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

Abstract

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.

HbSC disease: A time for progress

“…10,34 It was also associated with reduced activity of the K:Cl cotransporter but not the Gardos channel or P sickle , in 47 HbSC patients with α thalassemia compared with 25 non-thalassemic controls (p = .00045). 12 The clinical effects of α-thalassemia in HbSC disease are not clear-cut. 10,12,35 In 248 HbSC disease patients, 23 individuals with α-globin gene deletions were almost half as likely to have osteonecrosis, cholelithiasis and acute painful episodes as patients with the normal complement of 4 α-globin genes.…”

“…12 The clinical effects of α-thalassemia in HbSC disease are not clear-cut. 10,12,35 In 248 HbSC disease patients, 23 individuals with α-globin gene deletions were almost half as likely to have osteonecrosis, cholelithiasis and acute painful episodes as patients with the normal complement of 4 α-globin genes. They also had favorable clinical outcomes measured by a composite score of major organ failure.…”

“…HbSC disease has traditionally been considered “milder” than sickle cell anemia 10 . The estimated probability of death by age 10 years is 5.4%, 11 and the median survival in resource‐rich countries has risen to 80 years 12 . Hemolytic anemia is attenuated compared with sickle cell anemia and acute vasoocclusive events like pain and acute chest syndrome occur about half as often 13,14 .…”

“…10 The estimated probability of death by age 10 years is 5.4%, 11 and the median survival in resource-rich countries has risen to 80 years. 12 Hemolytic anemia is attenuated compared with sickle cell anemia and acute vasoocclusive events like pain and acute chest syndrome occur about half as often. 13,14 Among 179 HbSC disease patients, the most common chronic organ complications were retinopathy and sensorineural otological disorders in 70% and 29% of cases.…”

Sex differences in progression of kidney disease in sickle cell disease

“…4 While individuals with SCD have shortened life expectancy, female patients appear to live longer than male patients, although some more recent cohort studies show no differences in survival according to sex. 1 , 5 , 6 This difference in mortality may be driven by less end-organ damage in females. In mouse models of SCD, males present early development of elevated glomerular filtration rate (GFR), with a subsequent progressive decline in renal function over 20 weeks, findings which are not observed in females.…”