High Foetal Haemoglobin in Sickle Cell Disease: Not so Protective?

Sickle cell disease (SCD) comprises a group of genetic disorders in before one year of age in SCA and the adhesion of reticulocytes to the which the red blood cells (RBCs) produce abnormal sickle haemoglobin (HbS) that can polymerise when oxygen concentrations are low. The clinical manifestations of SCD are numerous, and vary from patient to patient, but recurrent vaso-occlusive processes can cause significant organ damage, resulting in increased morbidity and mortality in these individuals (Kato et al., 2009). Polymerised HbS confers a characteristic sickle shape to the RBC, in association with other cellular alterations; furthermore, these RBCs are more likely to rupture, releasing damaging cell-free haemoglobin (Hb) into the circulation (haemolysis), with significant consequences that include vascular nitric oxide (NO) consumption and oxidative stress (Kato et al., 2009). Newborn and very young infants with sickle cell anaemia (SCA) still produce significant amounts of foetal haemoglobin (HbF), the Hb that is made during intrauterine life, although this HbF production will begin to decline after the first few months due to the Hb-switching process (Quinn, 2013). As high concentrations of HbF inhibit the polymerisation of HbS, young infants are asymptomatic and are generally thought to display little in the way of pathophysiological alterations. In the current issue of E-BioMedicine, Brousse et al. (in press) report intriguing data to show that very young asymptomatic SCA infants, whilst still producing very high total levels of HbF, demonstrate significant alterations in reticulocyte membrane protein expression, in association with reticulocytosis. The infants with SCA studied by Brousse and colleagues were aged approximately 3–6 months and presented total HbF levels of 41.2 (±11.2) %, a level much higher than that generally sought during HbF-inducing hydroxycarbamide (hydroxyurea) therapy in SCA adults (McGann and Ware, 2011). However, despite presenting levels of total HbF thought to be protective in SCA, the adhesion molecule expression profile on the reticulocytes of these children was altered. Changes in adhesion molecule presentation on the erythroid surface can confer alterations in cellular adhesion and augmented RBC adhesive properties have been consistently observed in SCA, where erythroid cell adhesive interactions are believed to contribute to the initiation and propagation of vaso-occlusive processes (Colin et al., 2014). As such, the alterations observed in the expression profile of major adhesion molecules on the reticulocyte surface of young infants could have some important pathophysiological consequences; splenic vasoocclusion and the onset of hyposplenism, for example, usually occur