Chapter 099. Disorders of Hemoglobin (Part 14) Deferasirox is a promising oral iron-chelating agent. Single daily doses of 20 or 30 mg deferasirox produced reductions in liver iron concentration comparable to desferoxamine in chronically transfused adult and pediatric patients. Deferasirox produces some elevations in liver enzymes and slight but persistent increases in serum creatinine, without apparent clinical consequence. Other toxicities are similar to those of desferoxamine. Its toxicity profile is acceptable, although long-term effects are still being evaluated. Bone Marrow Transplantation, Gene Therapy, and Manipulation of HbF Bone marrow transplantation provides stem cells able to express normal hemoglobin; it has been used in a large number of patients with β-thalassemia and a smaller number of patients with sickle cell anemia. Early in the course of disease, before end-organ damage occurs, transplantation is curative in 80–90% of patients. In highly experienced centers, the treatment-related mortality is <10%. Since survival into adult life is possible with conventional therapy, the decision to transplant is best made in consultation with specialized centers. Gene therapy of thalassemia and sickle cell disease has proved to be an elusive goal. Uptake of gene vectors into the nondividing hematopoietic stem cells has been inefficient. Lentiviral-type vectors that can transduce nondividing cells may solve this problem. Reestablishing high levels of fetal hemoglobin synthesis should ameliorate the symptoms of β-thalassemia. Cytotoxic agents such as hydroxyurea and cytarabine promote high levels of HbF synthesis, probably by stimulating proliferation of the primitive HbF-producing progenitor cell population (i.e., F cell progenitors). Unfortunately, no regimen has yet been identified that ameliorates the clinical manifestations of β-thalassemia. Butyrates stimulate HbF production, but only transiently. Pulsed or intermittent administration has been found to sustain HbF induction in the majority of patients with sickle cell disease. It is unclear whether butyrates will have similar activity in patients with β-thalassemia. Aplastic and Hypoplastic Crisis in Patients with Hemoglobinopathies Patients with hemolytic anemias sometimes exhibit an alarming decline in hematocrit during and immediately after acute illnesses. Bone marrow suppression occurs in almost everyone during acute inflammatory illnesses. In patients with short RBC life spans, suppression can affect RBC counts more dramatically. These hypoplastic crises are usually transient and self-correcting before intervention is required. Aplastic crisis refers to a profound cessation of erythroid activity in patients with chronic hemolytic anemias. It is associated with a rapidly falling hematocrit. Episodes are usually self-limited. Aplastic crises are caused by infection with a particular strain of parvovirus, B19A. Children infected with this virus usually develop permanent immunity. Aplastic crises do not often recur and are rarely seen in adults. Management requires close monitoring of the hematocrit and reticulocyte count. If anemia becomes symptomatic, transfusion support is indicated. Most crises resolve spontaneously within 1–2 weeks. Further Readings Ataga KI, Orringa EP: Hypercoagulability in sickle cell disease: A curious paradox. Am J Med 115:721, 2003 [PMID: 14693325] DeSimone J et al: Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood 99:3905, 2002 [PMID: 12010787] Neufeld EJ: Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: New data, new questions. Blood 107:3436, 2006 [PMID: 16627763] Quek L, Thein SL: Molecular therapies in beta- thalassaemia. Br J Haematol 136:353, 2007 [PMID: 17129232] Steinberg MH: Pathophysiologically based drug treatment of sickle cell disease. Trends Pharmacol Sci 27:204, 2006 [PMID: 16530854] Switzer JA et al: Pathophysiology and treatment of stroke in sickle- cell disease: Present and future. Lancet Neurol 5:501, 2006 [PMID: 16713922] Ware RE et al: Predictors of fetal hemoglobin response in children with sickle cell anemia receiving hydroxyurea therapy. Blood 99:10, 2002 [PMID: 11756146] Bibliography Benz EJ: Hemoglobin variants associated with hemolytic anemia, altered oxygen affinity, and methemoglobinemias, in Hematology: Basic Principles and Practice , 3d ed, R Hoffman et al (eds). New York, Churchill Livingstone, 2000, pp 554–561 Clasta S, Vichin sky EP: Managing sickle cell disease. BMJ 327:1151, 2003 Embury SH, Vichinsky EP: Sickle cell disease, in Hematology: Basic Principles and Practice , 3d ed, R Hoffman et al (eds). New York, Churchill Livingstone, 2000, pp 510–554 Forget BG: Thalassemia syndromes, in Hematology: Basic Principles and Practice , 3d ed, R Hoffman et al (eds). New York, Churchill Livingstone, 2000, pp 485–510 Steinberg MH, Benz EJ Jr: Pathobiology of the human erythrocyte and its hemoglobins, in Hematology: Basic Principles and Practice , 3d ed, R Hoffman et al (eds). New York, Churchill Livingstone, 2000, pp 356–367 . Chapter 099. Disorders of Hemoglobin (Part 14) Deferasirox is a promising oral iron-chelating agent. Single daily doses of 20 or 30 mg deferasirox produced. to express normal hemoglobin; it has been used in a large number of patients with β-thalassemia and a smaller number of patients with sickle cell anemia. Early in the course of disease, before. Reestablishing high levels of fetal hemoglobin synthesis should ameliorate the symptoms of β-thalassemia. Cytotoxic agents such as hydroxyurea and cytarabine promote high levels of HbF synthesis, probably