Folic acid deficiency can be caused by drugs. Methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. Long-term therapy with phenytoin also can cause folate deficiency, but it only rarely causes megaloblastic anemia.
Parenteral administration of folic acid is rarely necessary, since oral folic acid is well absorbed even in patients with malabsorption syndromes. A dose of 1 mg folic acid orally daily is sufficient to reverse megaloblastic anemia, restore normal serum folate levels, and replenish body stores of folates in almost all patients. Therapy should be continued until the underlying cause of the deficiency is removed or corrected. Therapy may be required indefinitely for patients with malabsorption or dietary inadequacy. Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients, including pregnant women, patients with alcohol dependence, hemolytic anemia, liver disease, or certain skin diseases, and patients on renal dialysis.
The hematopoietic growth factors are glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow. The first growth factors to be identified were called colony-stimulating factors because they could stimulate the growth of colonies of various bone marrow progenitor cells in vitro. Many of these growth factors have been purified and cloned, and their effects on hematopoiesis have been extensively studied. Quantities of these growth factors sufficient for clinical use are produced by recombinant DNA technology.
Of the known hematopoietic growth factors, erythropoietin (epoetin alfa and epoetin beta), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 11 (IL-11), and thrombopoietin receptor agonists (romiplostim and eltrombopag) are currently in clinical use.
The hematopoietic growth factors and drugs that mimic their action have complex effects on the function of a wide variety of cell types, including nonhematologic cells. Their usefulness in other areas of medicine, particularly as potential anti-cancer and anti-inflammatory drugs, is being investigated.
Erythropoietin, a 34to 39-kDa glycoprotein, was the first human hematopoietic growth factor to be isolated. It was originally purified from the urine of patients with severe anemia. Recombinant human erythropoietin (rHuEPO, epoetin alfa) is produced in a mammalian cell expression system. After intravenous administration, erythropoietin has a serum half-life of 4–13 hours in patients with chronic renal failure. It is not cleared by dialysis. It is measured in international units (IU). Darbepoetin alfa is a modified form of erythropoietin that is more heavily glycosylated as a result of changes in amino acids. Darbepoetin alfa has a twofold to threefold longer half-life than epoetin alfa. Methoxy polyethylene glycol–epoetin beta is an isoform of erythropoietin covalently attached to a long polyethylene glycol polymer. This long-lived recombinant product is administered as a single intravenous or subcutaneous dose at 2-week or monthly intervals, whereas epoetin alfa is generally administered three times a week and darbepoetin is administered weekly.