summary for thalassemia types.

1. Thalassemia
23/02/1441
1

2. hemoglobin
- Adult Hb contains two α-chains and two β-chains.
- Globin and Heme.
23/02/1441
2

3. Hemoglobinopathy vs. thalassemia
 Qualitative deffect in the
structure of Hb resulting in
abnormal one.
 point mutation.
 usually normal Hb.
 Structural variant of
hemoglobin.
 Quanitative disorder of
Hb synthesis that produce
reduced amount of normal
Hb.
 Deletional & nondeletional
mutation.
 Reduced Hb and oxygen
caring capacity.
 Separate disease.
Hemoglobinipathy thalassemia
23/02/1441
3

4. Hemoglobinopathy vs. thalassemia
23/02/1441
4

5. Definition of thalassemia
- Mild genetic defects are asymptomatic.
- Severe genetic defects are symptomatic:
1. low Hb.
2. Increase in abnormal Hb.
3. Ineffective erythropoeisis.
4. Anemia = Hb + ineffective erythropoesis + hemolysis
5. Hepatosplenomegaly.
6. Infections.
7. Gallstones.
8. Bone deformities.
9. Chronic hemolysis.
23/02/1441
5

6. Clinical findings
23/02/1441
6

7. Types of Thalassemia
- Most common: α-thal (gene deletion) and
β- thal (promotor mutaytion, nonsense mutation
and stop mutaion)
- Reduction of δ synthesis doesn’t associated
with anemia (defected HA2 is rare ˜ 2.5%)
- Severe impairment of ζ , Ɛ or ɣ is lethal in utero.
23/02/1441
7

8. Common thalassemias
23/02/1441
8

9. Alpha Thalassemia
23/02/1441
9

10. α-thalassemia overview
CBC:
 slightly decreased or normal RBC’s count.
 decreased MCV,MCH and MCHC.
 increase in Reticulocytes number.
Chemistry:
 increased bibllirubin.
 inccreased haptoglobin.
Blood film:
 microcytic, hypochromic anemia.
 anisocytosis and poikelocytosis.
 basophilic stippling.
 NRBC’s.
 precipitated Hb.
B.M studies:
 not necessary.
 erythroid hyperplasia with basophilic stippling.
 seideroblasts.
 foam cells (severe form) 23/02/1441
10

11. Alpha Thalassemia types
23/02/1441
11

12. 4-genes affected
 Hydrops fetalis.
 Stillborn or die within hours after birth.
 Electrophoresis: 80-90 % Hb bart’s.
10-20 % Hb Portland.
No HbA1 , HbA2 or HbF.
23/02/1441
12

13. 3-genes affected
 HbH disease.
 Symptomatic but not fatal.
 The severity depends on which allele is
affected in parents genotype.
 Electrophoresis: HbBart’s (at birth)
HbH (Adult)
23/02/1441
13

14. 2-genes affected
 α-Thalassemia minor.
 Asymptomatic (only diagnosed by gene analysis)
 Mild anemia (border line)
 Electrophoresis: 5-6 % Hb Bart’s (only after birth)
 Occasional cells exhibit HbH inclusions after
incubation with brilliant cresyl blue.
23/02/1441
14

15. 1-gene affected
 Sielent “carrier”
 Electrophoresis: 1-2 % Hb Bart’s (infant).
23/02/1441
15

16. Hb electrophoresis
23/02/1441
16

17. Affinity to oxygen by different
Hbs
23/02/1441
17

18. 23/02/1441
18

19. β-thalassemia
23/02/1441
19

20. Classification of β-thalassemia
23/02/1441
20

21. β-thalassemis major
23/02/1441
21

22. β-thalassemis major
 Cooley’s anemia.
 Compensation by other Hb.
 Ineffective erythropoesis.
 Erythroid hyperplasia > 0.25
 Free α–chains contain free iron and chemichromes (ROS)
 Majority of hemolysis is st B.M (polychromatophilic
erythroblast)
 Extramedullary hematopoesis.
23/02/1441
22

23. β-thalassemis major in children
- Begins at 6th month of birth.
- Pallor, fuileir to thrive, gaining weight, diarrhae, and
fever.
- Groth retredation:
.characteristic bossing of the skull
.facial deformities
.“hair-onend” appearance of the skull
on x-ray
23/02/1441
23

24. Clinical findings of β-thalassemis
major
CBC:
 Microcytic hypochromic anemia, MCV< 67 fl.
 Hb is 2-3 g/dl.
 Normal /Increased RDW.
 2o Thrombocytopenia and leucopenia.
 Basophilic stippling and poly chromasia.
 Precipitated α-chains (methyl violet stain).
Chemistry:
 Elevated uncojugated billirubin (extravascular hemolysis)
 Dark brown urine.
Bone marrow:
Not necessary, M:E is 1:10 or less.
Molecular technique:
β-to-α chain ratio <0.25
23/02/1441
24

25. Electrophoresis
- From cord blood after birth
HbA is <2% , while
normal infant’s HbA is
20%
- For adults:
90% HbF
No HBA
Normal/abnormal HbA2. 23/02/1441
25

26. β-thalassemia minor
- Sufficient Hb.
 Asymptomatic.
 Moderate microcytic RBC’s.
 Heteroappearance at stress ( pregnancy& infections).
CBC:
 RBC’s > 5X1012/L
 Reteciolocytes: slightly increased.
 Rare NRBC’s.
 Hb: 9-14 g/dl.
 MCV: 55-70 fL
 MCHC normal or slightly decreased: 29-33
 MCH: < 22 pg.
 Anisocytosis & poikelocytosis (basophilic stippling& target cells).23/02/1441
26

