Since multivariate analyses showed that CRP was also an independent determinant of hepcidin levels in MDS along with GSK1363089 ferritin and MDS subtypes, we could hypothesize the observed hepcidin heterogeneity as the result of the relative strength of opposing stimuli in different clinical and pathological conditions. The main actors in this sense may be represented by the suppressing effect from ineffective erythropoiesis, variably counterbalanced by the stimulating effects from either increased iron stores or cytokines, of whom CRP is a surrogate measure. RARS may represent the prototype of MDS where the inhibition from the erythropoietic drive tends to prevail, only partially balanced by the RBC transfusions, either directly or indirectly through increased iron stores. This condition, characterized by the lowest hepcidin/ferritin ratio, indeed showed also the highest values of biochemical iron parameters indicating both an expansion of the plasma iron pool through increased absorption/recycling and parenchymal iron toxicity, like transferrin saturation and NTBI. Of note, studies from Mariani and colleagues on hepatic hepcidin mRNA in two RARS patients showed low levels consistent with this view. At the other end of the spectrum lies RAEB and CMML, where the highest levels of both hepcidin/ferritin ratio and CRP may mirror hepcidin stimulation through blast-derived cytokines that overcomes controls by iron. Consistently with this hypothesis, both RAEB and CMML lost their significant predictivity on hepcidin level in a multivariate model adjusted with CRP levels. In this condition, the relative excess of hepcidin could favour iron entrapment within macrophages, limiting toxicity due to uncontrolled release of the element into the plasma and redirection to parenchymal cells. As regards to the hepcidin suppression from the erythropietic drive, our results argue against a role of GDF-15 as the putative mediator of this biological effect in MDS, at variance with what observed in thalassemic syndromes. GDF-15, also known as bone morphogenetic protein 14, is a secreted morphogen of the transforming growth factor-beta super-family, conferring signaling by activation of Smad 1/5/8 or mitogen-activated protein kinase. It is highly expressed by erythroid precursors in conditions of ineffective erythropoiesis, but barely detectable in normal bone marrow. In our series, which again is the largest so far evaluating GDF-15 in MDS, mean serum levels of this protein were near six to ten-fold higher than reference values, with a relative homogeneity across different MDS subtypes.