This document summarizes microcytic anemia caused by thalassemia trait. It discusses the differences between alpha-thalassemia trait and beta-thalassemia trait. Alpha-thalassemia trait is caused by decreased alpha-globin production and results in persistent microcytosis, elevated hemoglobin Bart at birth and hemoglobin H at adulthood. Beta-thalassemia trait occurs after 3 months of age and is caused by beta-globin gene mutations, presenting as microcytosis and elevated hemoglobin A2. The document provides biomarkers and genetic testing details to distinguish between the two conditions. It also presents a case example of an Emirati family with alpha-thalassem

1. Microcytic Anemia II
Microcytosis (↓MCV) = Impaired (↓) Hemoglobin Synthesis
Abdul-Kader Souid9/26/2018
(1) Iron deficiency anemia; (2) Thalassemia trait; (3) Inflammation; (4) Sideroblastic anemia
Target cells in
thalassemia
trait
The quaternary structure of hemoglobin
consists of 2α (red) & 2β (blue) subunits,
each has iron-containing heme (green)
that binds O2.
Five important points
Synthesis of the a globin peaks prenatally. The b globin peaks at 3 mo
of age. Thus, a-thalassemia manifests at birth (cord blood MCV <94
fL) and b-thalassemia manifests after 3 mo of age.
Target cells have ↑cell
membrane (↑cell
surface)

2. 2
    b
3’5’
    b
3’5’
Chromosomes 11
(two alleles)
 a2 a1
3’5’
Chromosomes 16
(two alleles)  a2 a1
3’5’
Normal Hemoglobin Variants
The four globins (a, b, , ) form three normal hemoglobin variants:
A (>93%) = 2a + 2b
A2 (<3.5%) = 2a + 2 (↑ in b-thalassemia trait)
F (<3.5%) = 2a + 2 (↑ in b-thalassemia trait)
Must know (5 points)
Tetramers of “” or “b“ are abnormal variants and indicate a-thalassemia.
Hemoglobin Barts = 4 (newborn)
Hemoglobin H = 4b (≥1 y of age)

3. a-Thalassemia Trait
 a2 a1
3’5’
Chromosomes 16
(two alleles)  a2 a1
3’5’
When there is production of the α
gene on a chromosome 16 (only
one of the two α genes on a
chromosome is deleted; trans
deletion; (-,a/-,a), the designation
for that chromosome is α+
thalassemia (α+).
When both α genes on a single
chromosome 16 are deleted (cis
deletion; (-,-/a,a) ), the
designation α° (null allele) is used
for that chromosome.
Must know (2 points)
α° thalassemia (α°) is prevalent in China, Thailand, Malaysia, and Philippines (Asian & Mediterranean).
α+ thalassemia (α+) is benign and common in the UAE, occurring in >20% of the population

4. b-Thalassemia Trait
    b
3’5’
    b
3’5’
Chromosomes 11
(two alleles)
One b-globin gene mutation (heterozygous bo or b+; only one abnormal
allele) → b-thalassemia trait → mild anemia, ↓MCV, ↑RBC count + normal RDW
+ ↑A2 (2a, 2) >3.5%.
Two b-globin gene mutations (homozygous bo or b+; two abnormal alleles)
→ b-thalassemia major → severe anemia (transfusion dependent after 3 mo of age).
Must know (2 point)

5. Thalassemia Trait: Summary
• The term “thalassemia” refers to the inherited disorders characterized by
decreased (“trait”) or absent (“major”) a or b globin.
• a-thalassemia trait (a deletion allele) refers to ↓ a-globin (usually gene
deletion).
– Biomarkers for a-thalassemia trait include: (1) Persistent microcytosis (MCV at birth <94 fL
and MCV at adulthood <80 fL), (2) Hemoglobin Bart (4) at birth (2.5% to 5%) and H (4b) at
adulthood, (3) Normal A2 (2a2), (4) Two a gene deletions.
• b-thalassemia trait (bo or b+ allele) refers to ↓ b-globin (usually gene mutation).
– OMIM#613985
– Biomarkers for b-thalassemia trait include: (1) Microcytosis after 3 mo of age, (2) ↑
hemoglobin A2 (2a2), (3) HBB (hemoglobin beta) gene mutation.
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6. This Emirati family has a-thalassemia trait
• Father: Hemoglobin 127 g/L, MCV 68 fL, A = 95%,
F = 2.0%, A2 = 3.0% (a-thalassemia trait).
• Mother: Hemoglobin 115 g/L, MCV 72 fL, A = 95%,
F = 3.0%, A2 = 2.0% (a-thalassemia trait).
• Daughter (22 mo): Hemoglobin 115 g/L, MCV 61 fL,
A = 96%, F = 2.0%, A2 = 2.0% (a-thalassemia trait).
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trans deletion (-,a/-,a) α+ thalassemia (α+)
Frequency (f) of the silent allele (-,a) in UAE is about 50% (= 0.5).
Frequency (f2) of a-thalassemia (-,a/-,a) in UAE is 25% (0.5 x 0.5 = 0.25).
Must know

7. A 27-year-old woman presents with mild microcytosis, ↑A2, and normal serum ferritin
Alpha-Thalassemia PCR
Beta-Thalassemia PCR
https://www.omim.org/
IVS1-5 (G→C) mutation is the most common β-thalassemia mutation.
https://www.ncbi.nlm.nih.gov/clinvar/variation/15447/
NMD, nonsense-mediated mRNA decay; HBB gene (OMIM#141900), hemoglobin beta locus;
IVS-1 5, InterVening Sequence (intron).

8. Required Reading
• Harteveld CL, Higgs DR. Alpha-thalassaemia. Orphanet J Rare Dis. 2010;5:13.
doi:10.1186/1750-1172-5-13.
• Danckwardt S, Neu-Yilik G, Thermann R, Frede U, Hentze MW, Kulozik AE.
Abnormally spliced beta-globin mRNAs: a single point mutation generates transcripts
sensitive and insensitive to nonsense-mediated mRNA decay. Blood. 2002;99:1811-6.
PubMed PMID: 11861299.
• Kukreti R, Dash D, E VK, Chakravarty S, Das SK, De M, Talukder G. Spectrum of
beta-thalassemia mutations and their association with allelic sequence polymorphisms
at the beta-globin gene cluster in an Eastern Indian population. Am J Hematol.
2002;70:269-77. PubMed PMID: 12210807.
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