Co-inheritance of a-thalassemia dramatically decreases the risk of acute splenic sequestration in a large cohort of newborns with hemoglobin SC

Hemoglobin SC (HbSC) is the second most common variant of sickle cell disease worldwide after Hb SS. Hb C is caused by a mutation in the seventh codon of the HBB gene [HBB:c.19G>A(p.Glu7Lys)]. The β allele is associated with different β haplotypes that are named according to the region in which they originated, although such multicentric origin of the β allele has recently been proven to be unreliable. In addition to this anthropological importance, different β haplotypes can modulate the severity of sickle cell anemia. β haplotypes I, II, and III were first described by Boehm et al. There are no data in the literature on the association of β haplotypes with clinical and hematologic features. Likewise, the effect of co-inheritance of a-thalassemia (a-thal) in patients with HbSC is still unclear. This study was based on a retrospective cohort of 461 newborns from Minas Gerais, Brazil (birth date: 01/01/1999 to 31/12/2012). Results on the clinical and hematologic profiles have been recently published. Methods for the determination of a-thal and β-globin gene cluster haplotypes, as well as detailed statistical methods are available in the Online Supplementary Appendix S1. P<0.01 was considered significant. The study was approved by the institutional research ethics committee (protocol 13327713.5.0000.5149). Co-inheritance of a-thal was determined in 389 children; 77 (19.8%) were -a/aa and one (0.26%) -a/-a; 311 (79.9%) had wild HBA alleles (aa/aa). The patients were analyzed for a follow up of a total of 3,522.72 patient-years. There was no difference in follow up between the two groups (8.78 and 9.13 years for patients with or without co-inheritance of a-thal, respectively; P=0.51). The incidence of pain crises for all those 389 children was 52.1 episodes per 100 patient-years (95%CI: 49.8-54.6). The incidence of infections was 60.1 events per 100 patient-years (95%CI: 57.6-62.7), and that of red blood cell (RBC) transfusions, 4.4 events per 100 patient-years (95%CI: 3.73-5.15). The risks of pain crises, infections, and RBC transfusion were, respectively, 1.73 (95%CI: 1.5-1.99; P<1×10-), 1.31 (95%CI: 1.16-1.47; P=5×10), and 2.88fold (95%CI: 1.6-5.18; P=9×10) higher for aa/aa children compared with those with a-thal (Table 1). To the best of our knowledge, this is the first clear demonstration that co-inheritance of a-thal in children with HbSC decreases the incidence of these three events. In children with HbSS, the effect of a-thal on the incidence of pain crises before hydroxyurea was introduced in the management of patients with sickle cell anemia is controversial. In a contemporary cohort of 250 children with HbSS, our group found that the incidence of pain crises before hydroxyurea was started was 82.3 (95%CI: 75.8-89.3) per 100 patient-years for those with a-thal compared with 76 (95%CI: 72.0-80.2) for those without a-thal (P=0.11) (Rezende et al., 2019, unpublished data). Of the 78 children with co-inheritance of a-thal (-a/aa or -a/-a), only one (1.3%) had acute splenic sequestration crisis (ASSC) whereas 55 of 311 (17.7%) children without a-thal had at least one episode of ASSC (see Online Supplementary Appendix S1 for a definition of phenotype). The cumulative probability of ASSC in the groups with and without co-inheritance of a-thal was