LEG ULCERATION AND HAEMOLYTIC ANAEMIA: AN HYPOTHESIS

Leg ulceration is a well recognized complication of sickle-cell anaemia, jS-thalassaemia and hereditary spherocytosis (Wintrobe, 1974), In addition, it has also been reported rarely in hereditary elliptocytosis (Hunter & Adams, 1929), pyruvate kinase deficiency (Tanaka & Paglia, 1971), a-thalassaemia (Daneshmend & Peachey, 1978), thrombocytopenic purpura (Witts, 1942) and in patients with splenomegaly due to other conditions (Gendel, 1948), but in some of these cases it is possible that the association may have been coincidental. With the exception of sickle-cell anaemia, the cause of the leg ulceration is poorly understood. The purpose of the present review is to discuss recent advances in our understanding of the three main conditions, and in the light of these findings to put forward an hypothesis to explain the associated leg ulceration. Chronic leg ulcers occur in between 50 and 75% of older children and adults with homozygous sickle-cell anaemia. The incidence in patients with combination haemoglobinopathies is lower. In Jamaica it has been shown that the sickle-cell trait is significantly commoner in patients with leg ulcers than would be expected from the incidence of the trait in the Negro population (Serjeant & Gueri, 1970), Occasional patients with sickle-cell trait develop ulceration in the presence of associated systemic disease, such as pneumonia (Wolfort & Krizek, 1969), Adult human haemoglobin (Hb A) consists of four sub-units—a pair of a and a pair of fi polypeptide chains (Braunitzer et al., 1964)—to each of which is attached a haem group. Haemoglobin S is formed as a result of the substitution of valine for glutamic acid at the sixth residue from the N terminal end of the p polypeptide chain of haemoglobin. Cells assume the sickle shape when the haemoglobin they contain is deprived of oxygen. This change may begin within ten seconds of deoxygenation, being favoured by a lowering of pH, Under these conditions, sickle haemoglobin gels and polymerizes to give rod-like structures consisting of six monomolecular strands of haemoglobin S twisted into a spiral. The rods aggregate into bundles to form tactoids, which lie parallel to the long axis of the cell or project into the projecting spicules (White & Heagan, 1973; White, 1974), It is believed that tactoid formation within the cell causes deformity of the cell membrane and the changes of sickling, but there is also evidence to suggest that the state of the cell membrane can influence the configuration assumed by the polymers (White & Heagan, 1973), Reversion to a normal shape occurs rapidly on re-oxygenation of the cell, but after repeated sickling, cells may lose their ability to revert to normal and remain irreversibly sickled. Even though the haemoglobin in these cells may be in tlje unpolymerized state, the cell membrane—due to ATP depletion—accumulates calcium and becomfes rigid and misshapen (Bertles & Dobler, 1969), Recent work has shown that erythroycte deformability is a major factor determining blood viscosity (Chien et al., 1967a), In sickle-cell anaemia deoxygenation causes a marked rise in whole blood viscosity. This occurs as a result of increase in the internal viscosity of the individual cells, while in addition the sickled cells are relatively rigid and unable to alter their shape (Chien, Usami & Bertles, 1970), These changes may cause a gross reduction of blood flow within certain capillary beds. If blood flow through the bed is rapid, the time of exposure of the erythrocyte to hypoxia may be too short for sickling to occur, but in capillary beds subjected to venous stasis the time factor and low oxygen tensions act to the detriment of the erythrocyte (Gabuzda, 1975), In the thalassaemic syndromes it is now known that there is a deficiency of one or other of the normal polypeptide chains, which combine to form the haemoglobin molecule. Thus in ^-thalassaemia