Determinants of intertransfusion interval in children with transfusion-dependent thalassemia: a retrospective single-center cohort study in China

Introduction

Thalassemia is a group of monogenic hereditary diseases that is widely distributed worldwide and characterized by an imbalance in the production of globin chains (1). This imbalance leads to ineffective erythropoiesis, increased hemolysis, and the disruption of iron homeostasis (2). According to the clinical severity and transfusion requirements, thalassemia can be divided into transfusion-dependent thalassemia (TDT) and non-TDT (NTDT) (3). Among TDT, β-thalassemia is the most prevalent type that often requires transfusions starting at a young age and lifelong regular red blood cell (RBC) transfusions are needed (4,5). According to the Thalassemia International Federation (TIF) guidelines (5th edition, 2025), TDT necessitates lifelong regular RBC transfusions with a target pretransfusion hemoglobin of 9.5–10.5 g/dL to suppress ineffective erythropoiesis and prevent complications (6). However, the clinical efficacy of RBC transfusions can be influenced by multiple factors, including RBC product characteristics, patient-specific variables, and transfusion practices. In terms of RBC products, leukocyte-reduced RBC (LRBC) is recommended as first-line therapy due to its superior hemoglobin preservation, while washed RBC (WRBC) is reserved for patients with specific immunological indications. Research has shown that RBC suspension storage of more than 21 days may reduce oxygen-carrying capacity and increase the risk of inflammatory responses (7). The patient’s own iron metabolism status, genotype, and comorbidities also significantly influence transfusion reactions (8).

Intertransfusion intervals, defined as the number of days between two transfusions, are a core indicator for evaluating transfusion efficacy and monitoring the risk of iron overload (9). A shorter interval may accelerate iron overload, increasing the risk of damage to the heart, liver, and other organs (10); whereas a longer interval may lead to increased myocardial ischemia or neurological events due to worsening anemia (11). Bhalodiya et al. reported that high serum ferritin level in β-thalassemia was associated with increasing age in children and with increasing transfusion dependency (12). Moreover, the percentage of transfusion-transmitted infections in patients with frequent intertransfusion intervals (≤30 days) was significantly higher than that in patients with less frequent intertransfusion intervals (>30 days), according to a study performed in 148 transfusion-dependent β-thalassemia patients (13). TIF guidelines suggest that genotype severity independently predicts transfusion requirements, necessitating personalized management (6).

Therefore, it is crucial for pediatric patients with TDT to identify the factors influencing intertransfusion intervals and develop personalized transfusion regimens accordingly. In this retrospective observational study, our primary objective was to investigate the association between RBC intertransfusion intervals and potential influencing factors, including patient-specific characteristics, RBC characteristics, transfusion adequacy, and disease-related factors. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-423/rc).

Methods

Study design and participants

This single-center study was designed as a retrospective observational study. Pediatric patients with TDT who received continuous RBC transfusions at our center from August 2022 to July 2023 were included, while patients with discontinuous RBC transfusions at our center were excluded.

Following the above criteria, 21 pediatric β-thalassemia patients with 392 transfusions were finally enrolled. The 392 transfusions were divided into two groups based on the median intertransfusion interval (18 days), including group I (intervals ≤18 days) and group II (intervals >18 days). All patients underwent iron chelation therapy.

The primary objective was to determine the influencing factors of RBC intertransfusion intervals and the impact levels of different indicators on hemoglobin. The secondary objective was to characterize the occurrence and type of transfusion-related adverse reactions among the 21 pediatric β-thalassemia patients enrolled.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Children’s Hospital, Zhejiang University School of Medicine, National Children’s Regional Medical Center, National Clinical Research Center for Child Health (approval No. 2025-IRB-0166-P-01). Informed consent was waived due to the retrospective nature of the study.

Data collection

At every RBC transfusion, demographic and clinical data were extracted from the Hospital Information System (HIS) and Laboratory Information System (LIS), including age, gender, weight, hemoglobin level, and hematocrit. The genotype of thalassemia was obtained via telephone from the patient’s guardian and LIS. RBC product-related variables comprised the storage duration of RBC units (days) and product type (leukoreduced vs. washed). The transfusion efficacy indicators included transfusion volume (units) and transfusion adequacy. RBC product-related variables and transfusion efficacy indicators were collected from the Blood Information System (BIS). All data collection work was completed by two contributors: one was responsible for collecting data, and the other was responsible for verifying it. Permission to provide genetic data was declined by the legal guardians of three patients (No. 1, 3, and 17), and these patients were included in overall clinical analyses but excluded from all genotype-specific comparisons.

