To better understand if RDW variation can be an important marker during progression of hematological disease, in the present study we evaluated the correlation between RDW and Hb values, obtained from sequential hemograms over 10 years of follow-up, from 3 FA patients with different clinical progressions, not subjected to transfusions or bone marrow transplant. In general, whenever RDW was among normal ranges Hb was also among normal values. RDW increment was systematically correlated with Hb decrease. A graphic model for controlling adverse outcome is proposed, based on the position of sequential RDW and Hb values relatively to reference normal lines (red line for +2SD RDW values and blue line for -2SD Hb values) (Fig.
3). While RDW and Hb values are inside the two reference lines the hematological situation is stable. Whenever RDW and Hb values are outside the two reference lines, the clinical situation worsens. In fact, the adult patient P33, who is now clinically stable, presents RDW and Hb values inside the two reference lines, although during the 10 years follow-up the patient showed some anemia events accompanied by proportional increases in RDW values (values outside the two reference lines). Patient P11 is also stable at present, with RDW and Hb values inside the two reference lines, but after a sudden recovery from a severe situation of BMF, where RDW and Hb values were clearly outside the two reference lines. In fact, at 8 years she presented an unexplained progressive worsening of hematological disease, prolonged for about four years, after which, and in the absence of any treatment, a spontaneous recovery occurred. Sequential evaluation of chromosome instability revealed a reduction in the number of DEB-induced breaks, although not sufficient to be classified as a somatic mosaicism [
41], which could explain this new clinical situation (Porto B, personal communication). Patient P9, with a severe condition of BMF since childhood, presented during 10 years follow-up RDW and Hb values always outside the two reference lines, with a progressive detachment between the two values. When the patient started OXM treatment, Hb immediately increased up to normal values. However, Hb increase was not accompanied by RDW decrease. We hypothesize that erythropoiesis, for some reason, continues to be stressed. Androgens are widely used for FA treatment, but their mode of action is not completely understood. In a recent study [
42] aged
Fancd2
−/
− mice were used to assess the therapeutic efficacy of OXM. Chronic OXM treatment significantly improved hematological parameters, decreasing macrocytosis and pancytopenia, and stimulated the proliferation of hematopoietic stem and progenitor cells. However, competitive repopulation assays demonstrated that this therapy eventually results in stem cell exhaustion, which may have direct clinical implications for the treatment of BMF. In agreement with these results, we hypothesize that, in the case of patient P9, the fact that Hb demand is not accompanied by RDW decrease may probably lead to a risk of HSCs exhaustion in the long term.
Our study has two main limitations: the RDW value, per se, is not a diagnostic marker, because some patients, with a mild hematological disease, can still have normal RDW values. Therefore, its main importance is related to the progression of hematological disease, as shown by the present results. Additionally, as the follow-up data only relates to three patients, the hypothesis regarding the use of RDW to predict severity of disease and adverse outcomes must be evaluated in a future work, with a higher number of patients included.