27. β-thalassemia minor
Bone marrow:
 Slightly hyperplasia
 Erythroblasts poorly filled with Hb.
Electrophoresis:
 HbA2: 3.5-7 %
 HbF normal in 50% of cases.
23/02/1441
27

28. β-thalassemia intermedia
 Hb: 7-10 g/dl.
 Moderate microcytic, hypochromic anemia.
 Iron overload (in case of blood transfusion).
 Target cells are the predominant poikilocytes observed, Basophilic
stippling and nucleated red blood cells are also present.
Electrophoresis:
 HbA2: 5-10 %
 HbF: 30-75
 Milder forms of β-thalassemia intermedia is missy with minor β-Thal.
23/02/1441
28

29. β-thalassemia minima
- Asymptomatic.
- No CBC abnormalities.
- Discovered serendipitously during family studies.
23/02/1441
29

30. Other Thalassemias and
Thalassemia-Like Conditions
23/02/1441
30

31. Other Thalassemias and
Thalassemia-Like Conditions
δB-Thalassemia:
 Rare thalassemia, β- and δ-chains are affected.
 100% HbF in homozygous (thalassemia intermrdia phenotype and
anemia)
 Hetero form of the disease not anemic and looks like Thal minor.
Ɣδβ-Thalassemia:
 Rare thalassemia, deletion or inactivation of the entire β-gene complex.
 Homozygous form is incompatible with life due to absence of adult Hb.
 Heterozygous form is developed to mild form of β-thalassemia.
Hemoglobin Constant Spring (HbCS):
 Common in Thailand.
 combination of two structurally abnormal α-chains and two normal β-chains.
 Homozygous individual has two normal α-genes, one on each chromosome (α-
Thal minor) 23/02/1441
31

32. Hemoglobin Constant Spring
(HbCS)
 Hb Bart’s at birth
 HbCS makes up 5–7% of Hb.
 HbA2 and HbF are normal
and the reminder is HbA
 HbCS (0.2–1.7%)
 Normal HbA, HbA2 and HbF.
Homozygotes Heterozygotes
* In some areas, the coexistence of HbCS with α-thalassemia trait (- -/aaCS) can be
found:
- The clinical findings are similar to those of HbH disease.
- Hemoglobin electrophoresis characteristically shows;
HbA, HbH, Hb Bart’s, HbA2, and 1.5–2.5% HbCS.
23/02/1441
32

33. Hereditary Persistence of Fetal Hemoglobin
(HPFH)
Incidence:
0.1% of African Americans.
Cause:
absence of δ- and β-chains synthesis or a loss of suppression of the ɣ-globin gene.
Homozygous:
 100% HbF and absence of HbA and HbA2
 Erythrocytosis ranging from 6 * 1012/L to 7 * 1012/L (higher oxygen affinity)
 high hemoglobin levels from 14.8–18.2 g/dL
 Erythrocytes are microcytic and slightlyh ypochromic MCV of 75 fL and a mean MCH of 25.0 pg.
Heterozygous Patients present:
 slightly elevated erythrocyte count.
 with the corresponding elevation of the hematocrit.
 Slightly decreased MCH (27 pg).
 HbF is 10–30% of the total hemoglobin.
 HbA2 is decreased to 1–2% and the remainder is HbA. 23/02/1441
33

34. Hemoglobin Lepore
Cause
aberrant crossover event resulting in recombination of misaligned β- and
δ-genes on separate chromosomes.
Product:
 δ/β-fusion globin chain, two of which combine with two α-chains to form Hb Lepore, stable and
normally function,.
 Chromosome containing the β/δ-anti-Lepore fusion gene still contains intact β-and
δ-genes that are synthesized normally to form HbA and HbA2.
Homozygous form (β-thal major or β-thal intermedia):
 Hb Lepore is inadequately synthesized leading to an excess of α-chains and absence of HbA
and HbA2.
 hemosiderosis and chronic extravascular hemolysis.
 Hb Lepore ranges from 8–30%
Heterozygous (β-thal minor):
Asymptomatic, Hb Lepore concentration of 10%
23/02/1441
34

35. Combination Disorders
 HbS/β0-Type 1 (severe)
 HbS/β+ Type 1(moderate)
 HbS/β+ Type 2 (symptomatic)
 microcytic, hypochromic.
 target cells and the poikilocytes.
β:α ratio closer to 0.5
23/02/1441
35

36. Treatment
Regular blood transfusion:
 HbH disease (long-term thrapy, splenoctomy)
 β-Thal major (prolong life to 2ed or 3ed decade)
Moderate blood transfusion:
β-Thal intermedia (stress).
No need for blood transfusion:
α-Thal Minor, α-Trait, and βThal Minor.
-Regular transfusions minimize the stunting of growth and the
other consequences of chronic severe anemia.
- Iron chelation therapy with deferoxamine avoids iron overload
and the effects of iron toxicity. 23/02/1441
36

37. [Pearson Clinical Laboratory Science Series] Shirlyn B. McKenzie
Ph.D. CLS (NCA), Lynne Williams - Clinical Laboratory Hematology
(3rd Edition)
(2014, Pearson)
23/02/1441
37