The Pathogenesis of Chronic Immune Thrombocytopenic Purpura

https://doi.org/10.1053/j.seminhematol.2007.11.002Get rights and content

Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disorder in which the patient’s immune system reacts with a platelet autoantigen(s) resulting in thrombocytopenia due to immune-mediated platelet destruction and/or suppression of platelet production. Platelet membrane proteins, for reasons that are unclear, become antigenic and stimulate the immune system to produce autoantibodies and cytotoxic T cells. The initial antigenic response probably occurs in the spleen followed by stimulation of other antibody-producing tissues, particularly the bone marrow. Autoantibodies against platelet glycoprotein (GP) IIb-IIIa and/or GPIb-IX are produced by the majority of ITP patients and can be detected using antigen-specific assays. Many patients produce multiple antibodies; this has been attributed to the phenomenon of epitope spreading. Once produced, autoantibody may either bind to platelets, causing their destruction by either phagocytosis or possibly complement activation and lysis, or bind to megakaryocytes, resulting in decreased thrombopoiesis. Evidence for platelet destruction in ITP includes the following: (1) infusion of ITP blood or plasma into normal recipients may result in thrombocytopenia; (2) there is decreased intravascular survival of radiolabeled platelets in most ITP patients; (3) morphologic and in vitro evidence of platelet phagocytosis can be demonstrated; and (4) cytotoxic T cells can induce lysis of autologous platelets. Evidence for suppressed platelet production in ITP includes the following: (1) morphologic studies show megakaryocyte damage in most ITP patients; (2) there is normal or decreased platelet turnover in the majority of patients; (3) in vitro studies show antibody-induced inhibition of megakaryocyte production and maturation; and (4) an increase in the platelet count occurs in many ITP patients receiving treatment with thrombopoietin mimetics. In summary, activation of the immune system by platelet autoantigens in ITP may result in platelet destruction and/or inhibition of platelet production. The importance of each mechanism in the individual patient probably varies.

Section snippets

Introduction and History

Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disorder in which, for reasons that remain unclear, platelet surface proteins become antigenic and stimulate the immune system to produce autoantibodies and cytotoxic T lymphocytes, which results in immune-induced platelet destruction and suppression of platelet production. There have been several previous reviews on the pathophysiology of ITP.1, 2, 3, 4 The present understanding of this topic is shown schematically in Fig 1.

The

Antigenic Response and Antibody Production

The fundamental abnormality leading to an autoimmune response in ITP is unknown and probably differs among patients. The immune system is carefully regulated since it must protect the body from outside invasion and, at the same time, not respond to self antigens. The response to antigens is modulated by two T-cell populations, CD4+ helper-inducer cells and CD8+ suppressor-cytotoxic cells. Immature T cells (CD4CD8) are produced in the bone marrow and migrate to the thymus. During thymic

Measurement of Autoantibody

Early attempts to measure anti-platelet antibody, using platelet agglutination, complement activation, and platelet lysis assays, were unsuccessful because of their lack of sensitivity and/or reproducibility. In the 1970s, the measurement of platelet-associated IgG showed a very high level of positivity in chronic ITP (∼90%); however, subsequent studies showed that these assays lacked specificity and were therefore not clinically useful. In 1982, Van Leeuwen et al38 reported that antibody

Platelet Destruction

There is no doubt that platelet destruction is an important mechanism in many ITP patients. As noted above, infusion of ITP blood or plasma into recipients with normal platelet counts resulted in thrombocytopenia in about two thirds of these individuals. In addition, the survival of both homologous and autologous radiolabeled platelets is reduced in essentially all ITP patients. In a survey of five large studies,62, 63, 64, 65, 66 117 of 119 patients with chronic ITP had shortened intravascular

Morphologic Studies

As noted earlier, early light microscopic studies of ITP bone marrow showed normal or increased numbers of megakaryocytes with a shift to younger forms that lacked cytoplasmic granularity or platelet formation and manifested nuclear and cytoplasmic degenerative changes.7, 9 Phase contrast studies confirmed these findings and showed that these megakaryocytic abnormalities could be produced in healthy control subjects by the infusion of ITP plasma.8 Early electron microscopic studies showed

Conclusions

The studies that have been reviewed in this article provide convincing evidence that thrombocytopenia in chronic ITP can be due to either immune-induced platelet destruction or suppression of platelet production. It seems likely that the relative importance of these two mechanisms will vary among patients with ITP.

Acknowledgments

The development of this manuscript was supported by an unrestricted educational grant from GlaxoSmithKline. Assistance in the development of this article was provided by Robert Coover and Brett Moskowitz, MA.

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