Role of hydroxyurea therapy in the prevention of organ damage in sickle cell disease: a systematic review and meta-analysis.

BACKGROUND: Hydroxyurea is an affordable drug that reduces vaso-occlusive crises and transfusion requirements in sickle cell disease. However, its effectiveness in preventing chronic organ damage is still unclear. This systematic review and meta-analysis aimed to evaluate the role of hydroxyurea in preventing organ morbidity. METHOD: We included original articles published in English from 1st January 1990 to 31st January 2023, reporting hydroxyurea therapy and organ damage from PubMed, Google Scholar, Scopus, and CrossRef databases. A total of 45 studies with 4681 sickle cell disease patients were evaluated for organ damage. RESULTS: Our analysis showed that hydroxyurea intervention significantly lowered transcranial Doppler and tricuspid regurgitant velocity, with a standardized mean difference of - 1.03 (- 1.49; - 0.58); I 2 = 96% and - 1.37 (CI - 2.31, - 0.42); I 2 = 94%, respectively. Moreover, the pooled estimate for albuminuria showed a beneficial effect post-hydroxyurea therapy by reducing the risk of albuminuria by 58% (risk ratio of 0.42 (0.28; 0.63); I 2 = 28%). CONCLUSION: Our study found that a hydroxyurea dose above 20 mg/kg/day with a mean rise in HbF by 18.46% post-hydroxyurea therapy had a beneficial role in reducing transcranial doppler velocity, tricuspid regurgitant velocity, albuminuria, and splenic abnormality. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023401187.

Effect of hydroxyurea on erythrocyte apoptosis in hemoglobinopathy patients.

BACKGROUND: Hydroxyurea (HU) therapy improves the clinical severity of patients with hemoglobinopathies. Few studies have documented some mechanisms of HU, but the exact mechanism of action is unknown. Phosphatidylserine on erythrocytes is responsible for apoptosis. In this study, we investigate the expression of phosphatidylserine on the erythrocytes surface of hemoglobinopathies before and after HU treatment. RESEARCH DESIGNS AND METHODS: Blood samples from 45 thalassemia intermedia and 40 SCA and 30 HbE-b-thalassemia patients were analyzed before and after 3 and 6 months of HU treatment. The profile of phosphatidylserine was determined by flow-cytometry using the Annexin V-RBC apoptosis kit. RESULTS: Hydroxyurea proved effective in improving clinical severity of hemoglobinopathies. After treatment with hydroxyurea, the percentage of phosphatidylserine-positive cells was significantly reduced in all 3 patient groups (p < 0.0001). Correlation analysis using different hematological parameters as independent variables and % phosphatidylserine  as dependent variable showed a negative relationship with HbF, RBC, and hemoglobin in all 3 patient groups. CONCLUSION: Hydroxyurea reduces the expression of phosphatidylserine on erythrocytes, contributing to the beneficial effects of this therapy. We suggest that the use of such a biological marker in conjunction with HbF levels may provide valuable insights into the biology and consequences of early RBC apoptosis.

The study investigated the role of hydroxyurea in reducing the externalization of phosphatidylserine on the surface of the erythrocyte membrane of patients with hemoglobinopathies. In patients treated with hydroxyurea for 3 and 6 months, the percentage of phosphatidylserine exposure on the erythrocyte surface was reduced compared with baseline. The decreased percentage of phosphatidylserine correlated negatively with hematologic parameters such as red blood cell (RBC), hemoglobin, and fetal hemoglobin (HbF) in patients at baseline and after HU therapy. Treatment with hydroxyurea decreases the percentage of PS exposure on the surface of RBCs, contributing to the beneficial effects of this therapy. We, therefore, suggest that the use of such a biological marker on the erythrocyte cell surface in conjunction with HbF levels may provide valuable insights into the biology and consequences of early erythrocyte apoptosis.

Role of microRNA in hydroxyurea mediated HbF induction in sickle cell anaemia patients.

