Date Published: July 15, 2019
Publisher: Public Library of Science
Author(s): Sètondji Cocou Modeste Alexandre Yahouédéhou, Caroline Conceição da Guarda, Camylla Vilas Boas Figueiredo, Rayra Pereira Santiago, Suellen Pinheiro Carvalho, Luciana Magalhães Fiuza, Uche Samuel Ndidi, Rodrigo Mota Oliveira, Magda Oliveira Seixas Carvalho, Valma Maria Lopes Nascimento, Larissa Carneiro Rocha, Isa Menezes Lyra, Elisângela Vitória Adorno, Marilda Souza Goncalves, Ana Paula Arez.
This study investigated the effects of hydroxyurea (HU) on hematological, biochemical and inflammatory parameters in children with sickle cell anemia (SCA) in association with βS 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 βS haplotypes or α-thalassemia, HU seems to be linked to alterations in hemolytic, inflammatory, hepatic, lipid and glycemic profiles.
Sickle cell anemia (SCA) is one of the most common inherited monogenic diseases in the world, characterized by chronic hemolytic anemia, vaso-occlusive events (VOE) and chronic organ injury . Clinical profile and life expectancy vary widely among individuals with SCA, which can be explained by several factors, including genetic modifiers, such as haplotypes linked with the beta S (βS)-globin gene cluster and alpha 2 deletion of 3.7 kb thalassemia (α2 del 3.7kb thalassemia) . The Benin (BEN), Bantu or Central African Republic (CAR), Senegal, Cameroon and Arab/Hindu haplotypes identified in the βS-globin gene cluster have been associated with variability in fetal hemoglobin (HbF) levels, which is known to be a classic modulator of this disease [2–4]. Likewise, individuals with SCA who are carriers of α-thalassemia present increases in hemoglobin concentrations and red blood cell (RBC) count, as well as decreases in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), reticulocyte counts and bilirubin levels [5–7]. However, α-thalassemia has also been associated with an elevated frequency of VOE, which may be due to increased hematocrit and, consequently, blood viscosity in individuals with SCA .
The present study investigated the wider effect of HU on laboratory parameters in children with SCA, according to the presence of the βS haplotype and α-thalassemia. It has been reported that individuals with SCA taking HU may present an improved clinical profile before significant increases in HbF levels are seen, and it is known that HU response can vary according to βS haplotype and α-thalassemia [11,13,14].
The results of the present study confirm the association between HU therapy and higher HbF levels and suggest that exclusively focusing on HbF levels may not be the most suitable method of assessing HU response in children with SCA. Due to increases in HbF levels and/or via parallel pathways, HU therapy, whether in association or not with βS haplotypes and α-thalassemia, is positively correlated with improvements in hemolytic and inflammatory profiles. Unexpectedly, our results also suggest that, at a dose under MTD, HU may also affect metabolic biomarkers, since it was found to be associated with changes in glucose, total protein, albumin, AST and HDL-C. The principal limitation of the present study is its relatively small sample size. Accordingly, the effects on metabolic biomarkers linked to HU therapy reported herein deserve further scrutiny in a larger study population.