Heparin-associated thrombocytopenia is mediated by antibody recognition of a neoantigen on heparin/platelet factor 4 complexes; the antibody then activates the platelet by the FcgammaRIIA receptor.
Three aims are proposed: 1. Characterizing the sites on PF4 involved in the reaction. Sites will be defined using recombinant wild and mutated PF4 and chimeras of PF4 and the related chemokine, beta- thromboglobulin, using antibodies of affected patients; 2. Defining the immune complex/FcR interactions : IgG1 and IgG3 antibodies are thought to mediate platelet destruction through interaction with FcgammaR on macrophages. IgG2 antibodies react less well with macrophage FcR but activate platelets in patients with an allomorphic variant -His131 . They propose to study both the IgG response and the FcgammaR phenotype of patients with HAT, and with and without thrombocytopenia; 3. Defining the molecular nature of the antibodies: Antigen specific clones of lymphocytes will be isolated from patients and the antibody genetics will be studied in detail to seek evidence of antigen mediated selection of the HAT immune response. Such antibodies could provide basis for analysis of the antigen recognition site, and of the antibody - heparin/PF4 interaction. This in turn could lead to the finding of anti- idiotype antibodies of diagnostic and perhaps therapeutic usefulness.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL054749-04S1
Application #
6078802
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1995-09-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
2000-07-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Rauova, Lubica; Zhai, Li; Kowalska, M Anna et al. (2006) Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood 107:2346-53
Suvarna, Shayela; Rauova, Lubica; McCracken, Emily K E et al. (2005) PF4/heparin complexes are T cell-dependent antigens. Blood 106:929-31
McKenzie, Steven E; Reilly, Michael P (2004) Heparin-induced thrombocytopenia and other immune thrombocytopenias: lessons from mouse models. Semin Thromb Hemost 30:559-68
Eslin, Don E; Zhang, Chunyan; Samuels, Kathleen J et al. (2004) Transgenic mice studies demonstrate a role for platelet factor 4 in thrombosis: dissociation between anticoagulant and antithrombotic effect of heparin. Blood 104:3173-80
Kufrin, Dubravka; Eslin, Don E; Bdeir, Khalil et al. (2003) Antithrombotic thrombocytes: ectopic expression of urokinase-type plasminogen activator in platelets. Blood 102:926-33
Li, Zhong Q; Liu, Weiyi; Park, Kwang S et al. (2002) Defining a second epitope for heparin-induced thrombocytopenia/thrombosis antibodies using KKO, a murine HIT-like monoclonal antibody. Blood 99:1230-6
Konkle, B A; Bauer, T L; Arepally, G et al. (2001) Heparin-induced thrombocytopenia: bovine versus porcine heparin in cardiopulmonary bypass surgery. Ann Thorac Surg 71:1920-4
Arepally, G M; Kamei, S; Park, K S et al. (2000) Characterization of a murine monoclonal antibody that mimics heparin-induced thrombocytopenia antibodies. Blood 95:1533-40
Kowalska, M A; Ratajczak, J; Hoxie, J et al. (1999) Megakaryocyte precursors, megakaryocytes and platelets express the HIV co-receptor CXCR4 on their surface: determination of response to stromal-derived factor-1 by megakaryocytes and platelets. Br J Haematol 104:220-9
Aceto, J; Kieber-Emmons, T; Cines, D B (1999) Carboxy-terminal processing of the urokinase receptor: implications for substrate recognition and glycosylphosphatidylinositol anchor addition. Biochemistry 38:992-1001

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