Sickle cell anemia (SCA) is an autosomal recessive disorder caused by a single nucleotide mutation in the β-globin gene, leading to the production of abnormal hemoglobin S (HbS) (1). The polymerization of deoxygenated HbS results in erythrocyte rigidity, hemolysis, and vaso-occlusive crises, leading to multi-organ damage and reduced life expectancy (2,3). Managing SCA involves supportive care, blood transfusions, and disease-modifying therapies, with hydroxyurea (HU) being the primary pharmacologic intervention (4).

Hydroxyurea exerts its therapeutic effects by increasing fetal hemoglobin (HbF) production, reducing hemolysis, and improving erythrocyte deformability, thereby decreasing vaso-occlusive complications (5). It also reduces leukocyte and platelet counts, mitigating inflammation and endothelial activation, which play a key role in SCA pathophysiology (6). The standard dose of HU (20 mg/kg/day) has been widely used to achieve optimal hematological and clinical outcomes; however, concerns regarding potential toxicities have led to the exploration of lower-dose regimens (7).

Several studies have demonstrated the efficacy of HU in improving hemoglobin levels and reducing complications, but the optimal dosing regimen remains a subject of ongoing research. Some evidence suggests that low-dose HU (10 mg/kg/day) may provide hematological benefits with fewer adverse effects, while others advocate for the standard dose for better therapeutic outcomes (8,9). Understanding the impact of different HU doses on hematological parameters is crucial for optimizing treatment strategies and improving the quality of life for SCA patients.

This study aims to compare the effects of low-dose versus standard-dose HU therapy on hematological parameters in SCA patients over six months. The findings will contribute to the ongoing debate on HU dosing and provide insights into balancing efficacy and safety in SCA management.

Study Design and Participants

This comparative, observational study was conducted on 100 patients diagnosed with sickle cell anemia (SCA). The participants were recruited from a tertiary care center, following ethical approval from the institutional review board. Written informed consent was obtained from all participants or their legal guardians before enrollment.

Study Groups and Treatment Protocol

The study population was divided into two groups based on the hydroxyurea (HU) dosage regimen:

• Group A (Low-Dose HU): Patients received hydroxyurea at a dosage of 10 mg/kg/day.
• Group B (Standard-Dose HU): Patients were administered hydroxyurea at 20 mg/kg/day.

Hydroxyurea was prescribed orally, and adherence was monitored through regular follow-ups.

Inclusion and Exclusion Criteria

Inclusion criteria:

• Patients aged ≥5 years with a confirmed diagnosis of SCA (HbSS genotype).
• Individuals with a history of vaso-occlusive crises and anemia requiring medical management.
• Those who had not received hydroxyurea treatment in the past three months.

Exclusion criteria:

• Patients with co-existing hemoglobinopathies such as HbSC or thalassemia.
• Individuals with severe hepatic or renal dysfunction.
• Pregnant or lactating females.
• Patients with a history of non-adherence to treatment.

Hematological Assessments

Baseline hematological parameters were recorded before initiating HU therapy, and follow-up assessments were conducted at six months. The following parameters were evaluated using automated hematology analyzers:

• Hemoglobin (Hb) concentration (g/dL)
• Mean corpuscular volume (MCV) (fL)
• White blood cell (WBC) count (×10⁹/L)
• Platelet count (×10⁹/L)
• Fetal hemoglobin (HbF) levels (%), measured by high-performance liquid chromatography (HPLC)
• Lactate dehydrogenase (LDH) (U/L), as an indicator of hemolysis

Statistical Analysis

The data were analyzed using SPSS (Statistical Package for the Social Sciences) version 26.0. Descriptive statistics were presented as mean ± standard deviation (SD). Paired t-tests were used to compare baseline and post-treatment values within each group, while an independent t-test assessed differences between groups. A p-value of <0.05 was considered statistically significant.

Baseline Characteristics

A total of 100 patients diagnosed with sickle cell anemia (SCA) were included in the study, with 50 participants in each group. The mean age of patients in Group A (low-dose hydroxyurea) was 12.4 ± 3.1 years, while in Group B (standard-dose hydroxyurea), it was 13.1 ± 2.8 years. The male-to-female ratio was comparable between both groups. Baseline hematological parameters, including hemoglobin (Hb), fetal hemoglobin (HbF), white blood cell (WBC) count, platelet count, and lactate dehydrogenase (LDH), did not show significant differences between the two groups (p > 0.05) (Table 1).

Changes in Hematological Parameters After Six Months

Following six months of hydroxyurea therapy, significant improvements were observed in hematological parameters, with more pronounced changes in the standard-dose group (Group B).