Regarding the collected laboratory tests, it is important to note that RBC transfusions for TDT patients in this study were administered in an outpatient setting. Consequently, hemoglobin and hematocrit levels were measured prior to each transfusion event, without post-transfusion assessment.

Definitions

Severity of genotype

The severity of β-thalassemia can vary significantly based on the specific genotype involved, which includes β-thalassemia major, β-thalassemia intermedia, and β-thalassemia minor. All the 21 pediatric patients with TDT in this study had β-thalassemia, and their genotypes included β⁺/β, β⁺/β⁺, β⁰/β⁺, and β⁰/β⁰, where β refers to the normal synthesis of the β-globin chain, β⁺ denotes mild mutations that cause a relative reduction of β-globin chain synthesis, and β⁰ refers to severe mutations that can lead to a complete absence of the β-globin chain product. According to a review, β⁰/β⁰ belongs to β-thalassemia major, β⁺/β⁺ and β⁰/β⁺ belong to β-thalassemia intermedia, and β⁺/β belongs to β-thalassemia minor (14).

Severity of anemia

On the basis of the hemoglobin levels, the World Health Organization (WHO) classifies anemia into three categories: mild, moderate, and severe (https://www.who.int/publications/i/item/WHO-NMH-NHD-MNM-11.1). For children aged 6–59 months, hemoglobin levels of ≤10.9, ≤9.9, and <7 g/dL are respectively regarded as mild, moderate and severe anemia; for children aged 5–11 years, hemoglobin levels of ≤11.4, ≤10.9, and <8 g/dL are respectively regarded as mild, moderate and severe anemia; for children aged 12–14 years, hemoglobin levels of ≤11.9, ≤10.9, and <8 g/dL are respectively regarded as mild, moderate and severe anemia; for non-pregnant women (15 years of age and above), hemoglobin levels of ≤11.9, ≤10.9, and <8 g/dL are respectively regarded as mild, moderate and severe anemia; for men (15 years of age and above), hemoglobin levels of ≤12.9, ≤10.9, and <8 g/dL are respectively regarded as mild, moderate and severe anemia.

Transfusion adequacy

The increase in post-transfusion hemoglobin level was calculated on the basis of the patient’s weight, the actual volume of RBC transfusion, and the hematocrit of the RBC product. If the increase was less than the target hemoglobin level minus the pretransfusion hemoglobin level, it indicated insufficient transfusion; otherwise, it was considered adequate. The post-transfusion hemoglobin level was targeted at the range of 12–14 g/dL. The following calculation was used: [(desired hemoglobin − actual hemoglobin) × weight × 3]/hematocrit of RBC = volume (mL) to be measured, the units for desired and actual hemoglobin are g/dL, and the unit for weight is kg (15).

RBC suspension

LRBC and WRBC suspensions were involved in this study, which were prepared by suspending RBCs in a solution of mannitol-adenine-phosphate (MAP), which can be stored for 35 days at a temperature of 2 to 6 °C. The properties of LRBC and WRBC used in our center were as follows: LRBC units had a mean volume of 150 mL, hemoglobin concentration of 163.63 g/L, total hemoglobin content of 24.56 g, and hematocrit of 47.56%. WRBC units had a mean volume of 117.38 mL, hemoglobin concentration of 176.5 g/L, total hemoglobin content of 20.76 g, and hematocrit of 48.03% (Table S1). All RBC products were provided by the Blood Center of Zhejiang Province, China.

Statistical analysis

Continuous variables were expressed as mean ± standard deviation or median (interquartile range) following normality assessment using Shapiro-Wilk tests. Intergroup comparisons were performed using independent Student’s t-tests for normally distributed data or Mann-Whitney U tests for non-parametric distributions. Categorical variables were presented as frequencies (%) and analyzed by Chi-squared tests; Fisher’s exact test was substituted for small expected cell counts (<5); and correlation analysis was used to further analyze the relationship between each variable and intertransfusion intervals.

