The thalassaemia syndromes / D.J. Weatherall.

  • David Weatherall
Date:
1972
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Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

Credit: The thalassaemia syndromes / D.J. Weatherall. Source: Wellcome Collection.

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    288 THE THALASSAEMIA SYNDROMES mia and the sickling disorders. *Even if a line of cells producing haemo¬ globin A could be established it is unlikely that it would help patients with sickle-cell anaemia or sickle-cell thalassaemia unless it could contribute more than 70% of the total red cell mass. If this was not achieved the graft would act like a small blood transfusion, raising the blood viscosity but not reducing the number of cells capable of sickling to a safe level. The authors feel that, since the present position of bone marrow transplantation is so uncertain and frought with danger, children with thalassaemia should not be subjected to this type of experimental procedure until the immunological problems have been solved. After all, looked after properly, these children can have many years of reasonably happy life. There is no doubt that the stimulation of haemoglobin F production would be the logical approach to the therapy of both ^S-thalassaemia and the sickling disorders. Thus in both conditions cells containing relatively high levels of foetal haemoglobin have longer survival times. The reasons for this have been discussed in detail in Chapters 3 and 4. It is still not known how the neonatal switch from foetal to adult haemoglobin synthesis is controlled. Furthermore it is not clear whether all adult precursor cells are capable of reactivating foetal haemoglobin production. The hetero¬ geneous distribution of haemoglobin F, both in thalassaemia, the sickling disorders and acquired conditions such as aplastic anaemia, suggests that the marrow may contain a limited number of stem cells capable of reactiva¬ ting haemoglobin F production. If this is the case the possibility of reacti¬ vating y-chain synthesis to a therapeutic level in each red cell seems remote. Reinduction of y-chain synthesis or the possibility of 'arresting' the switch from y- to j8-chain synthesis seem to offer the most promising areas of research for a therapeutic approach to thalassaemia at the time of writing. * It seems likely that a molecular approach to the control of the sickling problem will be developed within the foreseeable future. Thus while the claims of Nalbandian (1971), who has used a high-dose urea schedule to both treat and prevent sickling crises, seem rather premature and exaggerated, there is now good evidence that sickling can be inhibited by cyanate and other ligands. The recent results of Kraus and Kraus (1971), who have inhibited sickling with carbamyl phosphate, are of particular interest since this effect is probably mediated by carbamyl phosphate entering the DPG site at the N-terminal ends of the /S-chains and carbamylating the a-amino groups. Since carbamylated haemoglobin S will not bind DPG cells treated in this way will have a higher oxygen affinity and should sickle less readily.
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