Blood Cell Stimulating Factors in Pediatrics, Part I: Erythropoietin

By Howard A. Pearson, MD, FAAP

The identification, characterization, and ultimately the production of commercial quantities of human hematopoietic cell stimulating factors represent a signal triumph of modern molecular biology. The hematopoietic growth factors are a group of polypeptide substances (cytokines) that stimulate proliferation of specific blood cell lines: erythrocytes, granulocytes, and platelets. Using recombinant DNA technology, the human genes for the hematopoietic growth factors have been identified and cloned. Using viral vectors, they have been inserted into the genomes of cultured yeast or mammalian cells. These so-called transfected cells can be stimulated to produce large amounts of the gene product—in this case, a recombinant human hematopoietic cell growth factor—which, in turn, can be recovered and purified for clinical use. Recombinant growth factors have the same biologic activity as the natural factors. The use of blood cell growth factors has proceeded from the basic science laboratory to the bedside in a remarkably brief time. These growth factors are the erythrocyte stimulating factor, erythropoietin (EPO), the granulocyte stimulating factor (GSF), and most recently the megakaryocyte growth and development factor (MGDF).

This special feature will describe the current use of EPO in pediatric practice. The use of GSF and MGDF will be presented in a subsequent issue of Pediatric & Adolescent Medicine Reports.

Erythropoietin (EPO)

Although the existence of a humoral stimulator of red cell production was long hypothesized, it was not until 1953 that EPO was isolated from the plasma of anemic rabbits.l In adults, EPO is almost exclusively produced by the peritubular cells of the kidney in response to tissue hypoxemia. In the fetus and newborn, the liver is the site of EPO production. The gene for EPO has been identified, isolated, cloned, and transfected into hamster ovary cell tissue cultures. These cultures can be stimulated to produce large amounts of the hormone designated rhuEPO.2 EPO is a polypeptide containing 165 amino acids. This is marketed as Epogen by Amgen, Inc. and Procrit by Ortho Biotech.

The Anemia of End-Stage Renal Disease (ESRD)

Clinical studies were first conducted in adult patients with ESRD in whom destruction of the renal parenchymal sites of EPO production occurred. These patients have low levels of EPO. A number of early studies demonstrated that sustained increases in the hematocrit could be produced by the injection of EPO, and, in 1989, the FDA approved the use of EPO for treatment of anemia in these adult patients. For maximum effectiveness, an adequate source of iron must be present to sustain red cell synthesis; thus, iron medication is often given concomitantly with EPO.3

EPO has also been successfully used in children with the anemia of ESRD, including those on hemo- or peritoneal dialysis. EPO is administered subcutaneously or intravenously in a dose of 50-100 U/kg three times per week. Families can be taught to give the subcutaneous injections. Oral iron supplementation is usually given. In most children, it is possible to avoid the need for blood transfusions and to maintain hemoglobin levels greater than 10.0 g/dL. Significant hypertension may occur in children during EPO therapy. Blood pressure must be monitored and may require the use of anti-hypertensive medication.4

The Anemia of Prematurity

A second use for EPO has been as prophylactic therapy for the exaggerated physiological anemia of low birth weight (LBW) infants. Small premature infants typically develop low hemoglobin levels during the first six weeks of life and often receive red cell transfusions. The anemia is often aggravated by blood that is drawn for repeated laboratory studies. These infants have been shown to have inappropriately low levels of EPO compared to older children with the same degree of anemia. This may be because the liver, which is the major source of EPO production in early life, is relatively insensitive to a hypoxemic stimulus. A number of controlled clinical trials have been conducted to determine whether treatment with EPO can moderate the degree of anemia and reduce the need for blood transfusion during the neonatal period. It should be pointed out that it is difficult to compare the results of different studies because of differences in patient selection and different indications for transfusion.

In a large U.S. study, criteria for entering an EPO study at 7-42 days of age included: (1) gestational age less than 31 weeks, birth weight less than 1250 g; (2) stable respiratory status with or without O2 or assisted ventilation; (3) oral feedings so that oral iron could be given; (4) phlebotomy requirements less than 7.5 mL/week; and (5) hematocrit less than 40%.5 EPO was administered subcutaneously in a dose of 175 U three times per week. Treated infants had slightly higher hematocrits than placebo infants after six weeks of treatment (32.0 ± 3.8% vs 27.3 ± 4.9%). The number of transfusions given was slightly less in the treatment group than in the placebo group (1.1 + 1.5 vs 1.6 + 1.7). The volume of transfused blood was also slightly lower in the EPO group. No toxicity was observed.

From a review of the reported studies, it can be concluded that EPO treatment is safe but has only a modest effect on decreasing the number and amount of red cell transfusions in premature infants during the first 2-3 months of life. It does not prevent severe anemia or the need for transfusions in many infants.

Other Uses of EPO

A number of reports have described the clinical use of EPO in other anemic states. Anemia is a frequent occurrence in HIV/AIDS, which may have several etiologies including the effect of drugs such as AZT. Inappropriately low levels of EPO have been noted in some of these patients with anemia, despite a lack of renal impairment.6 Treatment with EPO may correct the anemia and reduce transfusion requirements.

Low levels of EPO are observed in patients following both autologous and allogenic bone marrow transplantation, and the use of EPO post-transplantation may enhance red cell recovery.

The use of EPO has also been approved for adult patients donating their own blood prior to elective surgery.6

There is no consensus as to the possible value of EPO treatment in conditions where elevated levels of EPO are documented. A few small series in adults suggest a possible benefit of EPO in sickle cell anemia and thalassemia where it may stimulate fetal hemoglobin synthesis.7


l. Erslev A. Humoral regulation of red cell production. Blood 1953;8:349-357.

2. Lin FK, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci 1985;82:7580-7584.

3. Eschbach JW, et al. Recombinant human erythropoietin in anemic patients with end stage renal disease: Results of a phase III multicenter clinical study. Ann Intern Med 1989;111:992-1000.

4. Rigden SPA, et al. Recombinant human erythropoietin therapy in children. Pediatr Nephrol 1990;4:618-625.

5. Shannon K. Recombinant human erythropoietin in neonatal anemia. Clinics Perinatol 1995;22:627-640.

6. Goodnough LT, et al. Erythropoietin therapy. N Engl J Med 1997;336:933-938.

7. Olivieri NF, et al. Administration of recombinant human erythropoietin: Three patients with thalassemia intermedia. Blood 1992;80:3258-3260.