Primary immune system thrombocytopenic purpura (ITP) remains a diagnosis of exclusion

Primary immune system thrombocytopenic purpura (ITP) remains a diagnosis of exclusion both from nonimmune causes of thrombocytopenia and immune thrombocytopenia that develops in the context of other disorders (secondary immune thrombocytopenia). develop autoantibodies, generally IgG, that bind to platelets, which leads to their phagocytosis via Fc receptors expressed on tissue macrophages located predominantly in the spleen and liver.1,19-22 What provokes autoantibody production is unknown, but most ITP patients have antibodies against integrin IIb3 (glycoprotein IIa/IIIb), glycoprotein Ib/IX, or multiple platelet proteins by the time clinical disease, characterized by thrombocytopenia and mucocutaneous bleeding, is obvious.23 Platelet destruction within macrophages or dendritic cells degrades platelet antigens to peptides. Peptides are expressed around BIBW2992 the cell surface in the context of MHCII and costimulatory help for presentation to T cells, amplifying the initial immune response and possibly generating cryptic epitopes from other platelet glycoproteins, which spreads the immune response to involve multiple platelet antigens.24 ITP is characterized by reducing T-regulatory cells (reviewed in Stasi et al25) and Thy-2 cytokines,26 leading to a Thy1/Thy0 profile (reviewed in Ho-Yen et al27) and up regulation of costimulatory molecules28,29 that facilitates proliferation of antigen-derived CD4-positive T cells and T-cell B-cell cooperation to generate isotype-switched, high affinity antibodies.30 There is emerging evidence that cytotoxic T cells are increased in the bone marrow31 and may contribute to platelet destruction32,33 or impaired production (see below). The importance of platelet destruction in the periphery is usually affirmed by the fact that two-thirds of patients develop and maintain remission after splenectomy, which curtails phagocytosis, but may also reduce antibody production over time. Likewise, most first- and second-line medical therapies for ITP are believed to MMP10 work by impeding platelet destruction.2,3 Decreased platelet production For many years, it was assumed that platelet production increased dramatically in patients with ITP as a compensatory response to thrombocytopenia mediated by peripheral destruction. However, it has become apparent, based on studies of BIBW2992 in vivo kinetics, that platelet production varies from mildly increased to mildly BIBW2992 impaired in most sufferers with ITP. 34-36 Synthesis of TPO in the liver is not controlled at BIBW2992 the level of transcription.37 Plasma TPO levels in individuals with ITP are normal to minimally increased38 as a result of increased clearance of the hormone and binding to an expanded megakaryocyte mass.39 ITP antibodies, and possibly T cells,24 inhibit megakaryocyte development in vitro 35,36,40 and may cause apoptosis and intramedullary destruction of platelets in vivo,41 contributing to failure of splenectomy and other treatments that act by inhibiting clearance. These findings also provide additional rationale for the effectiveness of TPO-receptor agonists. Mechanisms of immune thrombocytopenia in secondary ITP Autoimmune disorders Systemic lupus erythematosus (SLE) Antinuclear antibodies are common in individuals with ITP, but few develop SLE. However, 20%-25% of individuals with SLE develop moderate-severe thrombocytopenia, which can be readily handled if immune mediated or can be a marker of severe systemic disease.42 The pathogenesis of thrombocytopenia is multifactorial and includes: (1) antiplatelet glycoprotein antibodies as found in ITP; (2) immune complexes of diverse composition; (3) antiphospholipid antibodies (APLA) (observe below); (4) vasculitis; 5) thrombotic microangiopathy; (6) hemophagocytosis; (7) autoantibodies to the c-Mpl receptor43 and megakaryocyte, and (8) bone marrow stromal alterations44 not characteristic of ITP.45 Therefore, a thorough clinical and laboratory assessment is often required before a diagnosis of secondary immune thrombocytopenia should be amused..