Immunological Analysis Of Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an immune disorder caused by administration of heparin. Immune complexes consisting of heparin, platelet factor 4 (PF4), and PF4/heparin specific antibodies are central to the pathogenesis of HIT. It is as yet unclear what triggers the initial induction of pathogenic antibodies, and the pathogenesis of HIT is not fully understood yet. In this thesis, we use immunological methods to dissect the basic mechanisms of the pathogenesis of HIT. Here, we show that anti-PF4/heparin antibodies are readily generated in wild-type mice on challenge with PF4/heparin complexes. By using this immunization model, we have found that mouse marginal zone (MZ) B cells play a critical role in PF4/heparin antibody production. In addition, we have identified that healthy humans and mice possess pre-existing inactive/tolerant PF4/heparin-specific B cells. The findings suggest that PF4/heparin-specific antibody production is regulated by immune tolerance, and indicate that breakdown tolerance can contribute to the PF4/heparin-specific B-cell activation and antibody production in patients developing HIT. Last, we also show that CD4 T cells are required for the initial development of HIT, which can provide helps in activating B cells and sequentially producing PF4/heparin-specific antibodies.