Hydroxyurea (HU) is found to be beneficial in sickle cell anaemia (SCA) patients, due to its ability to increase foetal haemoglobin (HbF), however, patients show a variable response. Differences in HbF levels are attributed to many factors; but, the role of miRNA in HbF regulation is sparsely investigated. In this study, we evaluated the effect of miRNA expression on HbF induction in relation to hydroxyurea therapy in 30 normal controls, 30 SCA patients at baseline, 20 patients after 3 and 6 months of hydroxyurea (HU) therapy. HbF levels were measured by HPLC. Total RNA and miRNA were extracted from CD71+ erythroid cells and the expression was determined using Taqman probes. The mean HbF level increased 7.54 ± 2.44 fold, after 3 months of HU therapy. After the HU therapy 8 miRNAs were significantly up-regulated while 2 were down-regulated. The increase in miR-210, miR16-1, and miR-29a expression and decrease in miR-96 expression were strongly associated with the HU mediated HbF induction. Post HU therapy, decreased miR-96 expression negatively correlate with HbF and γ-globin gene while increased expression of miR-210, miR-16-1 and miR-29a post HU therapy positively corelate with HbF and γ-globin gene. Thus, suggest that miR-210, miR-16-1 and miR-29a are positive regulator of γ-globin gene and miR-96 is negative regulator of γ-globin gene. The study suggests the role of miR-210, miR16-1, miR-29a, and miR-96 in γ-globin gene regulation leading to HbF induction. Identification of the relevant protein targets might be useful for understanding the HU mediated HbF induction.

Dynamic interplay of microRNA in diseases and therapeutic.

MicroRNAs are the major class of small non-coding RNAs, evolutionary conserved post-transcriptional regulators of gene expression. Since their discovery in 1993, they have been implicated as master regulators in numerous cellular processes. MicroRNA (miRNA)s regulate gene expression by attenuation and/or mRNA degradation and are commonly associated with cell development, differentiation, and homeostasis. Extensive research in past two decades has provided new insights into the potential implications of miRNA in the onset, progression, and therapeutic nature of miRNAs in disease manifestation. Owing to the novel discoveries, "miRNAs" would probably pave a new direction in therapeutic research. However, "micro" in length miRNAs have attracted considerable attention in numerous other fields. Understanding the functionality of miRNAs, in this review article, we discussed the mechanistic role of miRNAs in human diseases and have outlined most of the recent published work in clinical therapeutics. We have constructed different network models for miRNA and its targets which made us understand their interrelationship and association with diseases. Future research would surely overcome challenges and would introduce new strategies for the utility of miRNAs in a broader setting.

Genotypic-phenotypic heterogeneity of 뫧-thalassemia and hereditary persistence of fetal hemoglobin (HPFH) in India.

Large deletions in the ß-globin gene cluster lead to increased HbF levels by delaying the γ- to ß-globin switch process. However, these deletions when inherited as a homozygous condition or when co-inherited with ß-thalassemia result in variable clinical phenotypes. Individuals or families with a clinically presenting child, where the parents had HbF levels ≥ 10%, were further screened for the presence of large ß-globin cluster deletions. Six deletions in the ß-globin gene cluster were screened by GAP-PCR, and the uncharacterized deletions were further analyzed by gene dosage or by multiplex ligation-dependent probe amplification (MLPA). Among 192 individuals suspected for the inheritance of large deletions, 138 were heterozygous for large deletions, 45 were compound heterozygous of a large ß-globin cluster deletion and ß-thalassemia, and 9 were found to be homozygous for deletions. Among the heterozygotes, the Asian Indian inversion-deletion was found to be the most common deletion (39.9%), followed by the HPFH-3 deletion (30.0%). Other deletions 49.3 kb, δß-thalassemia (21.2%), and 32.6 kb deletion (4.4%) were also found to be prevalent in our population. Patients compound heterozygous or homozygous for HPFH-3 and 32.6 kb deletions showed a milder clinical presentation, as compared with the patients compound heterozygous or homozygous for the Asian Indian inversion-deletion and 49.3 kb δß-thalassemia. This comprehensive study highlights the mutation spectrum of large ß-globin cluster deletions and the clinical heterogeneity in the patients homozygous or compound heterozygous with ß-thalassemia, thus asserting the need for molecular characterization of these deletions.