HEMOGLOBIN DISORDERS Hemoglobin Structure Oxygen Dissociation Erythropoiesis Globin Gene Clusters Human β-Globin Gene Locus 1 Hemoglobin Switching Globin Switching-Pyr Complex Globin Gene Hemoglobinopathies & Thalassemias Transcription/Translation • Hemoglobinopathies: Qualitative Change- Mutation in nucleotide sequence of globin gene produces abllbittbnormal globin structure • Thalassemias: Quantitative Change- Decreased or absent production of a globin chain Hemoglobin Disorders and Malaria βThalassemia Defects 2 Globin Synthesis in β Globin Synthesis in β Thalassemia Homozygotes Thalassemia Homozygotes • Anemia results from: β Chain % α Chain % • Decreased β globin and Hemoglobin A • Excess α globin causing aggregates β+ 10 - 30 100 leading to intramedullary red cell death Thalassemia and hemolysis β0 0 100 • γ globin is insufficiently increased to Thalassemia compensate Blood Smear - β Thalassemia α Globin Aggregates - EM Major Blood Smear - β Thalassemia βThalassemia Trait Major 3 Hemoglobin in β Thalassemia Hemoglobin A In β Thal Trait 2 Syndromes State Anemia Hgb A Hgb A2 Hgb F Normal None Normal Normal Normal β+ Thal Severe Decr Variable Sl Inc β0 Thal Severe Absent Variable Sl Inc δβ Thal Mild Absent Absent Mod Inc HPFH None Absent Absent 100% Corfu Mild 10% Absent 90% Management of Thalassemia and Treatment-Related Complications Improvements in Supportive Care Rund D and Rachmilewitz E. N Engl J Med 2005;353:1135-1146 Oral iron chelation- LVEF αThalassemia - Deletions 4 αThalassemia- ATRX Complex Myelodysplasia(ATMDS) Hemoglobinopathies & Thalassemias Examples of Point Mutations • Hemoglobinopathies: Qualitative Change- Mutation in nucleotide seqqggpuence of globin gene produces abnormal globin structure • Thalassemias: Quantitative Change- Decreased or absent production of a globin chain Kinetics of Sickling RBC Sickling- Reversible 5 Desaturation of Normal and Variant Hemoglobins during Passage from Artery to Vein Benz E. N Engl J Med 2004;351:1490-1492 Hemoglobin Electrophoresis Blood Smear - SS Disease Pathophysiological Characteristics of Sickle Cell Anemia and the Effect of Hydroxyurea Blood Smear - SC Disease Platt O. N Engl J Med 2008;358:1362-1369 6 Figure 1. Percent survival Figure 3. Growth curves for children with sickle cell anemia receiving extended hydroxyurea therapy Hankins, J. S. et al. Blood 2005;106:2269-2275 Franco, R. S. et al. Blood 2006;108:1073-1076 Copyright ©2006 American Society of Hematology. Copyright restrictions may apply. Copyright ©2005 American Society of Hematology. Copyright restrictions may apply. Figure 2. Radionuclide liver-spleen scan showing normalization of splenic uptake after extended hydroxyurea therapy No Caption Found Zimmerman, S. A. et al. Blood 2007;110:1043-1047 Hankins, J. S. et al. Blood 2005;106:2269-2275 Copyright ©2005 American Society of Hematology. Copyright restrictions may apply. Copyright ©2007 American Society of Hematology. Copyright restrictions may apply. Figure 2. Kaplan-Meier estimates of the probability of remaining stroke-free among patients Cerebral Artery Damage and Healing in Sickle Cell Anemia receiving transfusion and patients on standard care Platt O. N Engl J Med 2005;353:2743-2745 Lee, M. T. et al. Blood 2006;108:847-852 Copyright ©2006 American Society of Hematology. Copyright restrictions may apply. 7 Figure 1. Kaplan-Meier probabilities of survival, thalassemia-free survival, and cumulative incidences of rejection and nonrejection mortality in 33 thalassemic patients aged younger than 17 years, prepared for transplantation with protocol 26 Antenatal Diagnosis Sodani, P. et al. Blood 2004;104:1201-1203 Copyright ©2004 American Society of Hematology. Copyright restrictions may apply. 8.