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.

Public Health Relevance

Direct thrombin inhibitors (DTIs) are the mainstay of management for heparin-induced thrombocytopenia (HIT), a potentially fatal prothrombotic complication of heparin therapy~ although these agents are effective in the treatment and prevention of HIT-associated thrombosis, they are expensive and are associated with a 10-20% risk of major hemorrhage. As a result of the poor specificity of widely available diagnostic tools and clinicians' fears of missing a case of true disease, many thrombocytopenic patients are misdiagnosed with HIT and unnecessarily exposed to costly DTIs and their attendant bleeding risk. In this proposal, we aim to understand the incidence and consequences of unnecessary DTI use and to evaluate the potential for two novel diagnostic tests, an expert-based clinical decision rule and a simple-to-perform functional laboratory assay, to ameliorate this underappreciated and important clinical problem.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-X (F1))
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Sarkar, Rita
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Martinez, Marissa R; Cuker, Adam; Mills, Angela M et al. (2014) Enhanced lysis and accelerated establishment of viscoelastic properties of fibrin clots are associated with pulmonary embolism. Am J Physiol Lung Cell Mol Physiol 306:L397-404
Cuker, Adam; Siegal, Deborah M; Crowther, Mark A et al. (2014) Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 64:1128-39
Gardiner, Elizabeth E; Andrews, Robert K; Cuker, Adam (2014) DiagnoSTic assays for heparin-induced thrombocytopenia. Br J Haematol 166:631-3
Cuker, Adam; Rauova, Lubica; Bolgiano, Douglas et al. (2014) Atherosclerosis is not a risk factor for anti-platelet factor 4/heparin antibody formation after cardiopulmonary bypass surgery. Thromb Haemost 111:1191-3
Cines, Douglas B; Cuker, Adam; Semple, John W (2014) Pathogenesis of immune thrombocytopenia. Presse Med 43:e49-59
Siegal, Deborah M; Cuker, Adam (2014) Reversal of target-specific oral anticoagulants. Drug Discov Today 19:1465-70
Cuker, Adam (2014) Clinical and laboratory diagnosis of heparin-induced thrombocytopenia: an integrated approach. Semin Thromb Hemost 40:106-14
Cuker, Adam; Rux, Ann H; Hinds, Jillian L et al. (2013) Novel diagnostic assays for heparin-induced thrombocytopenia. Blood 121:3727-32
Siegal, Deborah; Crowther, Mark; Cuker, Adam (2013) Thrombopoietin receptor agonists in primary immune thrombocytopenia. Semin Hematol 50 Suppl 1:S18-21
Tanhehco, Yvette C; Cuker, Adam; Rudnick, Michael et al. (2013) Investigation of a potential protective mechanism against heparin-induced thrombocytopenia in patients on chronic intermittent hemodialysis. Thromb Res 131:244-8