Response
We would like to thank Dr Rees and colleagues for their interest in our paper. Their own work on the King's College sickle cell anemia (SCA) cohort does not confirm our Centre Hospitalier Intercommunal Créteil (CHIC) study showing that G6PD deficiency is an independent significant risk factor for abnormal high arterial velocities on transcranial Doppler (TCD).
Measuring G6PD activity in SCA patients is difficult because of the high level of reticulocytes, which may result in an overestimation of the activity. In addition, the dosage has to be performed 3 months away from transfusions. Rees et al, however, found the same incidence of G6PD deficiency in their cohort as we did in ours (11% vs 11.1%); therefore, it seems unlikely that the observed discrepancy between our 2 studies could be explained by differences in G6PD activity measurements.
In contrast, we believe that major differences in the number of TCD evaluations, the length of study follow-up, and the definition of abnormal TCD could explain, in large part, the divergent results between our studies.
The CHIC experience of exploration by TCD is longer. Systematic TCD screening for CHIC began in 1992, whereas that of the King's College began in 2004.1
The number of patients with available G6PD status and TCD was 155 in the King's College cohort, but 325 in the CHIC cohort.
Furthermore, only 10/155 (6.5%) patients had TAMMX greater than or equal to 200 cm/second in the King's College cohort versus 55/325 (16.9%) in the CHIC cohort. This can be due to 2 factors:
· A shorter follow-up.
As we demonstrated in our newborn cohort,2 velocities greater than or equal to 200 cm/second occur before the age of 9 years; thus, the study by Rees et al could have missed this occurrence.
· Differences in the definition of abnormal velocities.
Rees et al have defined TAMMX greater than 169 cm/second as abnormal, whereas we have considered as abnormal TAMMX greater than or equal to 200 cm/second (as in the Stroke Prevention Trial in Sickle Cell Anemia [STOP] study) and only initiated transfusion programs in these patients. They justify the cutoff by stating that they used TCD imaging (also used in our cohort), which tends to give lower values than TCD nonimaging. It is unlikely that the difference is as large that TAMMX greater than or equal to 169 cm/second could be considered abnormal. Moreover, no significant difference was found in a recent report comparing both methods.3 Thus, the study by Rees et al may have included patients with only marginally abnormal velocities. In addition, if these patients were transfused early, it could have influenced the occurrence of vasculopathy.
Our findings on the role of G6PD as a risk factor for high velocities was strengthened by our study in 280 SCA patients from the CHIC cohort using magnetic resonance angiography/magnetic resonance imaging (MRA/MRI), (follow-up of 2139 patient-years), which showed that G6PD deficiency (P = .008) was a highly significant risk factor for stenoses.4
As Rees et al did not find an association between G6PD deficiency and cerebrovasculopathy in their cohort, we believe that additional studies in different cohorts will be necessary to definitively confirm the influence of G6PD deficiency on cerebral vasculopathy.
Nevertheless, our findings of an association between G6PD deficiency and abnormal TCD and stenoses seem relevant because of accumulating data now supporting a link between oxidative enzymopathies and vascular disease.5 In G6PD-deficient endothelial cells, there is increased oxidative stress and decreased NO levels.6 This “enzymatic vasculopathy” hypothesis could be particularly relevant in SCA, a monogenic disease with highly variable clinical profile, probably due to polymorphism in other factors, including those influencing vascular biology.
Authorship
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Françoise Bernaudin, Centre Hospitalier Intercommunal Créteil, 40 avenue de Verdun, Créteil, France 94010; e-mail: francoise.bernaudin@chicreteil.fr.
