The ITP syndrome: pathogenic and clinical diversity

Abstract

Immune thrombocytopenia (ITP) is mediated by platelet autoantibodies that accelerate platelet destruction and inhibit their production. Most cases are considered idiopathic, whereas others are secondary to coexisting conditions. Insights from secondary forms suggest that the proclivity to develop platelet-reactive antibodies arises through diverse mechanisms. Variability in natural history and response to therapy suggests that primary ITP is also heterogeneous. Certain cases may be secondary to persistent, sometimes inapparent, infections, accompanied by coexisting antibodies that influence outcome. Alternatively, underlying immune deficiencies may emerge. In addition, environmental and genetic factors may impact platelet turnover, propensity to bleed, and response to ITP-directed therapy. We review the pathophysiology of several common secondary forms of ITP. We suggest that primary ITP is also best thought of as an autoimmune syndrome. Better understanding of pathogenesis and tolerance checkpoint defects leading to autoantibody formation may facilitate patient-specific approaches to diagnosis and management.

Figure 1

Estimated fraction of the various forms of secondary ITP based on clinical experience of the authors. The incidence of HP ranges from approximately 1% in the United States to 60% in Italy and Japan. The incidence of HIV and hepatitis C approximates 20% in some populations. Miscellaneous causes of immune thrombocytopenia, for example, posttransfusion purpura, myelodysplasia, drugs that lead to the production of autoantibodies, and other conditions, are not discussed further in this review. ALPS indicates autoimmune lymphoproliferative syndrome; posttx, post–bone marrow or solid organ transplantation; SLE, systemic lupus erythematosus; APS, antiphospholipid syndrome; CLL, chronic lymphocytic leukemia; CVID, common variable immune deficiency. In the absence of a systematic analysis of the incidence of secondary ITP, the data shown represent our combined assessment based on experience and reading of the literature. Professional illustration by Paulette Dennis.

Figure 2

B-cell tolerance checkpoints and loss of self-tolerance in different forms of secondary ITP. Tolerance pathways are denoted by green dashed lines. Solid blue lines represent normal B-cell developmental stages. Where failures in central and peripheral B-cell tolerance might occur in secondary forms of ITP are shown by the solid pink lines. Central B-lymphocyte tolerance checkpoints operate during primary cell maturation in the bone marrow and include clonal deletion and receptor editing. Cross-linking of membrane-bound antibodies on immature B cells leads to apoptosis. Antigen receptor specificity is also revised by receptor editing, that is, the continuation or reinitiation of antibody gene rearrangement, usually at light chain loci, in lymphocytes that already have functional antibody. Receptor editing can change a self-reactive light chain (shown in pink) to a non–self-reactive light chain (shown in purple). Peripheral tolerance checkpoints monitor and alter the repertoire in lymphocytes that have exited from primary lymphoid organs. Even if central tolerance is perfect, there is a need to regulate peripheral tolerance because somatic mutation can randomly generate autoreactive specificities. Somatic mutations are shown as pink circles on the heavy and light chain V-regions. Heavy chain isotype switching (which usually accompanies somatic mutation during an immune response) is shown by the change in color of the heavy chain constant region from green to blue. Anergy and death of lymphocytes after an immune response also contribute to peripheral tolerance. Immune stimulation with a pathogen that mimics self-antigen (molecular mimicry) can also lead to a loss of peripheral tolerance and feed into the antiself ITP pathway. Peripheral AS cells in ITP can arise either primarily, through a defect in central or early tolerance checkpoints, or secondarily as a result of immune stimulation. Autoreactive peripheral B lymphocytes in ITP can include memory cells and plasma cells. Because of space constraints, only the activated cell arising from an immune response for the ITP pathway (not the plasmablast, memory cell or plasma cell) is shown. AS indicates antiself (autoreactive); NS, nonself-reactive; Ag, antigen. Professional illustration by Paulette Dennis.

Figure 3

Relationship between tolerance defect(s) and clinical outcome in secondary ITP. The abscissa indicates whether platelets are the sole hematopoietic lineage affected (right) or whether there is often concurrent hemolytic anemia and immune neutropenia (left). The ordinate indicates responsiveness to treatment of the inciting infection or underlying disease. The proposed corresponding tolerance checkpoint defects are given in shaded boxes at the base of the figure. All of the disease abbreviations are defined in the text. Professional illustration by Paulette Dennis.

Figure 4

Evolution of antiplatelet antibodies after HP infection. Platelets may be activated by binding of first-generation HP antibodies (1) to platelet FcγIIA or through an interaction between HP-bound von Willebrand factor (VWF) and platelet glycoprotein IB (gpIB). Activation may promote platelet clearance and antigen presentation, which augments production of antibacterial antibodies. Somatic mutation may lead to the development of second-generation antibodies (2) that recognize either bacterially derived factors that bind to platelets (3) or that cross-react with platelet antigens. (4) Improved mucosal permeability or bacterial eradication with proton pump inhibitors and antibiotics may initiate the clinical response in patients with anti-HP antibodies (early response), which may be followed by a decrease in bacterial antigen and reduction in the titer of cross-reacting antibody (late durable response). In patients with protracted disease unresponsive to antibiotic eradication, antibodies to HP may have undergone additional somatic mutations (third-generation antibodies), (5) that lose their reactivity with the inciting antigen but retain platelet reactivity, (6) leading to early relapse or no response. APC indicates antigen-presenting cell. Antibodies (light chains, heavy chains, isotype switching, and somatic mutations) are drawn as in Figure 2. Modified and reprinted with permission. Professional illustration by Paulette Dennis and Kenneth Probst.