STEPTRACKERHEMATOLOGY | PATHOLOGY + GENETICS | HIGH-YIELD REVIEW

Thalassemias

Too few globin chains: α-thalassemia from gene deletions, β-thalassemia from point mutations — the unpaired chains do the damage.

FOCUS ON
Count the α genes deleted (1–4) and the β alleles affected. Know the electrophoresis: ↑ HbA2 in β-thal minor; HbH (β₄) and Hb Barts (γ₄) in α-thal. β-thal major appears at ~6 months, when HbF gives way, and causes marrow expansion and iron overload.
TYPE
GENOTYPE
HB PATTERN
CLINICAL
α — silent carrier
chromosome 16
1 of 4 α genes deleted (−α/αα)
Normal
No anemia
α-thal trait
2 deleted — cis (−−/αα, Asian) or trans (−α/−α, African)
Normal adult electrophoresis
Mild microcytic anemia; cis carriers can have Hb Barts offspring
HbH disease
3 deleted (−−/−α)
HbH = β₄ tetramers → inclusions
Moderate–severe hemolytic anemia, splenomegaly
Hb Barts
All 4 deleted (−−/−−)
γ₄ tetramers — very high O₂ affinity
Hydrops fetalis; death in utero
β-thal minor
chromosome 11
One abnormal β allele (β/β⁺ or β/β⁰)
↓ HbA, ↑ HbA2 (> 3.5%), slightly ↑ HbF
Mild microcytic anemia, target cells; usually asymptomatic
β-thal intermedia
Two mild alleles (β⁺/β⁺)
Reduced HbA
Moderate anemia; occasional transfusion
β-thal major
Cooley anemia
Two severe alleles (β⁰/β⁰)
No HbA; HbF mostly; ↑ HbA2
Severe anemia at ~6 months; transfusion-dependent
Complications of β-major
Marrow expansion and extramedullary hematopoiesis; transfusional iron overload.
"Crew-cut" skull x-ray, chipmunk facies, hepatosplenomegaly
Secondary hemochromatosis → heart failure, diabetes · chelate (deferoxamine, deferasirox) · parvovirus B19 aplastic crisis · stem cell transplant cures

Mechanism — why unpaired chains hurt

Globin chain ↓Deletion or mutation
→
Less HbMicrocytosis
→
Excess other chainPrecipitates
→
Ineffective erythropoiesis+ hemolysis
→
Marrow expandsBone deformity, EMH

Free α chains (in β-thal) are far more toxic than free β chains, which can form HbH. That makes β-thal major the more destructive marrow disease.

Electrophoresis guide

CONDITION
HbA
HbA2
HbF
Normal adult
~97%
~2.5%
< 1%
β-thal minor
↓
↑ (> 3.5%)
Normal/↑
β-thal major
Absent
↑
↑↑ (dominant)
α-thal trait
Normal
Normal
Normal
HbH disease
Present
↓
+ HbH band

How it's tested

COMMON CONFUSIONα-thal trait has a normal adult electrophoresis. The diagnosis comes from microcytosis with normal iron studies, ethnicity, and genetic testing.
THE TRAPA β-thal major infant is well at birth and becomes ill around 6 months. HbF (α₂γ₂) needs no β chains, so it protects until the switch to HbA.
YOUR APPROACHMicrocytosis + normal ferritin + target cells → thalassemia. Then decide α vs β from ethnicity and HbA2, and count the genes.

If you see… think…

Microcytic anemia, normal ferritin, ↑ HbA2 → β-thal minor
High RBC count, MCV 64, Mentzer < 13 → thalassemia trait
Southeast Asian couple, both cis α-trait → risk of Hb Barts hydrops
Mediterranean child, severe anemia at 6 months, crew-cut skull → β-thal major
Transfused β-major teen with heart failure and diabetes → iron overload — chelate
Thal major with sudden Hb fall and no reticulocytes → parvovirus B19
β₄ inclusions on supravital stain → HbH disease (3 deletions)
Hydrops fetalis with γ₄ tetramers → Hb Barts (4 deletions)
Target cells + microcytosis + normal iron → thalassemia