T h a l a s s e m i a
General
Normal hemoglobin composition
1. Before 6 months of age:
• most of the circulating hemoglobin is fetal hemoglobin (HgbF),
which has two alpha chains and two gamma chains.
2. At age 6-9 months of age, hemoglobin composition starts switching to
adult pattern:
• 96% HgbA (two alpha chains, two beta chains)
• 3% HgbA2 (two alpha chains, two delta chains)
• 1% HgbF (two alpha chains, two gamma chains)
Main problem in thalassemia
Alpha thalassemia = decreased amount of alpha chain.
Beta thalassemia = decreased amount of beta chain.
Gene distribution
There are four alpha-chain genes (two on each chromosome 16), and two
beta-chain genes (one on each chromosome 11).
Disease severity
Depends on how much alpha or beta chain is produced!
1. In beta thalassemia, the defect is in transcription, translation, or
processing of mRNA.
• Beta thalassemia minor (asymptomatic; mild or no anemia):
beta chain production is only slightly decreased.
• Beta thalassemia intermedia (needs occasional transfusions):
beta chain production is moderately decreased.
• Beta thalassemia major (severe disease; regular transfusions):
beta chain production is absent or severely decreased.
2. In alpha thalassemia, the "defect" is really gene absence.
• one gene absent: silent (no disease)
• two genes absent: alpha thalassemia trait (asymptomatic)
• three genes absent: HbH disease (severe; requires transfusions)
• four genes absent: Hydrops fetalis (fatal in utero)
Pathogenesis
Alpha thalassemia
1. Problem is deletion of gene(s).
2. Anemia results from:
• insufficient alpha chains (leading to insufficient Hgb A)
• excess unpaired beta, delta, and gamma chains (leading to
premature destruction of the red cell)
• Newborns have higher % of HbF, so they make
gamma chain tetramers (Hb Barts).
• Adults have mostly HbA, so they make
beta chain tetramers (HbH).
Beta thalassemia
1. Problem is in transcription, translation, or processing of mRNA.
2. Anemia results from:
• insufficient beta chains (leading to insufficient Hgb A)
• excess unpaired alpha chains (leading to premature red cell destruction)
Morphology
Alpha thalassemia
• Silent carrier state and alpha thalassemia trait: no anemia.
• HbH disease: moderately severe anemia. Supravital staining reveals HbH
inclusions.
Beta thalassemia
1. Beta thalassemia minor
• Mild anemia.
• Abnormal-looking smear: hypochromasia, microcytosis,
basophilic stippling, and target cells.
However, in beta thalassemia minor, the MCV is very decreased
compared to the relatively mild decrease in Hgb; also, the RBC is
increased!
2. Beta thalassemia intermedia and beta thalassemia major
• Severe anemia (Hgb=3-6).
• Very abnormal-looking smear: marked anisocytosis and poikilocytosis
(small, very hypochromatic cells, target cells, and fragmented red blood
cells), nucleated red blood cells.
Clinical findings
Alpha thalassemia
• More common in Asians, blacks.
• Silent carrier state and alpha thalassemia trait: no symptoms.
• HbH disease: moderately severe anemia.
• Hydrops fetalis: fatal in utero.
Beta thalassemia
• More common in Mediterraneans, blacks, Southeast Asians.
• Beta thalassemia minor: patients almost always asymptomatic, with mild or
no anemia.
• Beta thalassemia major:
• Anemia very severe, starting at 6-9 months of age.
• Without therapy, children suffer growth retardation and die at a young age
from profound anemia.
• Therapy is repeated transfusions (with iron chelation to avoid iron overload).
Unless bone marrow transplant is performed, many patients die in
their 20s.
