Serum Thrombopoietin Level Is Not Regulated by Transcription but by the Total Counts of both Megakaryocytes and Platelets during Thrombocytopenia and Thrombocytosis

Abstract

SummaryThrombopoietin (Tpo) regulates platelet production, but the mechanisms regulating the serum Tpo level and platelet count in circulation have been a subject of debate. Tpo was reported to be expressed mainly in liver and kidney, but we found that Tpo is expressed in all tissues examined: abundantly in liver, kidney, muscle, colon, brain and intestine, and moderately in bone marrow, spleen, lung, stomach, heart, thymus, ovary, and endothelial and leukemic cell lines. The levels of Tpo transcripts in major Tpo producing organs, liver and kidney, and in the platelet production sites bone marrow and spleen, were constant during acute thrombocytopenia induced by anti-platelet monoclonal antibody administration in mice, and during thrombocytosis induced by Tpo injection. Furthermore, we noticed that platelet count is not exactly inversely proportional to serum Tpo level. During acute thrombocytopenia, serum Tpo level transiently increased a few hours after antibody injection, and returned to the basal level just when matured megakaryocytes accumulated in bone marrow and spleen but the platelet count was still low. Matured megakaryocytes in bone marrow and spleen increased when the serum Tpo level decreased, and decreased when platelet count rebounded. Taken together with other observations, we propose here a modified version of Kuter and Rosenberg’s theory, that is, Tpo is constitutively expressed in a variety of organs throughout the body, even in acute thrombocytopenia and thrombocytosis, and that the serum Tpo level is not regulated by Tpo gene expression nor only by platelet counts in circulation, but by the total counts of both megakaryocytes in bone marrow and spleen and of platelets in circulation

Increased plasma thrombopoietin levels in patients with myelodysplastic syndrome: a reliable marker for a benign subset of bone marrow failure

“…22,23 Plasma TPO levels are negatively regulated by platelets and megakaryocytes through their binding of TPO. 24,25 Some studies show an inverse correlation between TPO levels and BM megakaryocyte count, 26,27 but the TPO levels of patients with RAEB were consistently low in our study despite the low megakaryocyte content (data not shown). Low TPO levels in MDS patients with a poor prognosis may be Y. Seiki et al 904 haematologica | 2013; 98(6) Specificity Figure 2.…”

Determinants of platelet count in humans

“…When platelets and megakaryocytes are decreased in number, less thrombopoietin is removed from plasma, and the thrombopoietin level rises, while when platelet numbers increase, more thrombopoietin is cleared from the plasma and the thrombopoietin level falls again. 2 In addition to the thrombopoietin (THPO) and c-Mpl (MPL) genes, a large number of genes encoding membrane glycoproteins, cytoskeletal components and proteins involved in transcription, cell cycle regulation and signaling have been demonstrated to participate in the differentiation of pluripotent stem cells to mature platelet-shedding megakaryocytes. 3 Defined as a platelet count less than 150¥10 9 /L, thrombocytopenia is usually an acquired disorder.…”

Stress-induced cholinergic signaling promotes inflammation-associated thrombopoiesis

“…Thrombocytopenia, a reduction in platelets, stimulates the production of thrombopoietin (TPO) and promotes megakaryocytopoiesis. 7 As platelet counts return to normal, TPO is effectively cleared from the circulation. This involves TPO binding to its receptor, c-mpl, and its uptake into platelets and Mk.…”