New Approaches to Pathogenesis and Diagnosis of Heparin-Induced

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PROJECT SUMMARY/ABSTRACT This research is aimed at gaining a better understanding of the pathophysiology of heparin-induced thrombocytopenia/thrombosis (HIT), a common and sometimes life-threatening complication of heparin treatment, and developing better tools for early diagnosis and management. The candidate, Anand Padmanabhan M.D., Ph.D, is a junior faculty member at the BloodCenter of Wisconsin (BCW). BCW has made a firm commitment to protect the applicant's research time at the 75% level and to provide necessary space and personnel support. The applicant will be mentored by a highly experienced physician-investigator, Dr. Richard Aster, MD aided by Dr. Demin Wang, PhD and Dr. Jian Liu, PhD, recognized authorities in immunology and glycobiology, respectively. An ambitious career development plan is described that includes basic training in glycobiology, statistics and clinical immunology and will facilitate Dr. Padmanabhan's professional growth into an independent investigator. The research plan is based on Dr. Padmanabhan's recent finding that heparin-induced, platelet- activating (“pathogenic”) antibodies bind to platelets pre-treated with platelet factor 4 (PF4) in the absence of heparin, whereas non-activating (“benign”) antibodies do not. Dr. Padmanabhan hypothesizes that the distinction between the two types of antibodies is that pathogenic antibodies preferentially recognize subtle structural changes induced in PF4 when it reacts with chondroitin sulfate (CS) linked to an unidentified core protein that makes up the dominant platelet surface proteoglycan (PG). He anticipates that a better understanding at biochemical, structural and functional levels of the process by which PF4 “primes” platelets for pathogenic antibody binding and of the antibodies themselves will lead to new understanding of HIT pathogenesis and to improved diagnostic tools for early identification of patients at risk for HIT and its thrombotic complications. In support of this concept, he has developed a novel assay, the PF4-dependent p- selectin expression assay (PEA), which in preliminary testing was found to be more accurate and less technically demanding than the gold standard serotonin release assay (SRA). Dr. Padmanabhan will further assess the diagnostic utility and treatment impact of the PEA in a rigorously-designed prospective study in patients suspected of HIT. Dr. Padmanabhan is a promising junior physician-investigator in a supportive and scientifically-rich environment proposing a well defined and challenging project that has important clinical implications. The K08 award will enable him to focus the majority of his time on this promising research while expanding his scientific capabilities through formal training as outlined in his application. The program described will provide Dr. Padmanabhan ideal preparation for a career as an independent investigator in hematology/transfusion medicine.