The rationale for using hydroxycarbamide in the treatment of sickle cell disease” (Haematologica 2011;96:488–491). Reply

Rees’s elegant review of the utility of hydroxycarbamide in sickle cell disease (SCD) concludes with the wish that other drugs to ameliorate SCD would soon be found.1 One such may be hiding in plain sight: a double blind controlled study of the treatment of sickle patients with n-3 fatty acids found that they reduced the frequency of vaso-occlusive crisis (VOC) from 7.8 to 3.8 events/year (P<0.01). That trial was undertaken under the hypothesis that n-3 fatty acids would inhibit the coagulopathy that accompanies vaso-occlusive events.2 Perhaps because of this underlying rationale the study has received scant attention because there are numerous other negative trials of anticoagulation and anti-platelet interventions in SCD.3

However, it is now apparent that the effects of n-3 fatty acids extend beyond interfering with a coagulopathy. n-3 fatty acids replace the prior acyl chains in the red blood cell (RBC) phospholipids including those of phosphatidylserine (PS).2 The latter is normally confined to the inner layer of the RBC membrane. When sickle RBCs are deoxygenated, PS shifts to the outer layer.4 Sickle RBCs are abnormally adhesive (a factor in VOC) in part because of exteriorized PS. There is a close correlation between PS on the RBC surface and adhesion to endothelium; there is direct binding of PS bearing RBC to specific endothelial receptors.5

The assymetric transmembrane distribution of phosphatides in the RBC is enzymatically regulated and is strongly modified by the saturation of the phosphatide’s acyl chains, changing as much as 12-fold when the number of double bonds in the acyl chain is varied.6 Since the saturation of acyl chains of PS is changed by the n-3 fatty acids, it is likely that its transmembrane redistribution with sickle RBC deoxygenation would also be changed. Thus the effect of n-3 fatty acids on RBC adhesion in SCD may account for its beneficial effect and so renewed attention to n-3 fatty acids seems warranted.