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