Hemoglobinopathies Diagnosis and management Morgan L. McLemore, M.D. Hematology/Leukemia Department of Hematology and Oncology Winship Cancer Institute at Emory University mlmclem@emory.edu Disclosures Nothing relevant to report 1
Diffusion insufficient for multicellular organisms O2 relatively insoluble in water O2 needs to bound then released 2
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Hemoglobin Properties Soluble As Long as 2 normal and 2 normal like chains Charged residues are external in contact with water are relatively insoluble and function poorly Unpaired chains insoluble Increases O2 in blood 70X Cooperative Oxygen Binding Allosteric Molecule 5
Hgb F Hgb A 6
Adult Hemoglobin Hemoglobin A >95% Hemoglobin F <1.5% Hemoglobin A2 <3.5% Disorders of Hemoglobin Hemoglobinopathies Structural abnormalities Thalassemias Decreased production of Globin chains Porphyrias Defects in Heme synthesis 7
Hemoglobinopathies ~500,000 born each year with a clinically significant problem ~7% carry a gene for Red Blood Cell defect Hgb Defect and or red cell membrane or enzyme defect Elisabeth Kohne Dtsch Arztebl Int 2011; 108(31 32: 532 540 8
Hemoglobin Electrophoresis Alkalai 9
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Haemoglobin Reference Laboratories Titus HJ Huisman Hemoglobinopathy Laboratory at Georgia Regents University, Augusta, GA Boston University Hemoglobin Diagnostic Reference Laboratory Boston, MA Reference laboratory at Children s Hospital of Oakland Research Institute, Oakland, CA When to suspect a Hemoglobinopathy Microcytic anemia in the absence of iron deficiency Non immune hemolytic anemia After membrane, enzyme defects ruled out Spherocytosis, eliptocytosis, G6PD and Pyruvate Kinase Deficiency Heinz body positive Unstable Hemoglobin Polycythemia without obvious etiology and elevated Epo level Cyanosis and methhemoglobinemia 11
When to suspect a Hemoglobinopathy Adult Versus Pediatrics In the Adult world we are more often dealing with more subtle disorders Reaching a diagnosis is not always critical Some may become evident during pregnancy Exposure to Drugs may cause oxidative hemolysis Hemoblobinopathies Structural 100s of mutations described Majority of little clinical significance High affinity and low affinity hemoglobin's Methemoglobins Fe+3 not Fe+2 Unstable Decreased solubility and/or susceptible to oxidative stress 12
Hemoglobin S 8 10% African Americans heterozygotes 30+% in areas of western Africa Valine >Glutamic Acid codon 6 b Chain Deoxygenated form polymerizes leading to red cell rigidity and hemolysis Heterozygotes have no Phenotype Severe Hypoxia climbing Mount Everest Hemoglobin S Valine >Glutamic Acid codon 6 b Chain Deoxygenated form polymerizes leading to red cell rigidity and hemolysis Heterozygotes have no Phenotype Severe Hypoxia climbing Mount Everest Heat exposure in de conditioned individuals 13
Hemoglobin C Hemoglobin E Hemoglobin C Lysine > Glutamic Acid Codon 6 Beta Chain frequency 2 3% AA High in central west Africa Homozygotes have mild hemolytic anemia Hemoglobin E Glutamic Acid > Lysine Codon 26 beta chain High frequency in SE Asia Homozygotes have mild microcytic anemia Significance is when combine with other Defects Hgb SC, Hgb SE, Hgb E Thalassemia Misdiagnosed with iron deficiency Elisabeth Kohne Dtsch Arztebl Int 2011; 108(31 32: 532 540 14
Thalassemias Thalassemia rarely a problem due to gene duplication Thalassemia due to multiple mutations Promoter Mutations, Frame Shift, Splicing etc Normal production + decreased production from allele 0 no production from allele 15
