This proposal addresses the Broad Challenge Area of (03) Biomarker Discovery and Validation, specifically (03-HL-101), to identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac and respiratory tract dysfunction. Thrombosis is the major cause of death in the United States and heparin, in unfractionated (UFH) or low molecular weight form, is uniformly used for anticoagulation in the hospital setting. Heparin-induced thrombocytopenia (HIT) occurs in 1-5% of patients exposed to heparin, can have severe consequences with loss of limbs or life, and often occurs in elderly patients with advanced atherosclerotic disease and increased baseline risks of both thrombosis and hemorrhage. While alternative anticoagulants are available, they are associated with increased risks of bleeding and increased costs, and have not replaced UFH for common surgeries requiring cardiopulmonary bypass (CPB). If patients who are at greatest risk of HIT can be identified prior to heparin exposure, targeted alternative anticoagulation could be used. HIT is caused by antibodies against a complex of heparin/platelet factor 4 (PF4). Our laboratory studies, including animal models and human ex-vivo studies of platelet and vascular PF4 and glycosoaminoglycan/PF4 complex immunogenicity, support our ability to utilize novel biomarkers and clinical factors to determine the risk of HIT. We are currently studying platelet biomarkers of risk in patients undergoing cardiac catheterization and are now poised to validate these biomarkers, and markers of incipient antibody development, in a patient population at high risk of forming antiheparin/ PF4 antibodies. We hypothesize that a constellation of biomarkers and clinical factors will predict risk of heparin/PF4 antibody formation and HIT, and propose studies to evaluate this through Specific Aims: 1) To determine if novel platelet biomarkers and clinical factors predict anti-heparin/PF4 antibody formation post- CPB;2) To evaluate expression of antigen-specific B cells and evolution of antiheparin/PF4 antibody isotype and titer as precursors of HIT;and, 3) To observe if anti-heparin/PF4 antibody formation or platelet biomarkers predict in-hospital and 30 day cardiovascular and all cause morbidity and mortality. The University Of Pennsylvania School Of Medicine contributes substantially to the local economy. In 2008, the School of Medicine created 37,000 jobs and $5.4 billion in regional economic activity, with the areas highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. Through the proposed studies we will retain and increase staff employment (2.5 jobs) and our studies should improve use of a commonly prescribed medication and decrease adverse clinical events and medical costs. These goals are consistent with the purpose of the American Recovery and Reinvestment Act of 2009 to preserve and create jobs, and to promote economic recovery by spurring advances in science and health.

Public Health Relevance

Heparin is a commonly used blood thinner in all hospitals in the U.S. Heparin-induced thrombocytopenia (HIT) is a serious adverse effect of heparin that can result in loss of limbs or death. This study will help identify patients most at risk of developing HIT with heparin therapy so that the approach to their care can be altered, and thus, improved.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
NIH Challenge Grants and Partnerships Program (RC1)
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Special Emphasis Panel (ZRG1-VH-D (58))
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Kindzelski, Andrei L
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Puget Sound Blood Center
United States
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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
Litvinov, Rustem I; Yarovoi, Serge V; Rauova, Lubica et al. (2013) Distinct specificity and single-molecule kinetics characterize the interaction of pathogenic and non-pathogenic antibodies against platelet factor 4-heparin complexes with platelet factor 4. J Biol Chem 288:33060-70
Cuker, Adam; Rux, Ann H; Hinds, Jillian L et al. (2013) Novel diagnostic assays for heparin-induced thrombocytopenia. Blood 121:3727-32
Sachais, Bruce S; Litvinov, Rustem I; Yarovoi, Serge V et al. (2012) Dynamic antibody-binding properties in the pathogenesis of HIT. Blood 120:1137-42
Sachais, Bruce S; Rux, Ann H; Cines, Douglas B et al. (2012) Rational design and characterization of platelet factor 4 antagonists for the study of heparin-induced thrombocytopenia. Blood 119:5955-62
Cuker, A; Arepally, G; Crowther, M A et al. (2010) The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost 8:2642-50