Treatment algorithm for steroid dependent/unresponsive patients. In those patients accepting splenectomy as the second-line therapy, a course of rituximab is recommended before surgery (making sure vaccinations are completed before the rituximab). Most patients who do not accept splenectomy will respond to TPO-RAs, and such treatment should not be regarded as indefinite. Those in whom the platelet count does not respond to a TPO-RA or to whom such agents are not available can be treated with another medical therapy (another TPO-RA [alt TPO-RA], if available, or rituximab or fostamatinib). If one agent in this group fails, it is reasonable to try a different one. Treatment with immunosuppressive/immunomodulatory agents (we favor danazol, dapsone, azathioprine, or mycophenolate mofetil) can be considered. In those in whom 2 or more second-line therapies fail, reassess the diagnosis and the need for therapy. Such patients may be considered for a clinical trial or splenectomy. Splenectomy is best avoided for 1 to 2 years after diagnosis, if possible, but may be preferred by some patients in whom second-line or subsequent therapies fail. Boxes outlined in dashed lines denote alternative steps in treatment algorithm. Although clinical trials are suggested for the more refractory patients in this algorithm, they are also appropriate for patients earlier in their disease course.