Simultaneous measurement of serum thrombopoietin and expression of megakaryocyte c-Mpl with clinical and laboratory correlates for myelofibrosis with myeloid metaplasia

Objectives: We sought to investigate potential mechanisms of increased serum thrombopoietin (TPO) concentrations in myelofibrosis with myeloid metaplasia (NIMM) by simultaneously measuring serum TPO, platelet and megakaryocyte (MK) numbers, and MK c-Mpl expression. Methods: We studied 17 consecutive patients who had MMM and were not receiving therapy at the time of evaluation. Serum TPO was measured by a two-site immunochemiluminometric assay. Immunohistochemical staining of c-Mpl was accomplished with an immunoperoxidase method on simultaneously obtained bone marrow specimens. Results: Our findings confirmed the presence of inappropriately increased serum TPO despite mostly normal or increased peripheral platelet counts and markedly increased bone marrow MK numbers. In addition, we found an inverse correlation between platelet count and serum TPO (P<0.03) and splenic size (P<0.04). However, serum TPO did not correlate with either bone marrow MK number or c-Mpl expression. The lack of correlation of serum TPO and bone marrow megakaryocyte number may be accounted for by the unavoidable inaccuracies in quantifying megakaryocytopoiesis in a disorder of known altered hematopoietic progenitor cell distribution, both intramedullary and extramedullary. The significant inverse correlation between serum TPO and spleen size suggests that this site of extramedullary megakaryocytopoiesis may assume a role in the dysfunctional TPO regulatory axis. Conclusions: These observations suggest some preservation of the negative feedback regulation that appears to be dysfunctional at the MK c-Mpl level. Consistent with previous observations in animal models, our observations suggest the possibility that altered TPO regulation resulting in sustained ligand excess may have pathogenetic relevance in MMM.