• Hemoglobin (Hb) levels: In Group A, Hb levels increased from 7.4 ± 1.1 g/dL to 8.6 ± 1.0 g/dL (p < 0.05), whereas in Group B, they rose from 7.5 ± 1.2 g/dL to 9.8 ± 1.3 g/dL (p < 0.05) (Table 2).
• Fetal hemoglobin (HbF) levels: The HbF levels increased significantly in both groups. Group A showed an increase from 5.9% ± 2.0% to 10.8% ± 2.5% (p < 0.001), while in Group B, HbF rose from 6.2% ± 2.1% to 15.4% ± 3.2% (p < 0.001) (Table 2).
• White blood cell (WBC) count: A substantial decrease was observed in both groups. In Group A, WBC count reduced from 12.5 ± 3.4 ×10⁹/L to 9.8 ± 2.9 ×10⁹/L (p < 0.05), whereas in Group B, it declined from 12.7 ± 3.6 ×10⁹/L to 8.2 ± 2.6 ×10⁹/L (p < 0.05) (Table 3).
• Platelet count: A significant reduction in platelet count was noted, with Group A showing a decrease from 380 ± 85 ×10⁹/L to 320 ± 72 ×10⁹/L (p < 0.05), and Group B from 385 ± 88 ×10⁹/L to 290 ± 65 ×10⁹/L (p < 0.05) (Table 3).
• Lactate dehydrogenase (LDH) levels: Indicative of hemolysis, LDH levels showed a greater decline in Group B (from 600 ± 120 U/L to 410 ± 95 U/L) compared to Group A (from 590 ± 115 U/L to 460 ± 100 U/L) (p < 0.05) (Table 4).

Comparison Between Groups

The standard-dose hydroxyurea group (Group B) exhibited significantly greater improvements in Hb levels, HbF percentage, WBC count reduction, and LDH reduction compared to the low-dose group (Group A) (p < 0.05 for all comparisons) (Tables 2–4). These findings indicate that the standard dose of hydroxyurea provides superior hematological benefits in SCA patients.

Tables

Table 1. Baseline Characteristics of Study Participants

Table 2. Changes in Hemoglobin and HbF Levels After Six Months

Table 3. Changes in WBC and Platelet Counts After Six Months

Table 4. Changes in LDH Levels After Six Months

The results indicate that both hydroxyurea doses improved hematological parameters in SCA patients. However, the standard-dose group (Group B) showed superior outcomes in increasing hemoglobin and HbF levels while significantly reducing WBC count, platelet count, and LDH levels (p < 0.05). These findings suggest that a higher dose of hydroxyurea provides enhanced therapeutic benefits with manageable side effects.

The present study evaluates the impact of low-dose (10 mg/kg/day) versus standard-dose (20 mg/kg/day) hydroxyurea (HU) on hematological parameters in sickle cell anemia (SCA) patients over six months. The findings indicate that the standard-dose regimen significantly improves hemoglobin (Hb) and fetal hemoglobin (HbF) levels while reducing markers of hemolysis and inflammation, demonstrating superior therapeutic efficacy compared to the low-dose regimen.

Hydroxyurea is a well-established treatment for SCA due to its ability to increase HbF production, reduce erythrocyte sickling, and enhance oxygen-carrying capacity (1,2). In this study, Hb levels increased significantly in both groups, with a greater improvement in the standard-dose group (9.8 ± 1.3 g/dL) compared to the low-dose group (8.6 ± 1.0 g/dL, p < 0.05). This is consistent with previous studies where higher HU doses were associated with a greater rise in hemoglobin concentration due to reduced hemolysis and improved erythropoiesis (3,4).

The HbF percentage also increased significantly in both groups, with a more substantial rise in the standard-dose group (15.4% ± 3.2%) compared to the low-dose group (10.8% ± 2.5%, p < 0.001). The increase in HbF is crucial in SCA as it inhibits polymerization of hemoglobin S (HbS), reduces vaso-occlusive events, and enhances erythrocyte survival (5,6). Clinical trials have demonstrated that higher doses of HU lead to greater HbF induction, thereby reducing disease severity (7,8).

SCA is characterized by chronic inflammation, endothelial dysfunction, and increased leukocyte adhesion, contributing to vaso-occlusion and disease progression (9). Hydroxyurea has been shown to reduce WBC and platelet counts, leading to a lower risk of vaso-occlusive crises and inflammatory complications (10). The findings of this study align with prior research, where the standard-dose HU group exhibited a more pronounced decline in WBC count (from 12.7 ± 3.6 ×10⁹/L to 8.2 ± 2.6 ×10⁹/L, p < 0.05) compared to the low-dose group. Similar trends were observed in platelet counts, reinforcing HU's role in mitigating SCA-associated hypercoagulability (11,12).

Lactate dehydrogenase (LDH) serves as an indicator of intravascular hemolysis, with elevated levels correlating with disease severity and increased risk of complications (13). This study demonstrated a significant reduction in LDH levels in both treatment groups, with a greater decline in the standard-dose group. The higher HU dose likely led to enhanced HbF production and improved erythrocyte stability, thereby reducing hemolysis (14). These findings are consistent with previous reports where LDH reduction was directly associated with higher HbF levels and improved clinical outcomes in SCA patients (15,16).

The study demonstrates that standard-dose hydroxyurea (20 mg/kg/day) significantly improves hematological parameters in SCA patients compared to low-dose therapy (10 mg/kg/day). The greater increases in Hb and HbF levels, along with the reduction in WBC count, platelet count, and LDH levels, suggest that a higher HU dose provides enhanced therapeutic benefits. These findings support the use of standard-dose HU as an effective strategy for improving hematological outcomes in SCA. Further studies are needed to assess long-term safety and optimize individualized dosing regimens.

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