Thalassaemia — Alpha vs Beta Genetics, HbA2 and HbF, Screening Tests, Transfusion, Iron Chelation and Cure

Each adult haemoglobin molecule has two alpha-like and two non-alpha chains. In thalassaemia one type of chain is made in too small an amount. The unpaired excess chains precipitate in red cell precursors, causing ineffective erythropoiesis and haemolysis, and the cells that do mature are small and pale (microcytic, hypochromic).

Because there are four alpha alleles, severity rises step by step with each one lost. In fetal life the excess gamma chains form Hb Bart (γ4); after birth the excess beta chains form HbH (β4). Alpha-thalassaemia trait is thought to protect against malaria and is very common in Southeast Asia, the Mediterranean and the Middle East.

• HbH disease shows moderate reticulocytosis (3–6%), a fast-moving HbH band on electrophoresis and inclusion bodies of precipitated HbH after supravital staining.
• Even without regular transfusion, iron overload develops in HbH disease because anaemia increases gut iron absorption.
• HbA2 is normal in alpha-thalassaemia trait (and below 2% in HbH disease), so a normal HbA2 does not exclude alpha-thalassaemia — confirmation needs molecular testing.

Beta-thalassaemia is grouped by clinical severity, and the key dividing line between major and intermedia is dependence on regular transfusion.

• Skeletal changes from marrow expansion: frontal bossing and maxillary protrusion (the 'thalassaemic facies'), long-bone deformities and osteoporosis.
• Extramedullary haematopoiesis causes hepatosplenomegaly and masses of erythroid marrow.
• Peripheral smear: microcytic hypochromic cells with target cells, teardrop cells and coarse basophilic stippling; nucleated red cells in major.
• Delta-beta thalassaemia behaves like beta-thalassaemia but HbA2 is not raised, because the delta chain is also affected.

Diagnosis of beta-thalassaemia needs haemoglobin electrophoresis or HPLC to show the abnormal proportions of HbA, HbA2 and HbF, together with normal iron studies so that iron deficiency is excluded.

Sideroblastic anaemia is the other microcytic look-alike; thalassaemias lack ring sideroblasts in the marrow. For the full approach to a low MCV see anaemia classification.

In thalassaemia trait the marrow makes many small cells, so the red cell count stays relatively high while the MCV is very low, giving a low ratio. In iron deficiency fewer cells are made, so the ratio is higher. The index is a screening aid only; confirmation needs HbA2 measurement and iron studies.

The NESTROF test (Naked Eye Single Tube Red cell Osmotic Fragility) is a cheap field screen used in antenatal clinics. Microcytic thalassaemic cells have decreased osmotic fragility. A drop of blood is mixed with 2 mL of 0.36% buffered saline; normal cells lyse and the tube becomes clear, so a line behind it is visible (negative). If the line is not visible, the cells resisted lysis and the test is positive. Positive mothers' husbands are then tested; if both are positive the pregnancy is 'at risk' of thalassaemia major.

Regular red cell transfusion, usually every 2–4 weeks, corrects anaemia, suppresses ineffective erythropoiesis and reduces excess gut iron absorption. GeneReviews gives a pretransfusion target of about 9.5–10.5 g/dL; StatPearls quotes 9–10 g/dL before and 13–14 g/dL after transfusion. Started by 24 months, this lets growth and development proceed normally into late childhood.

• Complications of iron overload: heart (arrhythmias, dilated cardiomyopathy), liver (fibrosis, cirrhosis), endocrine glands (diabetes, hypothyroidism, hypoparathyroidism, hypogonadism, pituitary and adrenal failure), and growth failure and delayed puberty in children.
• Deferoxamine and deferiprone can be combined for severe iron overload.
• Thalassaemia intermedia: folic acid, transfusion when needed, iron chelation and sometimes splenectomy.

Complications come from three sources: the anaemia and marrow expansion itself, chronic haemolysis, and iron overload from transfusion and increased gut absorption. People with thalassaemia intermedia can develop jaundice and gallstones, hepatosplenomegaly, leg ulcers, pulmonary hypertension, extramedullary masses of erythroid marrow and an increased risk of thrombosis, even though they do not need regular transfusion.

In Hb Bart hydrops, the mother is also at risk: pre-eclampsia, polyhydramnios or oligohydramnios, antepartum haemorrhage and preterm delivery are common pregnancy complications, which is one more reason to screen at-risk couples before or early in pregnancy.