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  • Polymerisation of HbS initiates the clinical

    2021-11-29

    Polymerisation of HbS initiates the clinical complications of SCD (Bunn and Forget, 1986). The resulting sequelae are multiple and diverse, and their individual impact on pathogenesis is difficult to elucidate. Early changes include altered red cell membrane permeability (Gibson and Ellory, 2002, Lew and Bookchin, 2005, Tosteson, 1955, Joiner, 1993). That red SID 26681509 synthesis from SCD patients have elevated cation permeability, which can contribute to disease by mediating solute loss, dehydration and raised HbS concentration, has been established for some time (Tosteson, 1955). The reduced lag time to polymerisation upon deoxygenation observed in shrunken red cells with elevated [HbS] is considered central to disease progression (Eaton and Hofrichter, 1987). Previous reports of cation transport in red cells from HbSC patients have been published but studies were limited to a very small number of individuals (Canessa et al., 1986, Olivieri et al., 1992, Gibson et al., 2001). The present work investigates the behaviour of red cell samples from over a hundred HbSC patients. Of the three transporters involved in dehydration (Lew and Bookchin, 2005), the present findings are consistent with a lesser role for Psickle and Gardos in HbSC disease, whilst supporting a greater involvement of KCC activity (Table 1). The observation that KCC activity in red cells from HbSC patients correlates with frequency of hospitalisation (Rees et al., 2015), a marker of disease severity, emphasises the importance of understanding in detail how this transporter is regulated. The molecular identity of KCC has been established with four isoforms identified to date, of which three (KCC1, 3 and 4) are found in red cells (Gillen et al., 1996, Pellegrino et al., 1998). In addition, splice variants do occur (Crable et al., 2005), which may be relevant to the different behaviour of KCC in red cells from HbSS and HbSC patients. Physiological regulation of KCC is also complex (Gibson and Ellory, 2003), with evidence for cascades of protein kinases and phosphatases (Cossins et al., 1994), acting on both serine–threonine and tyrosine residues, impacting on transporter activity. This enzymatic regulation is probably key to the differences in response to O2 (Gibson et al., 1994, Merciris et al., 2001), perhaps interacting with Hb at the level of the red cell membrane (Sega et al., 2012, Sega et al., 2015). This aspect, however, remains to be fully elucidated. Maintaining red cell hydration would reduce some of the complications of SCD through reducing the tendency for HbS to polymerise, and represents a longstanding clinical goal (eg Rosa et al., 1980). This is particularly so in red cells from HbSC patients, in which HbS comprises roughly only 50% of the total intracellular Hb. Hydration of these cells would require only a modest increase to reduce the tendency of HbS to polymerise (Fabry et al., 1982). Again, most work has been carried out on red cells from homozygous HbSS patients. To SID 26681509 synthesis date, the most successful strategy has been identification of reagents which inhibit the Gardos channel. Clotrimazole (Ellory et al., 1992), the in vitro inhibitor employed in the current study, cannot be used clinically, as its imidazole ring appears to cause hepatopathy (Brugnara et al., 1996). Analogues such as ICA-17,043 (“senicapoc”) have progressed to clinical trials and were successful at increasing red cell hydration in SCD patients (Stocker et al., 2003, Ataga et al., 2008, Ataga et al., 2011). Their use has been discontinued as they were unable to reduce pain episodes. Partial Psickle inhibitors also exist. They include anion exchange inhibitors such as the stilbenes (Joiner, 1990), but the use of such compounds is precluded by the wide distribution of these transporters through body tissues. Dipyridamole, which is used clinically as an anti-thrombotic compound, also partially reduces Psickle activity (Joiner et al., 2001), and has had some success at reducing clinical signs of SCD (Chaplin et al., 1980, Wun et al., 2013).