Disorder Genoty pe MCV Anemia Hgb Electrophoresis Alpha Thalassemia Silent Carrier Nl None Normal Very Trait Low Mild Normal Common or In African Americans Hgb H Disease Low Moderate 5 30% Hgb H Major Low Fatal (fetal Hydrops) Beta Thalassemia Trait Low Mild Hgb A2 increased Hgb F increased in 50% Intermedia Others Low Moderate Hgb A2 increased Hgb F increased in 50% Major Low Severe Hgb A Absent Thalassemia Major Hematology Principles and Practice 2 nd Edition Hoffman Editor 16
Thalassemia Major Chronic Transfusion Protocol 2 4 units every 3 4 weeks Pre Transfusion goal of hgb 9 10 Suppress bone destruction and extramedullary hematopoiesis If well Chelated Life expectancy into the 60s Annual quantification of hepatic and cardiac iron by MRI Normal Iron Intake ~60 90mg/month 3 units/ month is ~600mg Body has no mechanism to excrete iron 2 oral and one parenteral chelator available Frequent side effects Often need two agents at once 17
30 Year Old Female 4 weeks pregnant instructed to take iron Italian descent Baseline Hgb 10.8 MCV 62 Hgb ELP A 93.7 A2 5.3 (1.5 3.7) F 1 Retic mildly elevated, Haptoglobin low/low normal 0 /beta thal minor Hgb dropped to 8 during pregnancy Supported with transfusions 18
27 Year Old Female Diagnosis of beta thal Indian descent Baseline Hgb 8.5 MCV 77, ferritn 452 Has required occasional transfusions in the past Hgb ELP A 88.5 A2 4.3 (1.5 3.7) F 7.2 + / + beta thal intermedia 19
beta thal intermedia Clinical diagnosis + or other combinations Hgb 8 10, transfusions when stressed May develop iron overload even in the absence of transfusions May require chelation in later life May develop extramedullary hematopoiesis Splenectomy may improve Hgb significantly, but associated with marked increase rate of venous thromboembolic disease Many respond to hydrea Current patient 8.5 to 9.8 on 1 gm of hydrea HgbE/beta thal Variable but similar to beta thal intermedia SE Asia Hgb E 25 80%, F 6 50%, A 5 50% Hgb 8 10, transfusions when stressed May develop iron overload even in the absence of transfusions May require chelation in later life May develop extramedullary hematopoiesis Splenectomy may improve Hgb significantly, but associated with marked increase rate of venous thromboembolic disease Many respond to hydrea 20
32 year old with microcytic anemia Hgb 12.1, MCV 72.8 Hgb ELP normal Colonoscopy and bone marrow biopsy normal African American Hgb ELP A 98.2%, A2 1.5% (1.5 3.7%) Low normal A2 and ethinicity suggestive of found in 20 30% of African americans Not an issue for family planning as trans deletion 18 year old student Originally from Middle East States he has Beta thal minor Neonatal jaundice, received transfusion as infant Hgb 9.5, MCV 64, Total Bili 1.8, Retic 240K/uL Haptoglobin Normal?!?! HgbELP A 98%, A2 1.4% (1.5 3.7%) Abnormal hgb noted on HPLC 21
Hemoglobin H Disease / a Middle east and SE Asia One operational alpha gene Variable clinical course Non Deletional mutations more likely to become transfusion dependent over time (more comon in SE Asia) May develop similar complications as beta thal intermdia (iron, VTE post splenectomy etc.), gall stones Prone to oxidative stress Risk of hydrops in offspring Does not respond to hydrea Elisabeth Kohne Dtsch Arztebl Int 2011; 108(31 32: 532 540 22
Conclusion Diagnosis of a Hemoglobinopathy requires some degree of suspicion and close work with a dedicated laboratory. Some disorders can present in adult hood and require close followup Beta thal intermedia, Hgb H, E/beta thal Elisabeth Kohne Dtsch Arztebl Int 2011; 108(31 32: 532 540 23