A thalassaemia

Two a globin genes on each chromosome 16, with total of 4 a globin genes per cell (normal person is designated aa/aa). Like sickle cell anaemia, patients can either have mild a thalassaemia (a thalassaemia trait) where one or two a globin genes are affected or may have severe a thalassaemia if three or four of the genes are affected. a thalassaemia is generally the result of large deletions within a globin complex.

Silent a thalassaemia (- a/aa)

One gene deleted. Asymptomatic. 5 MCV and MCH in minority. a thalassaemia trait (aa/— or - a/- a)

Asymptomatic carrier—recognised once other causes of microcytic anaemia are excluded (e.g. iron deficiency). Hb may be or minimally 5. MCV and MCH are 5. Absence of splenomegaly or other clinical findings. Requires no therapy.

Three a genes deleted; only one functioning copy of the a globin gene/cell. Clinical features variable. May be moderate anaemia with Hb 8.0-9.0g/dL. MCV and MCH are 5. Hepatosplenomegaly, chronic leg ulceration and jaundice (reflecting underlying haemolysis). Infection, drug treatment and pregnancy may worsen anaemia.

Blood film shows hypochromia, target cells, NRBC and increased reticulocytes. Brilliant cresyl blue stain will show HbH inclusions (tetramers of |3 globin, P4, that have polymerised due to lack of a chains). Hb pattern consists of 2-40% HbH (b4) with some HbA, A2 and F.

Treatment

Not usually required but prompt treatment of infection advisable. Give regular folic acid especially when pregnant. Splenectomy of value in some patients with HbH disease. Needs monitoring and may require blood transfusion.

Common cause of stillbirth in South East Asia. All 4 a globin genes affected. g chains form tetramers (HbBart's, 74) which bind oxygen very 87 tightly, with resultant poor tissue oxygenation. Fetus is either stillborn (at 34-40 weeks gestation) or dies soon after birth. They are pale, distended, jaundiced and have marked hepatosplenomegaly and ascites. Haemoglobin is ~6.0g/dL and the film shows hypochromic red cells, target cells, increased reticulocytes and nucleated red cells. Haemoglobin analysis shows mainly HbBart's (74) with a small amount of HbH (P4); HbA, A2 and F are absent.

There are only 2 copies of b globin gene per cell. Abnormality in one b globin gene results in b thalassaemia trait; if both b globin genes are affected the patient has b thalassaemia major or b thalassaemia intermedia. Unlike a thalassaemia, most b thalassaemias are due to single point muta-88 tions. Results in reduced b globin synthesis (b+) or absent b globin production (b°). In b thalassaemia major, patients have severe anaemia requiring lifelong support with blood transfusion (with resultant iron overload). There is ineffective erythropoiesis. Not obvious at birth due to presence of HbF (a2g2) but as g chain production diminishes and b globin production increases effects of the mutation become obvious. Children fail to thrive, and development is affected. Hepatosplenomegaly (due to production and destruction of red cells by these organs) is typical. Children also develop facial abnormalities as the flat bones of the skull and other bones attempt to produce red cells to overcome the genetic defect. Skull radiographs show 'hair on end' appearances reflecting the intense marrow activity in the skull bones.

Investigation and management

P thalassaemia trait

• Blood film: microcytic, hypochromic RBCs; target cells often present. Basophilic stippling especially in Mediterraneans.

• HbA2 (a2§2) 4—provides useful diagnostic test for b thalassaemia trait.

• Occasionally confused with iron deficiency anaemia, however, in thalassaemia trait the serum iron and ferritin are normal (or 4) whereas in IDA they are 5.

Blood film in thalassaemia trait

Treatment

Not usually required. Usually detected antenatally or on routine FBC pre-op.

ß thalassaemia intermedia

• Denotes thalassaemia major not requiring regular blood transfusion;

more severe than ß thalassaemia trait but milder than ß thalassaemia 89 major.

• May arise through several mechanisms e.g.

- Inheritance of mild ß thalassaemia mutations (e.g. homozygous ß+ thalassaemia alleles, compound heterozygote for two mild ß+ thalassaemia alleles, compound heterozygotes for mild plus severe ß+ thalassaemia alleles).

- Elevation of HbF.

- Coinheritance of a thalassaemia.

- Coinheritance of ß thalassaemia trait with e.g. HbLepore.

