1. Mark D. Browning, M.D. March 10, 2016
Hemoglobinopathies
Mark D. Browning, M.D.
March 10, 2016

2. Hemoglobin

3. Normal Hemoglobin 2 alpha chains 2 beta chains
141 amino acids
2 beta chains
146 amino acids
These 4 polypeptide chains form a helical structure
Hydrophobic pockets…holding four heme groups
Central cavity…between…2 beta globin chains houses 2-3 DPG

6. Hemoglobin Electrophoresis

7. *Hemoglobinopathies > 400 Hemoglobin variants defined
> ½ are clinically silent
Heterozygotes present with mild effect
Homozygotes present with moderate to severe effect
Hemolytic anemia
High oxygen affinity…erythrocytosis
Low oxygen affinity…cyanosis

8. Hemoglobinopathies Thalassemias Sickle Cell Disease & Hgbs C, D, & E
Quantitative defect in globin synthesis involving gene mutation or defect
Sickle Cell Disease & Hgbs C, D, & E
Qualitative (structural) defect in amino acid substitution in the globin chain

9. *Hemoglobinopathies Most Common
Hgb S, C, D & E
Present in their homozygote form, results in severe disease…SS, CC, DD, EE
Present in their heterozygous form, results in mild disease…AS, AC, AD, AE
Hemoglobin electrophoresis
Confirms diagnosis (Figure 7-2)
Confederate States of America (CFSA)…all but A2 hemoglobin on cellulose acetate at alkaline pH

10. Hemoglobin EE

11. Hemoglobin CC

12. Hemoglobin E

13. *Microcytic Hypochromic Anemia

14. *Hypochromic Mirocytic RBCs Differential: Iron Def. vs. Thal.

15. *Thalassemia Abnormal production of globin chain proteins
Gene mutations associated with quantitative failure in chain production
Diagnosis is based on changes in intracellular levels of major hemoglobin types (normal-below)
Hgb A = 97.5% = alpha (2) + beta (2)
Hgb A2 = 2% = alpha (2) + delta (2)
Hgb F = 1%= alpha (2) + gamma (2)

16. ***Thalassemia Alpha Thal
4 alpha genes
Missing 1 to 4 genes
Missing one alpha…silent carrier…normal phenotype…no anemia & normal MCV
**Missing 2 alphas
*Mild anemia & decreased MCV
*Alpha+/alpha-//alpha+alpha- African/American
*Alpha-/alpha-//alpha+alpha+ Asian
Inheritance of more severe form of alpha thal…Hgb H or Hydrops fetalis
Eg…Holy Land Patient

17. Holy Land Patient *Diagnosis Alpha Thal Minor Missing 2 alphas
Hgb 11.5
MCV 70
RBC 5.85 million
Hgb A=97
*Hgb A2=2% …normal
Hgb F =1%
*Diagnosis by exclusion

18. **Thalassemia Minor vs. Iron Deficient Anemia (Last 5)

19. *Thalassemia Alpha Thal (Hemoglobin H)
Missing 3 alpha genes
Hemoglobin H disease
Patient has 5-30% Hgb H (4 betas) on electrophoresis
Mild to moderate anemia (Hgb 7 to 10)f
Reticulocytosis, microcytosis, hypochromia & targeting….hemolysis….splenomegaly

20. Alpha Thalassemia ** ** ** ##

21. Thalassemia Alpha Thal…Hydrops Fetalis ##
Missing 4 alpha genes ##
More common in Asians
Stillborn
Less common in Blacks

22. **Thalassemia Beta Thal Minor
Gene deletion(Beta 0) or mutation(Beta +)
Heterozygous form
**Increase in Hgb A2 to 4-7%
Slight increase in Hgb F
Confusion with iron deficiency
Can lower A2 to normal
Iron studies to exclude iron deficiency

23. **Globin Chain Development A2 Increased in Beta Thal minor
Decreased in Beta Thal
Minor
Increased in
Beta Thal
Minor

24. Thalassemia—Differential Dx Alpha, Beta or Iron Deficiency
Anemia, decreased MCV (75) in all 3
Thalassemia
RDW is not increased because uniform red cells
Targets present because hemoglobin does not match the membrane synthesis
Beta Thalassemia…increased Hgb A2 **
Iron deficiency
Anisocytosis, poikilocytosis, pencil cells & increased RDW (red cell distribution width)