To identify the independent determinants of intertransfusion intervals, they were changed into binary data, and binary logistic regression was used involving variables with P<0.05 in univariate analysis. Multivariable linear regression model was then constructed to evaluate the factors influencing hemoglobin levels before the subsequent transfusions, with intertransfusion intervals as a continuous variable. Statistical significance was set at P<0.05, and analyses were performed using SPSS software, version 20.0 (SPSS, Chicago, IL, USA).

Results

Patients’ characteristics

Between August 2022 and July 2023, 28 patients diagnosed with β-thalassemia were assessed, of whom 7 were ineligible for less than 10 transfusions at our center and 21 met the inclusion criteria. Those subjects had a total of 407 blood transfusions in one year. Therefore, 392 transfusions were finally included in this study (the remaining 15 data points were severely incomplete), and the median intertransfusion interval was 18 days. Table 1 presents the statistical results of comparisons of biological characteristics and laboratory tests between two groups. The mean age in group I was 8.123±3.455 years, while that in group II was 5.865±4.438 years, with a P value of <0.001. The mean weight was 22.425±8.269 kg in group I and 20.617±10.707 kg in group II (P<0.001). In these 392 transfusions, males accounted for 42.42% in group I and 34.02% in group II, while females accounted for 57.58% in group I and 65.98% in group II (P=0.09). A Chi-squared test revealed statistically significant differences in the distribution of the four genotypes (β⁺/β, β⁺/β⁺, β⁰/β⁺, β⁰/β⁰) between the two groups (P<0.001). The average hemoglobin and hematocrit levels before current transfusions showed no significant difference between two groups (P=0.08 and 0.43), while these differences before the subsequent transfusions were significant (both P<0.001).

Major objective: analysis of the influencing factors of intertransfusion intervals

In the univariate analysis, the RBC products (WRBC vs. LRBC) and transfusion adequacy (yes vs. no) were found to be significantly associated with intertransfusion intervals (P<0.001 and P=0.03). However, no significant between-group differences were observed regarding the severity of anemia (P=0.45) and RBC storage time (P=0.14), as detailed in Table 2. The analysis using Pearson’s correlation coefficient revealed a statistically significant weak correlation of age and weight with intervals [r =−0.341, 95% confidence interval (CI): −0.428 to −0.248, P<0.001; r =−0.298, 95% CI: −0.388 to −0.203, P<0.001]. Furthermore, there was a significant weak correlation of genotype, RBC products, and transfusion adequacy with intervals (r =0.175, 95% CI: 0.061–0.285, P=0.002; r =−0.197, 95% CI: −0.292 to −0.097, P<0.001; r =−0.108, 95% CI: −0.207 to −0.006, P=0.04). Meanwhile, there was no correlation between intertransfusion intervals and gender or RBC storage duration (Table 3).

Subsequently, binary logistic regression was used to evaluate the association between the above significant indicators with intertransfusion intervals. It was found that genotype (major vs. minor) and RBC products (LRBC vs. WRBC) independently had significant inverse association with intertransfusion intervals, indicated by odds ratio (OR) =0.397 (95% CI: 0.171–0.922, P=0.03) and OR =0.378 (95% CI: 0.186–0.77, P=0.007). Meanwhile, no independent and statistically significant association of age, weight and transfusion adequacy with intervals was found. Detailed data were shown in Table 4.

Finally, a linear regression analysis was performed to evaluate the linear impact of variables that were significant in the univariate analysis on the hemoglobin level before the subsequent transfusion. In this model, genotype, RBC products, current pretransfusion hemoglobin, and the increase in hemoglobin were significant variables, as shown in Table 5. The hemoglobin level of patients with Intermedia and Major genotype before the subsequent transfusion was −5.534 g/L (95% CI: −9.942 to −1.126, P=0.01) and −8.428 g/L (95% CI: −12.967 to −3.89, P<0.001) lower than that of patients with Minor genotype. Compared with 1 unit of WRBC, the hemoglobin level before the subsequent transfusion might increase 2.681 g/L (95% CI: −0.099 to 5.462, P=0.049) in patients who received 1 unit of LRBC. For every 1 g/L increase in current pretransfusion hemoglobin and increase in hemoglobin, there would be 0.645 g/L (95% CI: 0.552–0.738, P<0.001) and 0.171 g/L (95% CI: 0.003–0.339, P=0.047) increase in the hemoglobin level before the subsequent transfusion.

