Red blood cell regeneration induced by subcutaneous recombinant erythropoietin: iron-deficient erythropoiesis in iron-replete subjects [see comments]

Abstract

Limited red blood cell (RBC) regeneration often prevents collection of sufficient blood from autologous donors. We studied the effects of subcutaneous recombinant erythropoietin (rEPO) in subjects making frequent blood donations. Six healthy iron-replete male subjects took rEPO (200 U/kg) subcutaneously daily, and donated blood (450 mL) twice a week for 3 weeks. During a control study, these subjects also attempted twice-weekly blood donations without rEPO. Four other males given rEPO, including one with idiopathic hemochromatosis, waited until day 8 to begin blood donations. All healthy subjects took oral ferrous sulfate. Subcutaneous rEPO given with blood donations resulted in a marked reticulocytosis (mean peak value 568 +/- 159 x 10(9)/L v 235 +/- 77 x 10(9)/L, control study; P < .05), and enhanced RBC production at 28 days (1,208 +/- 227 mL v 719 +/- 161 mL, P < .05). rEPO in advance of blood donations was slightly less effective in normal subjects (941 +/- 139 mL, P < .05); however, the subject with hemochromatosis produced substantially more RBCs (1,764 mL) than any normal subject. rEPO-treated normal subjects (but not the rEPO-treated patient with hemochromatosis or untreated controls) produced iron-deficient RBCs with elevated zinc protoporphyrin levels and low hemoglobin content. These cells appeared within 1 week of rEPO administration and before laboratory confirmation of depleted iron stores. Thus, subcutaneous rEPO is an effective stimulant of erythropoiesis in nonanemic blood donors. However, in addition to eventual depletion of iron stores, early functional iron deficiency affects response to the drug.

Erythropoietic activity and iron metabolism in autologous blood donors during recombinant human erythropoietin therapy

“…Administration of rhEPO induced a further reduction of serum ferritin; depletion of iron available for erythropoiesis was, however, most apparent by the sharp increase of FEP levels. Limited bone marrow response to rhEPO resulting from inadequate iron supply has been observed in autologous donors participating in aggressive blood donation programmes [21,22]. The present study demonstrates that even in patients who donate a restricted amount of blood prior to surgery (2 units), reduced availability of iron and depletion of iron stores affects the response to rhEPO.…”

Prevalence of hypochromia (without microcytosis) vs microcytosis (without hypochromia) in iron deficiency

“…The more advantageous sensitivity vs. speci¢city pro¢le of the MCH is consistent with the observation that under-haemoglobinization of normal sized red blood cells is the initial manifestation of iron de¢ciency. This is consistent with the changes seen after administration of erythropoietin in healthy subjects (Brugnara et al 1993). Similarly, in chronic renal failure, hypochromia >10% is the most useful and relevant marker to identify iron de¢ciency (Drueke et al 1997).…”

The role of intravenous iron in anemia management and transfusion avoidance

“…13 This fourfold increase in erythropoietic activity is accompanied by declining reticulocyte counts and the appearance of hypochromic RBCs by the second week of EPO therapy. 28,29 In a study of escalating (fourfold) increases in EPO dose administered to patients undergoing aggressive phlebotomy, the marrow erythropoietic index increased from 2.9 times (with endogenous EPO stimulation) to 3.6 times over basal rates of erythropoiesis, representing only a 58 percent increase in erythropoiesis. 4 The superior erythropoietic response in a patient with hemochromatosis further suggests iron-restricted erythropoiesis related to suboptimal transferrin saturation, in patients treated with EPO.…”