2014;14(9):462. and rituximab and the current era. Current therapy appears to have increased effectiveness. However, the definition of refractory, if it includes insufficient response to TPO brokers, explains a group with more severe and difficult-to-treat disease. The biology of refractory ITP is largely unexplored and includes oligoclonality, lymphocyte pumps, and other possibilities. Newer treatments, especially rapamycin, fostamatinib, FcRn, and BTK inhibitors, may be useful components of future therapy given their mechanisms of action; however, TPO agents, notwithstanding failure as monotherapy, appear to be critical components. In summary, refractory ITP is usually a complicated entity in which a precise specific diagnosis is as important as the development of effective combination treatments. Visual Abstract Open in a separate window Introduction Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with thrombocytopenia resulting from increased platelet Gefitinib hydrochloride destruction and inhibition of platelet production.1-4 Most children with ITP have good outcomes with a substantial rate of spontaneous improvement, and those who require intervention or progress to chronic disease usually respond well to treatment. Adults with ITP do not improve as often as children, Gefitinib hydrochloride but they have a higher rate of improvement than generally acknowledged, perhaps as much as 40% over 1 year and 60% over 3 years.5 Most patients can usually be managed with conventional treatment.1,6 However, small groups of patients exist who are very difficult to manage and do not respond to any treatment (ie, have refractory disease). Current treatment of ITP is not strictly regimented.7 First-line therapy usually consists of steroids (high-dose dexamethasone or prednisone) or IV immunoglobulin (IVIG), or even a combination of both for certain patients. Second-line treatment primarily includes thrombopoietin receptor agonists (TPO-RAs) and rituximab, with splenectomy deferred until 1 y from diagnosis. Additional second-line brokers include fostamatinib and immunosuppressive brokers (eg, azathioprine, cyclosporine, mycophenolate mofetil, as well as others). There are no guidelines to specify the order in which second-line agents should be used. The American Society of Hematology guidelines suggest TPO-RAs be used as the first second-line agent in patients with persistent disease. In patients with refractory disease, a number of brokers are likely to have been used, including steroids, IVIG, TPO-RAs, rituximab, and/or others, whereas splenectomy will not necessarily have been performed. Refractory ITP Defining refractory as no response to treatment is usually subjective.8 We will use the definition of response as outlined by Rodeghiero et al, achieving a platelet count of 30?000/L and doubling baseline platelet counts.9 Ideally the treatment would be repeated to enhance validity of the lack of response. Failure to respond to splenectomy is included in the definition of refractory according to Rodeghiero et al, although this is disputed in children. FGF9 Currently, there is increasing reluctance to undergo or recommend splenectomy among patients and physicians,10 such that refractory needs to be defined without reference to splenectomy. Furthermore, there is a reluctance to pursue splenectomy when other treatments have been ineffective, based on the not well-documented but widely believed consensus that splenectomy will likely not be effective in such a circumstance.11 Thus, splenectomy may not be performed in otherwise refractory patients. Therefore, we reserve the description of refractory for patients whose platelet counts do not respond to 2 treatments, there is no single medication to which they Gefitinib hydrochloride respond, and their platelet counts are very low and accompanied by bleeding. These refractory patients have not Gefitinib hydrochloride necessarily undergone splenectomy. Unlike the great majority of patients with ITP, refractory patients do not do well; they respond poorly to a variety of treatments, they develop worsening disease and medication-induced toxicities, they have markedly reduced quality of life, and they have a higher hemorrhagic and infectious morbidity and mortality. The most.