Thrombopoietin: Physiology, Pharmacology, Receptor, Clinical uses, Side effects
The primary site of thrombopoietin production is the liver. Lesser amounts are seen in the kidneys, brain and testes. Thrombopoietin is synthesized and immediately released as and when required like erythropoiesis. Following a fall in the platelet count thrombopoietin levels rises half maximally by 8 hours and peak by 24 hours.
Mpl receptor was discovered as the product of the gene c-mpl, the normal homologue of the oncogene v-mpl. V-mpl is the transforming gene of murine myeloproliferative leukemia virus. The human TPO receptor was cloned in 1992. It is a member of the cytokine receptor superfamily. Using the c-Mpl receptor, the protein that bound to it (c-Mpl ligand was identified, purified sequenced and cloned. c-MPL RNA transcript can be detected in hematopoietic cell lines, peripheral blood, bone marrow and spleen and cells of the megakaryocytic lineage. The TPO receptor does not contain intrinsic tyrosine kinase activity. Ligand binding to c-Mpl is associated with the activation of the tyrosine kinase JAK2 and the tyrosine phosphorylation of a number of molecular targets, including signal transducer and STAT proteins (activators of transcription), Shc adaptor protein and the c-Mpl receptor itself.
Pharmacologic Properties of Thrombopoietin
Of the hematopoietic growth factors thrombopoietin has got the longest half-life i.e. 30hours. PEGylation of thrombopoietin further increases the plasma half-life by 10 fold. Following systemic administration, the platelet count begins to increase after 3-5 days. This is because thrombopoietin acts by stimulating the production and maturation of megakaryocytes. The most common adverse events were disturbances of the gastrointestinal system, and arthralgia. In therapeutic doses MGDF doesn’t have any effect on platelet function.
Potential clinical uses of thrombopoietin
- Chemotherapy of solid tumors: both rhTPO and MDGF are effective in attenuating both the degree and duration of thrombocytopenia.
- Bone marrow transplantation:
- Chemotherapy of acute leukemias: as severe thrombocytopenia is routinely observed after induction therapy of AML, TPO might be beneficial in this setting.
- Radiation therapy
- Aplastic anemia and other bone marrow failure states
- ITP and thrombocytopenia of HIV
- Harvesting peripheral blood progenitor cells
- Platelet apheresis
Potential side effects of thrombopoietin
Clinical studies shows that TPO is well tolerated. Toxicities such as flu-like symptoms, fatigue or major organ toxicites that occur with other cytokines have not been reported.
- Marrow fibrosis possibly due to abnormal increase in megakaryocytes and with release of PDGF.
- Veno-occlusive disease; TPO may alter endothelial function and lead to an increase in VOD in the bone marrow transplant setting.
- Interaction with other growth factors
Clinical Trials of Thrombopoietin
1.Solid tumor chemotherapy
2. Bone marrow transplantation
3. Delayed recovery or engraftment failure