High levels of thrombopoietin in sera of patients with essential thrombocythemia: Cause or consequence of abnormal platelet production?

Abstract

Thrombopoietin (TPO) is the most important regulator of megakaryocyte development and platelet production. Platelet production is thought to be regulated by a negative regulatory feed back loop. In an attempt to evaluate the role of TPO in the pathobiology of essential thrombocythemia (ET), we have examined levels of TPO and other cytokines with thrombopoietic activity (interleukin-6 and interleukin-11) in sera obtained from 25 patients with ET (ten treated, 15 untreated) and 117 healthy control subjects. TPO serum levels were assessed using a sandwich-antibody ELISA that utilizes a polyclonal rabbit antiserum for both capture and signal. The mean serum TPO level in 25 ET patients was significantly elevated (545+/-853 pg/ml) as compared with that in healthy controls (95.3+/-54.0 pg/ml,p<0.001). The difference in TPO serum levels between ten treated (781+/-1229 pg/ ml) and 15 untreated ET patients (388+/-458 pg/ml) did not reach statistical significance (p = 0.09). We conclude that either consumption or production of TPO is altered in ET. Failure of appropriate feedback regulation and continued megakaryocyte stimulation by an elevated TPO may play an important role in the pathobiology of ET.

The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling

“…Serum TPO levels are lower than expected in patients with Immune Thrombocytopenia (IT), 39–41 and high in patients with ET. 41–43 Serum TPO levels are normal in Nfe2 −/− mice despite thrombocytopenia, 44 and mice deficient for Bak and Bax have normal to slightly increased serum TPO levels despite significantly increased platelet counts. 32 Circulating TPO concentrations are therefore likely to be regulated in a complex manner, a notion further supported by data showing that Mpl expression on megakaryocytes and platelets is not required for thrombopoiesis but is essential to prevent myeloproliferation.…”

Platelet clearance by the hepatic Ashwell-Morrell receptor: mechanisms and biological significance

“…In contrast to the “autoregulation” model of blood TPO levels described above, serum TPO levels are lower than expected in patients with Immune Thrombocytopenia (ITP) [36, 37], and high in patients with Essential Thrombocythemia (ET) [38, 39]. In patients with thrombocytopenia little of the hepatocyte produced TPO is presumed to be removed by platelets and TPO blood levels rise.…”

Regulating billions of blood platelets: glycans and beyond

“…In contrast to the "autoregulation" model of blood TPO levels, serum TPO levels are lower than expected in patients with immune thrombocytopenia (ITP) 36,37 and high in patients with essential thrombocythemia. 38,39 In patients with thrombocytopenia, little of the hepatocyte-produced TPO is presumed to be removed by platelets and TPO blood levels rise. In contrast, thrombocytosis should be accompanied by low steady state levels of blood TPO, because platelet-mediated TPO destruction surpasses its production.…”