Modeling the spectrum of HIT pathobiology

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DESCRIPTION (provided by applicant): The goal of this small grant application is to develop a research methodology for studies of Heparin-Induced Thrombocytopenia (HIT). HIT is a prothrombotic disorder caused by an allergic response to the anticoagulant drug, heparin. HIT is caused by antibodies directed towards a platelet protein, Platelet Factor 4 (PF4) and heparin (H). Because PF4/H antibodies can elicit life-threatening thrombotic complications in patients, experimental studies of disease pathogenesis have relied on animal models. Two distinct animal models have been developed to study HIT; one model studies thrombotic complications of HIT (murine HIT model) and the other, a murine immunization model developed by our lab to study the PF4/H immune response. In this R03 application, we propose to develop an integrated murine model for studies of human HIT pathogenesis. Based on preliminary studies, we hypothesize that pathogenicity of PF4/H antibodies is determined by the confluence of three factors, circulating antigen (PF4/H complexes), PF4/H Abs and activating platelet Fc RIIA receptors. We propose to test this hypothesis using one of two approaches relying on the presence of Fc RIIA expression (single transgenic model) with or without expression of hPF4 (double transgenic model). In the first approach, we will induce PF4/H antibodies in a single transgenic model (mice expressing hFc RIIA) with the goal of examining effects of antigen load, antibody titer and Fc RII expression. In the second approach, we wish to develop a "humanized" murine model using double transgenic mice expressing human (h)PF4 and hFc RIIA to examine the effects of hPF4 levels and hFcR expression on the immune response and disease expression. In pursuing this small research grant, we hope that these optimized murine models will facilitate future investigations on the mechanisms underlying evolution of pathogenic HIT antibodies.