Sickle cell disease is an important genetic cause of hemo-lytic anemia, a form of anemia due to increased erythrocyte destruction, instead of the reduced mature erythrocyte pro-duction seen with iron, folic acid, and vitamin B12 deficiency. Patients with sickle cell disease are homozygous for the aberrant β-hemoglobin S (HbS) allele (substitution of valine for glutamic acid at amino acid 6 of β-globin) or heterozygous for HbS and a second mutated β-hemoglobin gene such as hemoglobin C (HbC) or β-thalassemia. Sickle cell disease has an increased preva-lence in individuals of African descent because the heterozygous trait confers resistance to malaria. In the majority of patients with sickle cell disease, anemia is not the major problem; the anemia is generally well com-pensated even though such individuals have a chronically low hematocrit (20–30%), a low serum hemoglobin level (7–10 g/dL), and an elevated reticulocyte count. Instead, the primary problem is that deoxygenated HbS chains form polymeric structures that dramatically change erythrocyte shape, reduce deformability, and elicit membrane permeability changes that further promote hemoglobin polymerization. Abnormal erythrocytes aggregate in the microvasculature—where oxygen tension is low and hemoglobin is deoxygenated—and cause veno-occlusive dam-age. In the musculoskeletal system, this results in characteristic, extremely severe bone and joint pain. In the cerebral vascular system, it causes ischemic stroke. Damage to the spleen increases the risk of infection, particularly by encapsulated bacteria such as Streptococcus pneumoniae. In the pulmonary system, there is an increased risk of infection and, in adults, an increase in embolism and pulmonary hypertension. Supportive treatment includes analgesics, antibiotics, pneumococcal vaccination, and blood transfusions. In addition, the cancer chemotherapeutic drug hydroxyurea (hydroxycarbamide) reduces veno-occlusive events. It is approved in the United States for treatment of adults with recurrent sickle cell crises and approved in Europe in adults and children with recurrent vaso-occlusive events. As an anticancer drug used in the treatment of chronic and acute myelogenous leukemia, hydroxyurea inhibits ribonucleotide reductase and thereby depletes deoxynucleoside triphosphate and arrests cells in the S phase of the cell cycle (see Chapter 54). In the treatment of sickle cell disease, hydroxyurea acts through poorly defined pathways to increase the production of fetal hemoglobin γ (HbF), which interferes with the polymerization of HbS. Clinical trials have shown that hydroxyurea decreases pain-ful crises in adults and children with severe sickle cell disease. Its adverse effects include hematopoietic depression, gastrointesti-nal effects, and teratogenicity in pregnant women.
TfR RBC production F HCP1 Fe2+ DMT1 Fe Blood Intestinal epithelial cells Tf F F Hgb 4 Spleen, other tissues macrophage TfR Senescent RBC HgbHgb 1 Gut lumen 2 Bone marrow erythrocyte precursor Heme 3 Hepatocyte Erythroferrone DB FP FP Hepcidin Hepcidin FP – – – –