The impact of thrombopoietin on clinical practice

Prevention of hemorrhage secondary to thrombocytopenia has generally been managed by the transfusion of platelets. The need for such transfusion is related to the depth and duration of critical thrombocytopenia, a level that until recently was hotly debated. However a number of clinical trials have established that transfusion at a platelet count greater than 10 x 10(9)/L was safe in the absence of factors associated with increased tendency to bleed. Trying to predict which patients are at risk of bleeding due to thrombocytopenia has proven difficult outside of those scenarios that inevitably cause severe thrombocytopenia, such as treatment of leukemia and myeloablative chemotherapy with stem cell support. Models have been proposed but have yet to be validated. Of greater importance is the need for proof that intensive treatment of solid tumours with growth factor support leads to improved outcomes. The discovery of platelet growth factors raised expectations that an effective method for abrogating thrombocytopenia would be soon available in the clinic. The cytokines initially described were pleiotropic in nature, and stimulation of platelet production was generally modest. However, one of these agents, interleukin-11, was successfully shown to reduce the incidence of severe thrombocytopenia in patients receiving dose-intensive chemotherapy, and has now received approval from the FDA for this purpose. Initial clinical trials of thrombopoietin (TPO), the central regulator of megakaryocytopoiesis and thrombopoiesis, and its analogues showed these agents to be the most potent stimulators of thrombopoiesis and to be associated with few adverse effects. They have also been shown to enhance platelet recovery after chemotherapy, but early results from trials investigating their ability to prevent severe thrombocytopenia associated with the treatment of leukemia and bone marrow transplantation have been disappointing. In addition, subcutaneous administration of one of these agents, megakaryocyte growth and development factor, has been shown to induce the formation of antibodies that neutralize native TPO and cause thrombocytopenia. TPO remains a promising therapeutic agent, however its potential application is more limited than initially anticipated, and there are a number of obstacles to overcome before it finds an importance use in the clinic.