- Severe ß thalassaemia trait.

Clinical

• Present with symptoms similar to ß thalassaemia major but with only moderate degree of anaemia.

• Hepatosplenomegaly.

• Iron overload is a feature.

• Some patients are severely anaemic (Hb ~6g/dL) although not requiring regular blood transfusion, have impaired growth and development, skeletal deformities and chronic leg ulceration.

• Others have higher Hb (e.g. 10-12g/dL) with few symptoms.

Management

Depends on severity. May require intermittent blood transfusion, iron chelation, folic acid supplementation, prompt treatment of infection, as for ß thalassaemia major.

ß thalassaemia major (Cooley's anaemia)

Patients have abnormalities of both ß globin genes. Presents in childhood with anaemia and recurrent bacterial infection. There is extramedullary haemopoiesis with hepatosplenomegaly and skeletal deformities.

Clinical

• Reticulocytes 4.

• Blood film: marked anisopoikilocytosis, target cells and nucleated red cells.

• Methyl violet stain shows RBC inclusions containing precipitated a globin.

• Hb electrophoresis shows mainly HbF (a2g2). In some ß thalassaemias there may be a little HbA (a2ß2) if some ß globin is produced.

• HbA2 may be or mildly elevated.

|3 thalassaemia major note bizarre red cells with marked anisopoikilocytosis Management

• Regular lifelong blood transfusion (every 2-4 weeks) to suppress ineffective erythropoiesis and allow normal growth and development in childhood.

• Iron overload (transfusion haemosiderosis) is major problem —damages heart, endocrine glands, pancreas and liver. Desferoxamine reduces iron overload (by promoting iron excretion in the urine and stool), and is given for 8-12h per day SC for 5 days/week. Compliance may be difficult, especially in younger patients. Complications of desferoxamine include retinal damage, cataract and infection with Yersinia spp.

• Splenectomy may be of value (e.g. if massive splenomegaly or increasing transfusion requirements) but best avoided until after the age of 5 years due to 4 risk of infection. Infective episodes should be treated promptly with intravenous antibiotics.

• Bone marrow transplantation has been carried out using sibling donor HLA-matched transplants with good results in young patients with |3 thalassaemia major. The procedure carries a significant procedure-related morbidity and mortality, along with GvHD (ffl BMT section p324-326).

Screening

Screen mothers at first antenatal visit. If mother is thalassaemic carrier, screen father. If both carriers for severe thalassaemia offer prenatal diagnostic testing. Fetal blood sampling can be carried out at 18 weeks gestation and globin chain synthesis analysed. Chorionic villus sampling at 10+ weeks gestation provides a source of fetal DNA that can be analysed in a variety of methods: Southern blotting, oligonucleotide probes or RFLP analysis may determine genotype of fetus. Moving towards PCR based techniques; likely to improve carrier detection.

Weatherall, D.J. & Provan, A.B. (2000) Red cells I: inherited anaemias. Lancet, 355, 1169-1175.

Heterozygous Sß thalassaemia

Produces a picture similar to ß thalassaemia trait with 4 HbF (5-20%) and microcytic RBCs; HbA2 is or 5.

92 Homozygous Sß thalassaemia

Homozygous condition is uncommon. There is failure of production of both 8 and ß globins. Milder than ß thalassaemia major, i.e. ß thalassaemia intermedia. Represents a form of thalassaemia intermedia. Hb 8—11g/dL. Absence of HbA and HbA2; only HbF is present (100%).

Heterozygous ß thalassaemia/Sß thalassaemia

Similar to ß thalassaemia major (but less severe). Hb produced is mainly HbF with small amount of HbA2.

gSß thalassaemia

Homozygote is not viable. Heterozygous condition is associated with haemolysis in neonatal period and thalassaemia trait in adults with 6 HbF and HbA2.

HbLepore

This abnormal Hb is the result of unequal crossing over of chromosomes. Affects ß and 8 globin genes with generation of a chimeric globin with 8 sequences at NH2 terminal and ß globin at COOH terminal. Production of 8ß globin is inefficient; there is absence of normal 8 and ß globins. The phenotype of the heterozygote is thalassaemia trait; the homozygote picture is thalassaemia intermedia.

BCSH haemoglobinopathy diagnosis guidelines ^ www.bcshguidelines.com/pdf/bjh809.pdf

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