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Inconsistent therapeutic responses have been observed among patients with sickle cell anemia (SCA) undergoing hydroxyurea (HU) following the adoption of the standardized protocol. Moreover, this treatment regimen necessitates a prolonged period to reach the maximum tolerated dose in which beneficial therapeutic effects are observed in most SCA patients. To overcome this limitation, several studies have performed HU dose adjustments in SCA patients based on individualized pharmacokinetic profiles. The present systematic mini-review aims to select and analyze published data to present an overview of HU pharmacokinetics studies performed in SCA patients, as well as evaluate the effectiveness of the dose adjustment strategy. A systematic search was performed in the Embase, Pubmed, Scopus, Web of Science, Scielo, Google Scholar, and the Virtual Library of Health databases from December 2020 to August 2022, with a total of five studies included. Inclusion criteria consisted of studies in which the dose adjustment was performed in SCA patients based on pharmacokinetic parameters. Quality analyzes were performed using QAT, while data synthesis was performed according to the Cochrane Manual of Systematic Reviews of Interventions. Analysis of the selected studies revealed improved HU treatment effectiveness using personalized dosages in SCA patients. Moreover, several laboratory parameters were utilized as biomarkers of the HU response, and methods designed to simplify the adoption of this practice were presented. Despite the scarcity of studies on this topic, HU-personalized treatment based on individualized pharmacokinetic profiles represents a viable alternative for SCA patients who are candidates for HU therapy, especially for pediatric patients. Registration number: PROSPERO CRD42022344512. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) patients often exhibit a dyslipidemic sub-phenotype. Paraoxonase 1 (PON 1) is a serum glycoprotein associated with the high-density lipoproteins cholesterol (HDL-C), and variability in PON1 activity depends on the PON1 genotypes. We investigated the influence of PON1c.192Q > R and PON1c.55L > M polymorphisms on PON1 activity and laboratory parameters and the association between PON1 activity and clinical manifestations in SCD patients. We recruited 350 individuals, including 154 SCD patients and 196 healthy volunteers, which comprised the control group. Laboratory parameters and molecular analyses were investigated from the participants' blood samples. We have found increased PON1 activity in SCD individuals compared to the control group. In addition, carriers of the variant genotype of each polymorphism presented lower PON1 activity. SCD individuals carrying the variant genotype of PON1c.55L > M polymorphism had lower platelet and reticulocyte counts, C-reactive protein, and aspartate aminotransferase levels; in addition to higher creatinine levels. SCD individuals carrying the variant genotype of PON1c.192Q > R polymorphism had lower triglyceride, VLDL-c, and indirect bilirubin levels. Furthermore, we observed an association between PON1 activity history of stroke and splenectomy. The present study confirmed the association between PON1c.192Q > R and PON1c.55L > M polymorphisms and PON1 activity, in addition to demonstrate their effects on markers of dislipidemia, hemolysis and inflammation, in SCD individuals. Moreover, data suggest PON1 activity as a potential biomarker related to stroke and splenectomy. [ABSTRACT FROM AUTHOR]

Priapism is a urologic emergency characterized by an uncontrolled, persistent and painful erection in the absence of sexual stimulation, which can lead to penile fibrosis and impotence. It is highly frequent in sickle cell disease (SCD) associated with hemolytic episodes. Our aim was to investigate molecules that may participate in the regulation of vascular tone. Eighty eight individuals with SCD were included, of whom thirty-seven reported a history of priapism. Priapism was found to be associated with alterations in laboratory biomarkers, as well as lower levels of HbF. Patients with sickle cell anemia using hydroxyurea and those who received blood products seemed to be less affected by priapism. Multivariate analysis suggested that low HbF and NOm were independently associated with priapism. The frequency of polymorphisms in genes NOS3 and EDN1 was not statistically significant between the studied groups, and the presence of the variant allele was not associated with alterations in NOm and ET-1 levels in patients with SCD. The presence of the variant allele in the polymorphisms investigated did not reveal any influence on the occurrence priapism. Future studies involving larger samples, as well as investigations including patients in priapism crisis, could contribute to an enhanced understanding of the development of priapism in SCD. [ABSTRACT FROM AUTHOR]

