Author

Mary Hughes

Date of Award

9-2000

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

John G. Kelton

Abstract

Idiopathic thrombocytopenic purpura (ITP) is a common autoimmune disorder characterized by the premature destruction of autoantibody-sensitized platelets. For many years, elevated platelet-associated IgG (PAIgG) was thought to be a diagnostic characteristic of ITP. However, observations that PAIgG is increased in both immune and non-immune thrombocytopenia, questioned the clinical significance of PAIgG measurements, and the mechanism(s) by which IgG accumulates in platelets. The origin of IgG on the surface of platelets of patients with non-immune thrombocytopenia, is not known. Additionally, it is not clear why these IgG-sensitized platelets escape destruction by phagocytic cells of the reticuloendothelial system. In this investigation, possible biological explanations for the elevated PAIgG in adult patients with ITP and non-immune thrombocytopenia, were examined. Traditionally, laboratory investigation of ITP, has focused on the development of serologic assays to measure anti-platelet autoantibodies. As an alternative investigative approach, ultrastructural techniques were used to evaluate platelets from patients with ITP and non-immune thrombocytopenia. Using these techniques, it was possible to localize IgG in platelets, and determine the immunomorphologic characteristics of PAIgG in patients with immune and non-immune thrombocytopenia. The results of these investigations demonstrated, that apart from differences in numbers, ITP platelets and platelets from patients with non-immune thrombocytopenia are morphologically identical to normal platelets and show no evidence of structural abnormalities. Additionally, elevated total PAIgG levels in thrombocytopenic patients are not attributable to alterations in the physical characteristics of platelets, including increased platelet size or increased numbers of storage granules per platelet, but reflected quantitative abnormalities in the pool of exogenous a-granule proteins. Immunomorphologic characteristics of PAIgG in patients with ITP and non-immune thrombocytopenia differ. In patients with ITP, elevated PAIgG is observed both within and on the surface of platelets. In patients with non-immune thrombocytopenia, elevated PAIgG was observed within but not on the platelet surface. In these platelets, IgG is not elevated on the platelet surface and, consequently, platelets were not prematurely cleared by phagocytic cells of the reticuloendothelial system. These results further explain why patients with non-immune thrombocytopenia have a normal platelet lifespan. Demonstrations that immunomorphologic characteristics of surface PAIgG, in platelets from patients with non-immune thrombocytopenia change over time suggests that in vitro leakage of α-granule IgG onto the surface of platelets may account for the origin of surface PAIgG in these patients. Immunomorphologic characteristics of surface PAIgG in patients with immune and non-immune thrombocytopenia suggest that rim patterns of surface PAIgG in ITP reflect the binding of autoantibodies to glycoprotein targets on the platelet surface whereas, "beaded necklace" patterns of surface PAIgG in non-immune thrombocytopenia reflect IgG exocytosis from internal platelet storage pools in vitro . In summary, ultrastructural techniques have been useful for the study of early structural events leading to the pathogenesis of disease and more recently have been utilized in studies of platelet pathology. Whereas current measurements of PAIgG do not provide good diagnostic or prognostic value, ultrastructural patterns of IgG distribution in ITP platelets may in themselves, or in conjunction with other laboratory measures, provide additional information about a common thrombocytopenic disorder.

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