Hydroxyurea alters hematological, biochemical and inflammatory biomarkers in Brazilian children with SCA: Investigating associations with βS haplotype and α-thalassemia

Abstract

This study investigated the effects of hydroxyurea (HU) on hematological, biochemical and inflammatory parameters in children with sickle cell anemia (SCA) in association with β S haplotype and α-thalassemia. We included 22 children with SCA who were followed for an average of 14.5 months. Laboratory parameters were assessed by electronic methods, and molecular analysis was investigated by PCR-RFLP and allele-specific PCR. Results showed significant increases in hemoglobin, HbF, hematocrit, MCV, MCH, glucose, HDL-C and albumin levels, as well as significant decreases in MCHC and AST levels, WBC, neutrophils, eosinophils, lymphocytes and reticulocytes, in children during HU therapy. HbF levels were positively correlated with hemoglobin, hematocrit, MCV and total protein, yet negatively correlated with MCHC, RDW, AAT and AST during HU therapy ( p <0.05). Children who carried the Central African Republic haplotype, in response to HU therapy, presented significant increases in hemoglobin, hematocrit, triglycerides and uric acid levels, as well as significant decreases in MCHC, AST and direct bilirubin levels, WBC, neutrophils, eosinophils, lymphocytes and reticulocytes. Those with the Benin haplotype presented increases in HbF and albumin levels, and a reduction in platelet counts ( p <0.05). Children with α-thalassemia presented decreased ALT during HU use, while those without this deletion presented increases in hemoglobin, hematocrit, MCV, MCH, HDL-C and albumin, as well as decreases in MCHC, neutrophils, lymphocytes, reticulocytes and AST ( p <0.05). Hence, regardless of its use in association with β S haplotypes or α-thalassemia, HU seems to be linked to alterations in hemolytic, inflammatory, hepatic, lipid and glycemic profiles.

Sickle Cell Anemia: Variants in the CYP2D6, CAT, and SLC14A1 Genes Are Associated With Improved Hydroxyurea Response

“…These findings corroborate previous studies, which also demonstrated improvements in hemolytic, hepatic and inflammatory profiles in patients with SCA undergoing HU therapy ( de Souza Santos and Maia, 2010 ; Voskaridou et al, 2010 ; de Souza Torres et al, 2012 ; Pallis et al, 2014 ; Belini Junior et al, 2015 ; Shome et al, 2016 ; Quarmyne et al, 2017 ; Colombatti et al, 2018 ). We further observed an increase in HDL-C concentration, demonstrating the effect of HU on lipid metabolism, which is consistent with our previous results ( Yahouédéhou et al, 2018b ; Yahouédéhou et al, 2019 ).…”

“…These findings corroborate previous studies, which also demonstrated improvements in hemolytic, hepatic and inflammatory profiles in patients with SCA undergoing HU therapy (de Souza Santos and Maia, 2010;Voskaridou et al, 2010;de Souza Torres et al, 2012;Pallis et al, 2014;Belini Junior et al, 2015;Shome et al, 2016;Quarmyne et al, 2017;Colombatti et al, 2018). We further observed an increase in HDL-C concentration, demonstrating the effect of HU on lipid metabolism, which is consistent with our previous results (Yahouedehou et al, 2018b;Yahouedehou et al, 2019). The present analysis of genotype and/or allele distribution of rs2740574, rs3892097, and rs7943316 revealed frequencies divergent to those observed in other studies conducted in different patient populations, as well as healthy controls (Maruf et al, 2012;Sayed and Imam, 2012;Liu et al, 2015).…”

“…These reductions in both lymphocytes and AAT, specifically in those who were carriers of variant alleles, may be due to the positive correlation, which exists between these inflammatory biomarkers in individuals undergoing HU therapy. Moreover, studies have demonstrated that levels of AAT, known as an acute-phase protein with anti-inflammatory properties, can decrease during HU therapy, either as a consequence or a cause of reductions in WBC counts ( Pallis et al, 2014 ; Yahouédéhou et al, 2019 ). Hence, our findings suggest the likelihood that lower catalase expression and activity may lead to higher HU bioavailability, which could explain the associations seen herein between the CAT -21A>T and -262C>T and improvement in inflammatory biomarkers.…”

“…Reports have demonstrated that HU treatment leads to increases in fetal hemoglobin (HbF), mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV), as well as decreases in white blood cell (WBC), platelet and reticulocyte counts. Furthermore, HU is also associated with reduced adhesion molecule expression and greater nitric oxide (NO) bioavailability ( King, 2003 ; Rees et al, 2010 ; Sassi et al, 2010 ; Silva-Pinto et al, 2013 ; Yahouédéhou et al, 2019 ). Clinically, patients with SCA undergoing HU treatment present a lower incidence of painful crises, rates of hospitalization, acute chest syndrome episodes, blood transfusion and mortality ( King, 2003 ; Rees et al, 2010 ; Sassi et al, 2010 ; Silva-Pinto et al, 2013 ).…”

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 result is in keeping with analysis from the MSH 37 and BABY‐HUG 38 studies, although other smaller studies have reported contrasting findings 36 . In keeping with a recent publication, 60 we also demonstrated that treatment with HU precipitated a fall in MCHC, and that this was still seen in those with α‐thalassemia despite the lower baseline MCHC. This likely represents an important therapeutic effect of HU in addition to its primary effect of raising the HbF%.…”