The pathophysiology of ITP revisited: ineffective thrombopoiesis and the emerging role of thrombopoietin receptor agonists in the management of chronic immune thrombocytopenic purpura.

Autoimmune thrombocytopenia (ITP) is characterized by autoantibody-mediated platelet destruction that can be demonstrated by shortened radiolabeled platelet survival. An additional role of ineffective thrombopoiesis was suggested by autologous platelet kinetic studies performed in the 1980s. Sera of patients with ITP have been demonstrated to inhibit megakaryocyte growth in culture supporting the concept of suboptimal platelet production as a contributing factor to the thrombocytopenia. The relatively modest rise in thrombopoietin (TPO) levels in thrombocytopenic patients with ITP has helped to identify the TPO receptor as a potential target for the treatment of ITP. Initial studies with recombinant TPO in patients with ITP were encouraging, and novel compounds designed to stimulate the TPO receptor and resultant pathways have been shown in randomized trials to be effective in raising the platelet count and sustaining it at safe levels. Adverse effects of these agents have been relatively mild, although rare serious events including increased bone marrow reticulin deposition, increased numbers of circulating blasts and thrombosis have occurred, and theoretic risks of stimulation of megakaryocytopoiesis and platelet activation remain a concern. As these agents become available it will be important to identify those patients who will most benefit from their use. The place of these drugs in the current management algorithms of ITP will evolve over time as results of clinical trials with these agents and experience with their use in the clinic clarify short-term and long-term efficacy and potential toxicities.