Heparin-induced thrombocytopenia, with or without thrombosis (HIT/T), is an important cause of morbidity and mortality in patients treated with this otherwise extremely useful anticoagulant. From studies in our lab and by others, much has been learned about HIT/T in recent years but its pathogenesis is still not understood adequately at the molecular level. HIT/T is remarkable, and probably unique among immune disorders in several respects: 1) the responsible antibodies appear to be specific for complexes made up of two normal body constituents, heparin and platelet factor 4 (PF4), 2) antibodies with this specificity are produced by a high percent of certain patient populations given heparin but are almost never found in persons not exposed to heparin and 3) only a minority of patients who make antibodies develop HIT/T. In this application, I propose studies to determine the molecular basis for immune response to PF4:heparin that appears to be central to the pathogenesis of HIT/T. In one phase of this work, I will characterize immunoglobulin V genes utilized in mounting a pathogenic response and define at a molecular level the epitopes on PF4:heparin complexes recognized by HIT/T antibodies and characterize Ig CDR3 sequences critical for this interaction. In the other phase II, I will apply methods recently developed in our laboratory to generate antigen-specific T cell lines and clones from blood of patients with HIT/T and will utilize these to characterize T cell receptor utilization and immunogeneic peptides derived from PF4. The hypothesis on which this application is based is that a more complete understanding for the molecular basis of the unusual immune response characteristic of HIT/T will suggest new approaches to diagnosis, treatment, prevention and identification of patients at risk for this disorder. More speculatively, findings made could provide clues to the mechanism(s) by which heparin triggers an antibody response to PF4 - an otherwise immunologically inert protein - and could therefore be relevant to certain autoimmune and immune complex disorders.
| Visentin, Gian Paolo; Liu, Chao Yan (2007) Drug-induced thrombocytopenia. Hematol Oncol Clin North Am 21:685-96, vi |
| Liu, Chao Yan; Battaglia, Manuela; Lee, Seon Ho et al. (2005) Platelet factor 4 differentially modulates CD4+CD25+ (regulatory) versus CD4+CD25- (nonregulatory) T cells. J Immunol 174:2680-6 |
| Lee, Seon Ho; Liu, Chao Yan; PaoloVisentin, Gian (2002) Heparin-induced thrombocytopenia: molecular pathogenesis. Int J Hematol 76 Suppl 1:346-51 |
| Visentin, G P; Moghaddam, M; Beery, S E et al. (2001) Heparin is not required for detection of antibodies associated with heparin-induced thrombocytopenia/thrombosis. J Lab Clin Med 138:22-31 |
