Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease.
BACKGROUND
Hydroxyurea increases the production of fetal hemoglobin in patients with sickle cell anemia, inhibiting the polymerization of hemoglobin S and potentially improving vaso-occlusive manifestations and hemolysis. Recombinant erythropoietin increases the number of reticulocytes containing fetal hemoglobin in laboratory animals and in humans. We studied whether hydroxyurea and erythropoietin might have a potentiating effect on the production of fetal hemoglobin in patients with sickle cell disease.


METHODS
We treated four patients who were receiving hydroxyurea for sickle cell disease (three who were homozygous for sickle cell anemia and one with sickle beta zero-thalassemia) with escalating doses of intravenous erythropoietin for seven weeks, along with oral iron sulfate. Doses of hydroxyurea on four consecutive days were alternated with doses of erythropoietin on three consecutive days.


RESULTS
There was a 28 percent increase in the number of reticulocytes containing fetal hemoglobin and a 48 percent increase in the percentage of fetal hemoglobin, as compared with the maximal values obtained with hydroxyurea alone. The percentage of erythrocytes containing fetal hemoglobin (F cells) increased from 64 to 78 percent. As compared with hydroxyurea alone, treatment with hydroxyurea and erythropoietin decreased the mean (+/- SD) serum indirect bilirubin level from 0.8 +/- 0.2 to 0.5 +/- 0.1 mg per deciliter (13.3 +/- 2.9 to 8.9 +/- 2.2 mumol per liter) (P = 0.02), suggesting a further decrease in hemolysis. Red-cell filterability improved.


CONCLUSIONS
Intravenous recombinant erythropoietin with iron supplementation alternating with hydroxyurea elevates fetal-hemoglobin and F-cell levels more than hydroxyurea alone. Such increases decrease intracellular polymerization of hemoglobin S and improve the overall rheologic characteristics of erythrocytes. A reduced dosage of hydroxyurea alternating with erythropoietin may prove less myelotoxic than hydroxyurea given daily or in pulsed-dose regimens. It may also increase levels of fetal hemoglobin in patients with sickle cell disease who have not been helped by hydroxyurea alone.
Rodgers
G P
GP
Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md 20892.
Dover
G J
GJ
Uyesaka
N
N
Noguchi
C T
CT
Schechter
A N
AN
Nienhuis
A W
AW
D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000188:drug therapy; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004906:Erythrocyte Count; D004909:Erythrocyte Indices; D004921:Erythropoietin / Q000627:therapeutic use*; D005296:Ferrous Compounds / Q000627:therapeutic use; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D008297:Male; D011994:Recombinant Proteins / Q000627:therapeutic use; D012156:Reticulocytes; D017086:beta-Thalassemia / Q000097:blood* / Q000188:drug therapy
D005296:Ferrous Compounds; D011994:Recombinant Proteins; D004921:Erythropoietin; C020748:ferrous sulfate; D005319:Fetal Hemoglobin; D006918:Hydroxyurea