thrombopoiesis

**Pathway:** Hematopoietic stem cell → common myeloid progenitor → megakaryocyte-erythroid progenitor (MEP) → megakaryoblast → megakaryocyte → proplatelets → platelets.

**Key regulators:** - **Thrombopoietin (TPO):** Produced constitutively by the liver (also kidney, marrow stroma). It binds the c-Mpl receptor (JAK2/STAT signaling) on megakaryocytes and their progenitors, and on platelets. Regulation is by receptor-mediated clearance: platelets and megakaryocytes bind and remove TPO. Low platelet mass means more free TPO and more production. High platelet mass means less free TPO. Hepatic TPO synthesis also increases with IL-6 (reactive thrombocytosis) and falls in liver disease. - **Other cytokines:** IL-3, IL-6, IL-11 (oprelvekin) and GM-CSF act synergistically.

**Megakaryocyte maturation:** - Endomitosis: DNA replicates without cell division, producing a large polyploid cell (up to 64N) with a multilobed nucleus. - Cytoplasm matures with demarcation membranes and granules. - Megakaryocytes extend proplatelets through the sinusoidal endothelium. Shear forces in the blood release platelets, and each megakaryocyte yields about 1,000-3,000 platelets. - Transcription factors: GATA-1, FOG-1, RUNX1, NF-E2.

**Platelet kinetics:** Lifespan is about 8-10 days. About one-third of platelets are sequestered in the spleen. Normal count is 150,000-450,000/µL. Platelets are anucleate fragments with α-granules (vWF, fibrinogen, PDGF, fibronectin) and dense granules (ADP, Ca²⁺, serotonin).

**Clinical correlations:** - **Thrombocytopenia from decreased production:** - Aplastic anemia, marrow infiltration or myelodysplasia, and chemotherapy or radiation. - Megaloblastic anemia (B12/folate deficiency), which causes ineffective hematopoiesis. - Liver disease/cirrhosis, from reduced TPO plus splenic sequestration. - Congenital disorders: Wiskott-Aldrich (small platelets, eczema, immunodeficiency), May-Hegglin/MYH9-related disorders, and TAR syndrome (thrombocytopenia with absent radii). - **Increased destruction (marrow megakaryocytes increased):** ITP, TTP/HUS, DIC and HIT. Marrow biopsy shows increased megakaryocytes, and large platelets on smear suggest a compensatory response. - **Thrombocytosis:** - Primary: essential thrombocythemia (JAK2, CALR or MPL mutations). - Reactive: infection, inflammation, iron deficiency, malignancy, post-splenectomy. Reactive thrombocytosis is IL-6/TPO-mediated. - **Pharmacology:** - TPO receptor agonists: romiplostim (peptibody, SC), eltrombopag and avatrombopag (oral small molecules), and lusutrombopag. They are used for chronic ITP, aplastic anemia, thrombocytopenia in chronic liver disease before procedures, and chemotherapy-induced thrombocytopenia. Eltrombopag carries a hepatotoxicity risk. - Oprelvekin (IL-11) is used for chemotherapy-induced thrombocytopenia. Its side effects include fluid retention and allergic reactions. - Anagrelide reduces megakaryocyte maturation in essential thrombocythemia. - Hydroxyurea is cytoreductive.

**High-yield pearls:** - TPO is made by the liver, just as EPO is made by the kidney. - Platelet production is regulated by TPO clearance, not by feedback on TPO transcription. - Megakaryocytes are the largest hematopoietic cells in the marrow. - Platelets come from megakaryocyte cytoplasm fragmentation, not cell division.