Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin therapy that involves thromboctyopenia and thrombosis. Platelet Factor 4 (PF4)/heparin complexes are involved in the development of HIT. The studies proposed below will further define the molecular basis of the development of HIT. In addition, we believe that these studies may provide insights into other related disorders, such as the Anti-phospholipid Syndrome, which are also immune-based disorders combining thrombocytopenia and a high risk of developing thrombosis. There are 3 specific aims to this application: I. Characterize the antigenic sites on PF4/heparin involved in HIT. We have clearly shown that there are at least two antigenic sites recognized by HIT antibodies. Using mutant forms of PF4, we have defined one as being immediately adjacent to PF4's Cys36. We have also developed a HIT-like murine (m) monoclonal antibody (MoAb) KKO that recognizes a second site and have used a random peptide phage-display library to define a mimetope for KKO. By using mutant PF4/heparin complexes, HIT-like moAbs, further studies with the random peptide phage-display and NMR studies, we plan to fully characterize the antigenic sites on PF4/heparin. We also plan to determine whether either HIT antigenic sites is linked to the clinical course in HIT. II. Define the immune response in HIT patients. We plan to isolate additional MoAbs and characterize them as described above for KKO. We will also have established a phage-display library from a patient with HIT and thrombosis. HIT-like phage-display clones will be isolated from this library and from libraries to be established from HIT patients without thrombosis and from patients with anti-PF4/heparin antibodies who do not develop HIT. The hypervariable regions, isotype utilization and antigen affinity and specificity will be compared to each other. Such studies should provide additional insights into how HIT antibodies develop and lead to disease. III. Use a murine HIT model to characterize risk factors and treatment strategies. We have developed a murine passive immunization HIT model in which we have documented thrombocytopenia, but no obvious thrombosis. We plan on maximizing this system, and then test variables, such as the specific nature of the MoAb, the nature of the platelet Fc receptor and the presence of pre- existing vascular disease, on the development of thrombosis. The model may also allow us to test strategies to prevent HIT. Thus, we believe that our proposed studies will not only provide insights into the etiology and progression of HIT, but may provide novel new approaches for its prevention and/or its treatment.
| Grosser, Tilo; Fries, Susanne; Lawson, John A et al. (2013) Response to letters regarding article, ""Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin"". Circulation 128:e191 |
| Grosser, Tilo; Fries, Susanne; Lawson, John A et al. (2013) Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin. Circulation 127:377-85 |
| Ricciotti, Emanuela; FitzGerald, Garret A (2011) Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 31:986-1000 |
| Skarke, Carsten; FitzGerald, Garret A (2010) Training translators for smart drug discovery. Sci Transl Med 2:26cm12 |
| Yu, Y; Ricciotti, E; Grosser, T et al. (2009) The translational therapeutics of prostaglandin inhibition in atherothrombosis. J Thromb Haemost 7 Suppl 1:222-6 |
| Reilly, Dermot F; Curtis, Anne M; Cheng, Yan et al. (2008) Peripheral circadian clock rhythmicity is retained in the absence of adrenergic signaling. Arterioscler Thromb Vasc Biol 28:121-6 |
| Siegel, Don L (2008) Translational applications of antibody phage display. Immunol Res 42:118-31 |
| FitzGerald, Garret A (2008) Translational therapeutics at the platelet vascular interface. Introduction. Arterioscler Thromb Vasc Biol 28:s3-4 |
| FitzGerald, Garret A (2008) Translational therapeutics at the platelet vascular interface. Summary. Arterioscler Thromb Vasc Biol 28:s51-2 |
| Suvarna, Shayela; Espinasse, Benjamin; Qi, Rui et al. (2007) Determinants of PF4/heparin immunogenicity. Blood 110:4253-60 |
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