The thrombopoietin (TPO)-thrombopoietin receptor (MPL/c-Mpl) signaling pathway regulates megakaryopoiesis and platelet production. A unique feature of TPO regulation is:

• A TPO production increases when platelet count falls via acute phase response proteins from liver triggered by IL-6 from platelets
• B Plasma TPO levels are regulated by platelet mass; platelets and megakaryocytes bind and internalize TPO via MPL receptors, so high platelet counts lower free plasma TPO (absorptive regulation) ✓
• C TPO is stored in megakaryocyte alpha granules and released upon platelet activation, providing autocrine stimulation of bone marrow progenitors
• D TPO receptor (MPL) is upregulated by thrombin, creating a positive feedback loop to increase platelet production after consumption coagulopathy

Explanation

Thrombopoietin (TPO) is constitutively produced by the liver at a constant rate. Its plasma concentration is not regulated by transcription but by consumption: TPO binds to MPL receptors on circulating platelets and megakaryocytes and is internalized and degraded. When platelet count is high (large total surface area of MPL receptors), more TPO is cleared, lowering free plasma TPO and reducing megakaryopoiesis. When platelet count is low (fewer MPL receptors in circulation), less TPO is cleared, free plasma levels rise, stimulating megakaryocyte proliferation and differentiation. This 'absorptive regulation' model explains how thrombocytopenia is self-correcting. Romiplostim and eltrombopag are MPL agonists used in ITP.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.