Four globin chains each with a haem group; HbA is two alpha and two beta
Mnemonic
“Two alpha and two beta”, with the variants defined by which chains are present:
- HbA - alpha2 beta2, about 97 per cent in adults
- HbA2 - alpha2 delta2, about 2 per cent. Raised in beta thalassaemia trait
- HbF - alpha2 gamma2. The fetal form, with a left shifted curve because it binds 2,3-DPG poorly, letting it take oxygen from maternal blood
Alpha chains are on chromosome 16 with four genes; beta chains on chromosome 11 with two.
That gene dosage explains the disease patterns:
- Alpha thalassaemia ranges from silent carrier (one gene) to HbH disease (three) and Hb Barts hydrops fetalis (all four), which is fatal in utero
- Beta thalassaemia presents at about 6 months, as HbF declines and beta chains are needed
Sickle cell disease is a single point mutation, glutamate to valine at position 6 of the beta chain, which is why it also presents at around 6 months and why HbF is protective, and the basis of treating it with hydroxycarbamide to raise HbF.
Expansion
Each haemoglobin molecule has four globin chains, each with a haem group containing ferrous iron, so it binds four oxygen molecules.
| Type | Chains | Proportion in adults |
|---|---|---|
| HbA | alpha2 beta2 | about 97 per cent |
| HbA2 | alpha2 delta2 | about 2 per cent |
| HbF | alpha2 gamma2 | under 1 per cent |
HbF predominates in fetal life and is replaced over the first 6 months. Because it binds 2,3-DPG poorly, its oxygen affinity is higher, which favours placental transfer. This is also why sickle cell disease and beta thalassaemia present only after the switch, and why hydroxycarbamide, which raises HbF, is beneficial in sickle cell disease.
Alpha chains are encoded by four genes and beta chains by two, which is why alpha thalassaemia has a graded severity from silent carrier to haemoglobin Bart hydrops fetalis, while beta thalassaemia presents as trait or major.
HbA2 is raised in beta thalassaemia trait, and is the diagnostic test for it.