的高级课程、参加校园研讨会、教学以及护理止血和血栓障碍患者来扩大。