Secondary objective: occurrence and type of transfusion-related adverse reactions

Among the 21 patients with β-thalassemia included in this observational study who received continuous regular RBC transfusion treatment for one year, patients 4, 10, 11, and 18 had a history of allergic reaction to RBC transfusion. Patient No. 2 developed a non-hemolytic febrile reaction at the second transfusion, patient No. 10 showed a positive antibody screening before the eighth transfusion, patient No. 11 had a positive direct antiglobulin test before the eleventh transfusion, patient No. 19 developed urticaria during the eleventh transfusion, and patient No. 21 already had anti-E antibody before enrollment. Remarkably, patient No. 4, who was a child with a history of allergic reaction to RBC transfusion, was administered WRBC transfusions six times initially. However, due to inventory reasons, LRBC transfusions were given instead at the 7th transfusion without allergic reactions, and the procedure was performed later. It was speculated that the previous allergic reaction might have been related to the immune status at that time. The remaining patients had no history of adverse transfusion reactions (Table 6).

Discussion

Globally, two principal transfusion strategies are used in thalassemia management. The first is a hypertransfusion regimen, endorsed as standard-of-care by the TIF, which involves scheduled transfusions at fixed intervals (typically every three or four weeks) to maintain a target pretransfusion hemoglobin level above 9.5–10 g/dL (6). This approach aims to suppress ineffective erythropoiesis and reduce associated complications such as impaired growth and skeletal abnormalities (5). This retrospective study, based on the actual situation, evaluated the association between RBC intertransfusion intervals and potential factors in pediatric TDT patients, including patient-specific characteristics, RBC product features, transfusion adequacy, and disease-related variables. Our findings indicated that thalassemia genotype severity and RBC product type were independent factors of intertransfusion intervals, while unexpectedly, RBC storage duration showed no significant correlation with intertransfusion intervals.

The clinical heterogeneity in β-thalassemia minor warrants particular attention. While patients with β^⁺/β genotype typically do not require regular transfusions (16), therapeutic intervention may be necessary under specific circumstances, such as individuals carrying severe β^⁺ mutations [e.g., IVS-II-654 (C>T), IVS-II-745 (C>G), IVS-I-5 (G>C/T), and IVS-I-110 (G>A) (17)]. In our cohort, two pediatric patients (No. 16 and 21) with β⁺/β received regular transfusions, and both had the IVS-II-654 (C>T) mutation where functional β-globin output is extremely low, closer to β⁰. Patient 16 was a 2-year-old girl. Although her hemoglobin levels rarely dropped below 10 g/dL, and her pretransfusion hemoglobin levels typically ranged between 10 and 11 g/dL, she had been receiving regular transfusion therapy at our center due to her developmental delays. Currently, she has been developing well. Patient 21 was a 7-year-old girl. Although she also had the β⁺/β genotype, her hemoglobin levels before each transfusion ranged between 8 and 9.5 g/dL. Therefore, we suspected that she may have undetected genetic mutations affecting the expression of α- or β-globin, resulting in moderate anemia. These situations underscores that clinical decisions should be based on dynamic assessment rather than genotypic classification alone, highlighting the risk of therapeutic inadequacy when patients are labeled as “mild” or “minor” in resource-limited settings.

After adjusting for confounders such as age and weight, children with major thalassemia genotype exhibited longer intertransfusion intervals compared to those with minor genotype. This observation, supported by multivariate linear regression results (Table 5), suggested that major genotype patients had lower pretransfusion hemoglobin levels, potentially contributing to prolonged intervals. It is plausible to assert that these children have a greater tolerance for lower hemoglobin and develop symptoms of anemia later (18). Alternatively, factors not assessed in this study, such as socioeconomic status or awareness, might also influence this outcome. Current TDT management guidelines emphasize maintaining pretransfusion hemoglobin levels at 9–10 g/dL to support growth and development in pediatric patients (5). Although the exact mechanisms require further investigation, in this study, children with β-thalassemia intermedia and major genotype exhibited decreases of 5.534 and 8.428 g/L, respectively, in pretransfusion hemoglobin levels at subsequent transfusions compared to minor genotype patients. Additionally, age and weight showed significant negative correlations with transfusion tolerance (r =−0.341 and −0.298, respectively; P<0.001), emphasizing the need for age-adjusted protocols. These findings confirm previous TIF guidelines, that is, β⁰/β⁰ genotypes are associated with a more rapid hemoglobin decline (8.428 g/L reduction in our study), reinforcing genotype-driven protocol individualization.