Differences in hydroxyurea response in sickle cell anemia may arise due to a series of factors with genetic factors appearing to be predominant. This study aims to investigate the effects of single nucleotide polymorphisms in genes encoding drug-metabolizing enzymes and solute carriers on hydroxyurea response, in patients with sickle cell anemia. For that purpose, a total number of 90 patients with sickle cell anemia were recruited, 45 were undergoing hydroxyurea treatment, while 45 were not under the treatment. Association analyses were performed between CYP3A4 (rs2740574), CYP2D6 (rs3892097), CAT (rs7943316 and rs1001179), and SLC14A1 (rs2298720) variants and laboratory parameters. According to our findings, patients with hydroxyurea treatment demonstrated higher HbF levels and a significant improvement in hemolytic, hepatic, inflammatory, and lipid parameters in comparison to those without the treatment. We also found significant associations between the CYP2D6 (rs3892097), CAT (rs7943316 and rs1001179), and SLC14A1 (rs2298720) variants and an improvement of the therapeutic effects, specifically the hemolytic, hepatic, inflammatory, lipid, and renal parameters. In conclusion, our results highlight the importance of the investigated variants, and their strong association with hydroxyurea efficacy in patients with sickle cell anemia, which may be considered in the future as genetic markers. [ABSTRACT FROM AUTHOR]

The excessive release of heme during hemolysis contributes to the severity of sickle cell anemia (SCA) by exacerbating hemoglobin S (HbS) autoxidation, inflammation and systemic tissue damage. The present study investigated the effect of hydroxyurea (HU) on free radical neutralization and its stimulation of antioxidant genes in human peripheral blood mononuclear cells (PBMC) and human umbilical vein endothelial cells (HUVEC) in the presence or absence of hemin. HU (100 and 200 μM) significantly reduced the production of intracellular reactive oxygen species (ROS) induced by hemin at 70 μM in HUVEC. HUVECs treated with HU+hemin presented significant increases in nitric oxide (NO) production in culture supernatants. HU alone or in combination with hemin promoted the induction of superoxide dismutase-1 (SOD1) and glutathione disulfide-reductase (GSR) in HUVECs and PBMCs, and glutathione peroxidase (GPX1) in PBMCs. Microarray analysis performed in HUVECs indicated that HU induces increased expression of genes involved in the antioxidant response system: SOD2, GSR , microsomal glutathione S-transferase (MGST1), glutathione S-transferase mu 2 (GSTM2), carbonyl reductase 1 (CBR1) and klotho B (KLB). Significant increases in expression were observed in genes with kinase activity: protein kinase C beta (PRKCB), zeta (PRKCZ) and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (PIK3C2B). HU also induced a significant increase in expression of the gene p62/sequestosome (p62/SQSTM1) and a significant decrease in the expression of the transcriptional factor BACH1 in HUVECs. Upstream analysis predicted the activation of Jun, miR-155-5p and mir-141-3p. These results suggest that HU directly scavenges free radicals and induces the expression of antioxidant genes via induction of the Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) consists of a group of hemoglobinopathies in which individuals present highly variable clinical manifestations. Sickle cell anemia (SCA) is the most severe form, while SC hemoglobinopathy (HbSC) is thought to be milder. Thus, we investigated the clinical manifestations and laboratory parameters by comparing each SCD genotype. We designed a cross-sectional study including 126 SCA individuals and 55 HbSC individuals in steady-state. Hematological, biochemical and inflammatory characterization was performed as well as investigation of previous history of clinical events. SCA patients exhibited most prominent anemia, hemolysis, leukocytosis and inflammation, whereas HbSC patients had increased lipid determinations. The main cause of hospitalization was pain crises on both genotypes. Vaso-occlusive events and pain crises were associated with hematological, inflammatory and anemia biomarkers on both groups. Cluster analysis reveals hematological, inflammatory, hemolytic, endothelial dysfunction and anemia biomarkers in HbSC disease as well as SCA. The results found herein corroborate with previous studies suggesting that SCA and HbSC, although may be similar from the genetic point of view, exhibit different clinical manifestations and laboratory alterations which are useful to monitor the clinical course of each genotype. