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

TY - JOUR

T1 - The pleiotropic effects of α-thalassemia on HbSS and HbSC sickle cell disease

T2 - Reduced erythrocyte cation co-transport activity, serum erythropoietin, and transfusion burden, do not translate into increased survival

AU - Brewin, John N.

AU - Nardo-Marino, Amina

AU - Stuart-Smith, Sara

AU - El Hoss, Sara

AU - Hanneman, Anke

AU - Strouboulis, John

AU - Menzel, Stephan

AU - Gibson, John S.

AU - Rees, David C.

N1 - Funding Information: This study was supported by the Action Medical Research (GN 2030) and Stroke Association. Stephan Menzel and John Strouboulis are supported by MRC project grant MR/T013389/1. Publisher Copyright: © 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.

PY - 2022/10

Y1 - 2022/10

N2 - α-Thalassemia is one of the most important genetic modulators of sickle cell disease (SCD). Both beneficial and detrimental effects have been described previously. We use a 12-year data set on a large cohort of patients with HbSS (n = 411) and HbSC (n = 146) to examine a wide range of these clinical and laboratory associations. Our novel findings are that α-thalassemia strongly reduces erythrocyte potassium chloride co-transporter (KCC) activity in both HbSS and HbSC (p =.035 and p =.00045 respectively), suggesting a novel mechanism through which α-thalassemia induces a milder phenotype by reducing red cell cation loss. This may be particularly important in HbSC where reduction in mean cell hemoglobin concentration is not seen and where KCC activity has previously been found to correlate with disease severity. Additionally, we show that α-thalassemia not only increases hemoglobin in patients with HbSS (p =.0009) but also reduces erythropoietin values (p =.0005), demonstrating a measurable response to improved tissue oxygenation. We confirm the reno-protective effect of α-thalassemia in patients with HbSS, with reduced proteinuria (p =.003) and demonstrate a novel association with increased serum sodium (p =.0004) and reduced serum potassium values (p = 5.74 × 10−10). We found patients with α-thalassemia had a reduced annualized transfusion burden in both HbSS and HbSC, but α-thalassemia had no impact on annualized admission rates in either group. Finally, in a larger cohort, we report a median survival of 62 years in patients with HbSS (n = 899) and 80 years in those with HbSC (n = 240). α-thalassemia did not influence survival in HbSS, but a nonsignificant trend was seen in those with HbSC.

AB - α-Thalassemia is one of the most important genetic modulators of sickle cell disease (SCD). Both beneficial and detrimental effects have been described previously. We use a 12-year data set on a large cohort of patients with HbSS (n = 411) and HbSC (n = 146) to examine a wide range of these clinical and laboratory associations. Our novel findings are that α-thalassemia strongly reduces erythrocyte potassium chloride co-transporter (KCC) activity in both HbSS and HbSC (p =.035 and p =.00045 respectively), suggesting a novel mechanism through which α-thalassemia induces a milder phenotype by reducing red cell cation loss. This may be particularly important in HbSC where reduction in mean cell hemoglobin concentration is not seen and where KCC activity has previously been found to correlate with disease severity. Additionally, we show that α-thalassemia not only increases hemoglobin in patients with HbSS (p =.0009) but also reduces erythropoietin values (p =.0005), demonstrating a measurable response to improved tissue oxygenation. We confirm the reno-protective effect of α-thalassemia in patients with HbSS, with reduced proteinuria (p =.003) and demonstrate a novel association with increased serum sodium (p =.0004) and reduced serum potassium values (p = 5.74 × 10−10). We found patients with α-thalassemia had a reduced annualized transfusion burden in both HbSS and HbSC, but α-thalassemia had no impact on annualized admission rates in either group. Finally, in a larger cohort, we report a median survival of 62 years in patients with HbSS (n = 899) and 80 years in those with HbSC (n = 240). α-thalassemia did not influence survival in HbSS, but a nonsignificant trend was seen in those with HbSC.

UR - http://www.scopus.com/inward/record.url?scp=85134369298&partnerID=8YFLogxK

U2 - 10.1002/ajh.26652

DO - 10.1002/ajh.26652

M3 - Article

C2 - 35802781

AN - SCOPUS:85134369298

SN - 0361-8609

VL - 97

SP - 1275

EP - 1285

JO - American Journal of Hematology

JF - American Journal of Hematology

IS - 10

ER -