Normal newborn has 90%+ HbF (alpha-gamma chains), dropping with age. In childhood, normal HbF is <2%. HbA2 (alpha-delta instead of alpha-beta) is normally <3.5%, and HbA:HbA2 ratio should be at least 40:1.

Alpha thalassaemia

4 genes for alpha chains. Deletions are extremely common in the Mediterranean, Africa, SE Asia but actually Africans tend to carry the deletional α+ allele not the “–” defect that predisposes to disease.

  • If only 1 abnormal, then no detectable clinical problem but carrier. If baby born to other parent with Zero deletion, then risk of HbH disease but not hydrops.
  • If 2 abnormal, then there is usually mild microcytic anaemia, easily confused with iron deficiency. Risk of hydrops in child.
  • If 3 abnormal, then abnormal tetramers form viz Hb Barts (4 deltas) and HbH (4 betas) (“HbH disease”). There is mild to moderate anaemia, Heinz bodies (accumulations of excess beta chains) and splenomegaly. Most people do not need any treatment, however.
  • If all 4 abnormal, then survival is not possible. The baby is born with hydrops, as the unstable Hb forms do not deliver oxygen appropriately, and death occurs in utero or soon after birth.

Electrophoresis will show high quantities of Hb Barts in thal disease. In the trait form, there are often normal levels of HbA and HbA2 so need to do gene deletions.

Beta thalassaemia

Seen in the Mediterranean, Africa, SE Asia. Just 2 genes, so a heterozygote is a carrier, may have mild microcytic anaemia. In the Mediterranean form, the gene is usually a zero producer, so the disease is more severe than in Africa, where production is reduced but not absent.

Beta thal Major (homozygous) present after 6 months of age with anaemia, frontal bossing, growth failure, hepatosplenomegaly.

In Beta-thal trait, HbA2 is obviously increased eg 3.5-7%, and ratio reduced eg 20:1. The only exception is if there is co-existing severe iron deficiency. In beta-thal disease, you may not see such an increase if there’s lots of HbF around (about half the cases), and increased HbF is not specific; but the clinical picture doesn’t leave much doubt. Inclusions (alpha chains) seen esp post splenectomy. Retic count surprisingly normal due to severe intramedullary erythroblast destruction.

Treatment is with folate and regular blood transfusion, which then leads to cirrhosis, pigmentation, diabetes etc. Splenectomy reduces transfusion requirements but because of the increased vulnerability to pneumococcal infection this is usually deferred until later childhood.

Deferipone is oral chelating agent, used in Europe but not licensed in US. Acrimonious debate between lead researcher and drug company about research.

An intermediate beta thal exists, where transfusion is only required at times of increased stress.

Combined alpha thalassaemia and sickle cell disease tends to give less anaemia, but more vaso-occlusive crises.

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