Rodgers G P, Dover G J, Uyesaka N, Noguchi C T, Schechter A N, Nienhuis A W
Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md 20892.
N Engl J Med. 1993 Jan 14;328(2):73-80. doi: 10.1056/NEJM199301143280201.
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.
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.
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.
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.
羟基脲可增加镰状细胞贫血患者胎儿血红蛋白的生成，抑制血红蛋白S的聚合，并可能改善血管阻塞性表现和溶血。重组促红细胞生成素可增加实验动物和人类中含有胎儿血红蛋白的网织红细胞数量。我们研究了羟基脲和促红细胞生成素对镰状细胞病患者胎儿血红蛋白生成是否可能具有增强作用。
我们对4例正在接受羟基脲治疗的镰状细胞病患者（3例为镰状细胞贫血纯合子，1例为镰状β0地中海贫血）给予递增剂量的静脉注射促红细胞生成素，持续7周，同时口服硫酸亚铁。连续4天的羟基脲剂量与连续3天的促红细胞生成素剂量交替使用。
与单独使用羟基脲所获得的最大值相比，含有胎儿血红蛋白的网织红细胞数量增加了28%，胎儿血红蛋白百分比增加了48%。含有胎儿血红蛋白（F细胞）的红细胞百分比从64%增加到78%。与单独使用羟基脲相比，联合使用羟基脲和促红细胞生成素治疗使平均（±标准差）血清间接胆红素水平从0.8±0.2mg/dl（13.3±2.9μmol/L）降至0.5±0.1mg/dl（8.9±2.2μmol/L）（P = 0.02），提示溶血进一步减轻。红细胞滤过性改善。
静脉注射重组促红细胞生成素并补充铁剂，与羟基脲交替使用，比单独使用羟基脲更能提高胎儿血红蛋白和F细胞水平。这种增加减少了血红蛋白S的细胞内聚合，并改善了红细胞的整体流变学特性。与每日或脉冲剂量方案使用羟基脲相比，与促红细胞生成素交替使用较低剂量的羟基脲可能证明骨髓毒性较小。它还可能提高单独使用羟基脲无效的镰状细胞病患者的胎儿血红蛋白水平。
