A 24-year-old student from Ghana attends Accident and Emergency with severe chest wall pains. He gives a history of sickle cell disease (SCD) and has been admitted to another hospital with crises at least twice in the past year. He thinks the pain is due to another crisis and his usual analgesics do not alleviate it. His haemoglobin is 8.5 g/dl, mean cell volume 94 fl, white blood cells (WBC) 12.3 × 109/l, platelets 450 × 109/l and reticulocyte count is 325 × 109/l. The blood film shows prominent sickle cells, target cells, basophilic stippling and Howell–Jolly bodies and a sickle solubility test is positive. His oxygen saturation is 98% on air. A chest X-ray (CXR) is normal.
What is your initial management plan?
The sickling syndromes are genetic conditions in which at least one β-globin gene allele on chromosome 11 carries the βS (Val6Glu) mutation. A single nucleotide change in the β-globin gene leads to substitution of valine for glutamic acid at position 6 of the β-globin chain. Conformational change upon deoxygenation of the resultant haemoglobin (haemoglobin S; HbS) exposes a hydrophobic area at the site of the β6 valine. Interaction with a complementary site on a β subunit of another haemoglobin tetramer (α2βS2) initiates polymerization, which causes deformation, or sickling, of the red blood cell (RBC).
The homozygous state, HbSS or sickle cell anaemia, is one of the most severe forms of SCD and is the most common (around 70% in the UK);1 HbSC compound heterozygotes account for the majority of the remainder. Other compound heterozygous states can also produce SCD (HbS/β0 thalassaemia, HbS/β+ thalassaemia [including HbS/Hb Lepore], HbS/DPunjab and HbS/OArab).
The heterozygous state (HbAS) is not associated with sickling at normal oxygenation.
DNA studies have led to the belief that the sickle cell mutation has arisen independently in several different populations. Falciparum malaria then acted as a selection factor, as sickle cell trait, not SCD, confers a survival advantage against malaria. This selection pressure has resulted in high frequencies of the mutant gene in areas of high malarial transmission, e.g. sub-Saharan Africa, India, Saudi Arabia and Mediterranean countries. In west African countries, such as Ghana and Nigeria, the frequency of the trait is 15% to 30%.2 Subsequent migration has raised the frequency of the gene in other parts of the world.
The primary event is polymerization of HbS within the red cell. The resultant sickling leads to vaso-occlusion and it is this manifestation that differentiates SCD from other haemolytic anaemias.
The tendency to polymerization of haemoglobin within the red cell depends on a number of factors including:
percentage of HbS ...