Improving the diagnosis of heparin-induced thrombocytopenia

描述（由申请人提供）：肝素诱导的血小板减少症（HIT）是肝素治疗的潜在致命的血栓前并发症。处理包括立即停药肝素和开始直接凝血酶抑制剂（DTI）。在实践中，HIT的诊断通常是具有挑战性的。该疾病的主要临床表现-血小板减少在肝素暴露环境中-是住院患者中常见的发现，对此往往存在似是而非的解释。免疫测定法是HIT最广泛使用的实验室检测方法，它非常敏感，但受假阳性率高达100%的限制。由于需要供体血小板和放射性等技术障碍，更具体的功能测定，如血清素释放测定（SRA），仅在选定的参考实验室可用。肝素化患者中血小板减少的频率，广泛可用的实验室检查的低特异性，以及临床医生对错过一个真正的HIT病例的恐惧，共同促成了频繁的过度诊断和过度治疗的氛围。因此，大量血小板减少患者不必要地暴露于昂贵的dti和随之而来的10-20%的大出血风险。这项建议的总体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（目的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。这些测试中的第一个，HIT专家概率（HEP）评分（Aim 1），是由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性研究中显示，安全减少DTI使用41%的潜力。第二种是创新的功能性实验室检测，利用转染人Fc？RIIA和一个荧光素酶报告基因（Aim 3）。在初步研究中，该分析已被证明操作简单，可重复性高，有望取代技术上更繁琐的SRA。Cuker博士是这项应用的主要研究者，他是宾夕法尼亚大学（University of Pennsylvania）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。他通过完成转化研究硕士学位以及参加美国血液学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。他还发表了原创的第一作者论文和评论，并在他的领域的国家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来完成他的研究和职业发展。他将继续与他过去四年的主要导师Douglas Cines博士合作，Douglas Cines博士是哈工大的国际权威，也是一位经验丰富的导师，以培养年轻教师成为独立的，nih资助的，

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.