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

Abstract

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 S allele is associated with different β S haplotypes that are named according to the region in which they originated, 1 although such multicentric origin of the β S allele has recently been proven to be unreliable. 2 In addition to this anthropological importance, different β S haplotypes can modulate the severity of sickle cell anemia. 3 β C haplotypes I, II, and III were first described by Boehm et al. 4 There are no data in the literature on the association of β C 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. 5 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 3.7 /aa and one (0.26%) -a 3.7 /-a 3.7 ; 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 transfu-

Clinical, laboratory, and molecular characteristics of a cohort of children with hemoglobinopathy S/beta-thalassemia

“…Some studies showed a strong modulation of α-thal in HbSβ-thal phenotype, 42 , 43 while other studies did not find significant influence. 10 , 39 , 44 We have previously observed influence of α-thal in clinical and laboratory characteristics of children with HbSS and HbSC, 8 , 9 suggesting an impact of α-thal in morbidity of SCD in our population. However, co-inheritance of α-thal had no significant influence on the laboratory and clinical parameters of children with the most frequent mutations in this study (IVS I-1 G > A and CD 39 C>T).…”

“… 7 In previous papers, we demonstrated that co-inheritance of α-thal significantly decreased the risk of cerebrovascular disease in SS children and of acute splenic sequestration in SC children. 8 , 9 However, the association of haplotypes or α-thal with the clinical course of HbSβ-thal has been only occasionaly reported. 10 …”

The pleiotropic effects of α‐thalassemia on HbSS and HbSC sickle cell disease: Reduced erythrocyte cation co‐transport activity, serum erythropoietin, and transfusion burden, do not translate into increased survival

“…This co-transporter is markedly upregulated in sickle red cells, particularly in patients with HbSC disease 43 and is thought to be an important driver of red cell T A B L E 2 Effect of hydroxyurea therapy in patients with HbSS, and the effect co-inheritance of α-thalassemia has on the key changes seen dehydration. The mechanism by which α-thalassemia induces a milder phenotype in HbSC 39,40 has so far been poorly understood. By demonstrating a significant reduction in KCC activity in the red cells of patients with HbSC, we have identified a novel biological mechanism by which α-thalassemia may be acting in these patients to improve the cation content of the red cell and reduce the rate of hemoglobin polymerization.…”

“…37,38 Co-inheritance of α-thalassemia in patients with HbSC leads to a milder phenotype, with a significantly reduced risk of acute splenic sequestration, reduced frequency of pain episodes, lower risk of osteonecrosis, and an overall improved survival rate. 39,40 Assessment of laboratory parameters has shown a reduction in mean cell volume (MCV), mean cell hemoglobin (MCH), reticulocyte percentage, white cell count (WCC), and lactate dehydrogenase (LDH), but no change in baseline hemoglobin (Hb), hematocrit, nor hemoglobin F percent (HbF %). 41,42 Hemoglobin C (HbC) is thought to contribute to intracellular HbS polymerization by encouraging red cell dehydration, in a way that hemoglobin A (HbA) does not.…”

Hemoglobin SC Disease: Phenotypic Variability and Therapeutic Options

“…It has been recently reported that co-inheritance of α-thalassemia decreases the risk of acute splenic sequestration in HbSC disease [25]. Unlike its counterpart the homozygous SS disease, the genetic modifiers of disease severity in HbSC have not been extensively studied.…”