thrombopoietin

**Source and regulation** - Produced mainly by hepatocytes, with smaller amounts from kidney and bone marrow stroma. Synthesis is constitutive. - Circulating TPO level is set by platelet (and megakaryocyte) mass. Platelets and megakaryocytes express c-Mpl, bind TPO and internalize and degrade it. - Low platelet count: less TPO is cleared, so free TPO is high and platelet production rises. - High platelet count: more TPO is cleared, so free TPO is low. - Hepatic TPO production also rises with IL-6 (an acute phase reactant), which explains reactive thrombocytosis in inflammation. - Hepatic Ashwell-Morell receptors clear desialylated senescent platelets. This triggers more hepatic TPO production.

**Mechanism** - TPO binds the c-Mpl receptor (MPL). It signals through JAK2/STAT (also PI3K and MAPK pathways). - Effects: it promotes survival and proliferation of hematopoietic stem cells and of megakaryocyte progenitors (CFU-Meg). It also drives megakaryocyte maturation and endomitosis (polyploidy), which leads to platelet release.

**Clinical correlations** - **Immune thrombocytopenia (ITP):** TPO levels are normal or only mildly increased, because antibody-coated platelets are cleared in the spleen and marrow output is inadequate. TPO receptor agonists are used in refractory ITP: - Romiplostim: a peptide "peptibody" given subcutaneously. - Eltrombopag and avatrombopag: oral small molecules. - Eltrombopag: take it separately from polyvalent cations, and watch for hepatotoxicity. - Risks of TPO receptor agonists: marrow reticulin fibrosis, thrombosis. - **Aplastic anemia:** TPO is very high because there are few megakaryocytes and platelets to clear it. Eltrombopag is used to stimulate multilineage recovery. - **Chronic liver disease or cirrhosis:** Reduced hepatic TPO synthesis and splenic sequestration cause thrombocytopenia. Avatrombopag and lusutrombopag are used before procedures. - **Myeloproliferative neoplasms:** MPL mutations (e.g., W515L/K) occur in essential thrombocythemia and primary myelofibrosis (alongside JAK2 V617F and CALR). The mutations cause constitutive signaling. - **Congenital amegakaryocytic thrombocytopenia:** Loss-of-function MPL mutations cause very high TPO with absent megakaryocytes and progression to marrow failure. - **Gain-of-function THPO or MPL mutations:** cause hereditary thrombocythemia. - **Chemotherapy-induced thrombocytopenia:** TPO receptor agonists are sometimes used. - Recombinant full-length TPO was abandoned. Neutralizing antibodies against endogenous TPO developed (with the pegylated truncated form, PEG-rHuMGDF) and caused thrombocytopenia.

**High-yield contrasts** - Thrombopoietin → platelets. - Erythropoietin (kidney peritubular interstitial cells) → RBCs. - G-CSF/GM-CSF → neutrophils/granulocytes. - IL-11 (oprelvekin) → platelets. Its use is limited by fluid retention and allergic reactions. - Thrombopoietin acts on megakaryocytes; the platelet count is the readout of its effect.