Hemoglobinopathies Diagnosis and management Morgan L. McLemore, M.D. - - PDF document

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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

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Diffusion insufficient for multicellular

• rganisms

O2 relatively insoluble in water O2 needs to “bound” then “released”

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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

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       

Hgb F Hgb A

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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

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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

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Hemoglobin Electrophoresis Alkalai

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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

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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

• xidative stress

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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

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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

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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

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Disorder Genoty pe MCV Anemia Hgb Electrophoresis Alpha Thalassemia Silent Carrier  Nl None Normal Trait  

• r

 Low Mild Normal Hgb H Disease   Low Moderate 5‐30% Hgb H Major (fetal Hydrops)    Low Fatal 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 Very Common In African Americans

 Thalassemia Major

Hematology Principles and Practice 2nd Edition Hoffman Editor

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 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

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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

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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

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beta thal intermedia

• Clinical diagnosis
• + or other combinations
• Hgb 8‐10, transfusions when stressed
• May develop iron overload even in the absence
• f 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

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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

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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

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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