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the association of Nε-carboxymethyllysine (CML) with laboratory parameters and βS haplotypes in pediatric sickle cell anemia (SCA) patients with or without hydroxyurea (HU) therapy. We included 55 children with SCA (SCAtotal), where 27 were on HU treatment (SCA-HU+) and 28 without HU treatment (SCA-HU-). Laboratory characteristics were determined using electronic methods while CML was measured using competitive ELISA. βS haplotypes were determined by RFLP-PCR. Significant increases in MCV and MCH and significant decreases in leukocytes, eosinophils, basophils, atypical lymphocytes, lymphocytes, and monocytes were found in SCA-HU+ compared to SCA-HU-. SCA-HU+ presented significant reduction in aspartate transaminase and lactate dehydrogenase and increase in creatinine levels compared to SCA-HU-. CML levels were significantly higher in both SCA-HU+ and SCA-HU- compared to the healthy control. In addition, a negative correlation was found between CML and alanine transaminase in SCA-HU+ and SCAtotal (p<0.01). A significant association was found between CML levels and βS haplotypes. The results suggest that CML has a role to play in SCA complications, independent of HU therapy. [ABSTRACT FROM AUTHOR]

Sickle cell anemia is one of the most prevalent genetic diseases worldwide, showing great clinical heterogeneity. This study compared the gene expression patterns between sickle cell anemia pediatric patients in steady state and in crisis state, as compared to age‐paired, healthy individuals. RNA sequencing was performed from these groups of patients/controls using Illumina HiSeq 2500 equipment. The resulting differentially expressed genes were loaded into QIAGEN's ingenuity pathway analysis. The results showed that EIF2 pathway and NRF2‐mediated oxidative stress‐response pathways were more highly activated both in steady state and in crisis patients, as compared to healthy individuals. In addition, we found increased activation of eIF4 and p70S6K signaling pathways in crisis state compared to healthy individuals. The transcription factor GATA‐1 was found exclusively in steady state while SPI was found exclusively in crisis state. IL6 and VEGFA were found only in crisis state, while IL‐1B was found exclusively in steady state. The regulator effects analysis revealed IgG1 as an upstream regulator in steady state compared to healthy individuals, resulting in invasion of prostate cancer cell lines as the disease/function outcome. For crisis‐state patients versus healthy individuals, two networks of regulator effects revealed STAT1, CD40LG, TGM2, IRF7, IRF4, and IRF1 acting as upstream regulators, resulting in disease/function outcomes, including engulfment of cells and aggregation of blood cells and inflammation of joints. Our results indicated genes and pathways that can provide clues on the molecular events involved in the severity of sickle cell disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Sickle leg ulcers (SLU) are malleoli lesions with exuberant hemolytic pathophysiology. The microRNAs are potential genetic biomarkers for several pathologies. Thereby, we aimed to assess the expression of circulating miR-199a-5p, miR-144, and miR-126 in association with hemolytic biomarkers in SLU. This cross-sectional study included 69 patients with sickle cell disease, 52 patients without SLU (SLU-) and 17 patients with active SLU or previous history (SLU+). The results demonstrated elevated expression of circulating miR-199a-5p and miR-144 in SLU+ patients while miR-126 expression was reduced. Circulating miR-199a-5p and miR-144 were associated with hemolytic biomarkers such as LDH, indirect bilirubin, AST, GGT, iron, ferritin, RBC, hemoglobin, and NOm, in addition to association with impaired clinical profile of SLU. Furthermore, in silico analyses indicated interactions of miR-199a-5p with HIF1A, Ets-1, and TGFB2 genes, which are associated with vasculopathy and reduced NO. In contrast, miR-126 was associated with an attenuating clinical profile of SLU, in addition to not characterizing hemolysis. In summary, this study demonstrates, for the first time, that hemolytic mechanism in SLU can be characterized by circulating miR-199a-5p and miR-144. The circulating miR-126 may play a protective role in SLU. Thus, these microRNAs can support to establish prognosis and therapeutic strategy in SLU. [ABSTRACT FROM AUTHOR]