Thrombopoietin (TPO) is the primary regulator of platelet production. Where is TPO predominantly synthesized, and how does the circulating platelet mass regulate TPO levels?

• A TPO is synthesized by liver hepatocytes and kidney tubular cells at a constant rate; circulating platelets and megakaryocytes express Mpl (TPO receptor) which binds and clears TPO, so when platelet count is low, less TPO is cleared and free TPO rises to stimulate megakaryopoiesis ✓
• B TPO synthesis is upregulated by IL-6 in the bone marrow stroma whenever platelet count falls below normal
• C Platelets themselves synthesize and store TPO, releasing it upon activation to stimulate megakaryocyte differentiation
• D TPO is constitutively released from megakaryocytes and acts in an autocrine manner without peripheral platelet feedback

Explanation

TPO is constitutively synthesized at a constant rate by hepatocytes (primarily) and renal tubular cells. It is not transcriptionally regulated by platelet count; instead, its free plasma level is determined by its removal. Platelets and megakaryocytes express the high-affinity Mpl receptor, which internalizes and degrades TPO. When the total megakaryocyte/platelet mass is high (thrombocytosis), more TPO is removed → lower free TPO. When platelet count falls (thrombocytopenia), less TPO is removed → more free TPO stimulates megakaryopoiesis. This elegant clearance-based feedback is exploited by thrombopoietin receptor agonists (romiplostim, eltrombopag) in ITP.

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

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