In this study, it was obvious that patients receiving WRBC had shorter intertransfusion intervals than those transfused with LRBC. Normally, WRBC units may not provide the full 1 g/dL increase in hemoglobin per unit because 10–20% of the RBCs are lost in the washing process when compared to the leukoreduced RBC (19). Table S1 shows the comparison of hemoglobin, volume, hematocrit, and total hemoglobin levels between 1-unit LRBC and 1-unit WRBC. Critically, the significantly reduced volume of WRBC units (117.38 vs. 150 mL in LRBC; P<0.001) directly contributes to shortened intertransfusion intervals (r =−0.165; P=0.001). Although WRBC exhibits higher hemoglobin concentration (176.5 vs. 163.63 g/L; P=0.20), the 13.4% lower total hemoglobin mass per unit (20.76 vs. 24.56 g; P=0.02) results in diminished oxygen-carrying capacity per transfusion episode. This volume-related deficit necessitates more frequent transfusions to maintain equivalent hemoglobin support. The washing process not only affects the quantity but also the quality of RBC. In the WRBC, there was less microvesicle accumulation, greater band-3 expression, less phosphatidylserine (PS) expression, a decrease in cell-free hemoglobin accumulation, and a decrease in osmotic fragility (20). These changes disrupt the balance between pro-phagocytic (“eat me”) signals (e.g., oxidized band 3 proteins and PS) and anti-phagocytic (“don’t eat me”) signals (e.g., CD47-SIRPα interaction), accelerating RBC clearance by splenic macrophages (21,22). Contrarily, Yun et al. reported that the RBC washing process had no significant impact on the hemolysis rate at the end of storage (23). Therefore, this study cannot determine whether the impact of the washing process on RBC quality affects the transfusion intervals in thalassemia patients.

Different from certain studies, our analysis found no association between RBC storage time and intertransfusion intervals, while prolonged storage induced metabolic dysfunction, oxidative stress, and microvesicle release (24). In a previous study of children in internal medicine, our group found that children who received fresh RBC did not show longer intertransfusion intervals but presented shorter hospital stays (25). Thus, we speculated that RBC viability was not significantly changed in the controlled storage duration. A marked extension of intertransfusion intervals was observed in study group patients receiving neocytes transfusion (average 45.8 days) over control group patients [i.e., those receiving conventional packed RBC (average 26.1 days)], and there was an average 40.8% reduction in the volume of RBC required in the study group compared to the control group (P<0.001) (26). Nonetheless, the types of RBC product in our study were not the same as those in the latter study. In addition, many factors in the preparation process of RBC products may affect the vitality and function of RBC. For example, the selection of anticoagulants, irradiation, leukocyte filtration, washing and rejuvenation, pathogen reduction methods, etc., may all aggravate storage-related damage and attenuate RBC activity and function (27), while genetic and environmental factors in the donor can also influence the progression of red cell storage damage (28). Our null finding resonates with TIF’s statement that storage duration within approved limits (≤35 days) may not alter efficacy if RBC viability is preserved, particularly for MAP-suspended products, though microvesicle release from prolonged storage remains controversial (6).

Among the 21 β-thalassemia patients in this study, two experienced transfusion reactions, and three developed unexpected antibodies. To minimize alloimmunization, strategies such as promoting Rh phenotype/genotype-matched transfusions, optimizing iron chelation, and advancing novel therapies (e.g., luspatercept or CRISPR/Cas-based gene editing) are essential (29-31). Short-term goals include reducing transfusion complications, while long-term objectives focus on curative gene therapies to eliminate transfusion dependence.

Limitations

This study has several limitations inherent to its retrospective observational design. Most notably, the small patient cohort (n=21) restricts the statistical power to detect subtle effects and limits subgroup analyses. Although we included 392 transfusion events in the analysis to strengthen longitudinal assessment, the limited number of unique patients reduces generalizability and increases susceptibility to type II errors, particularly for variables with moderate effect sizes (e.g., genotype severity). Additional constraints include single-center data collection from a non-endemic region, which may not reflect practices or patient characteristics in thalassemia-prevalent areas; unmeasured confounding variables such as socioeconomic status, caregiver education, iron assessment [magnetic resonance imaging of liver iron concentration is recommended for accurate monitoring by TIF (6)], compliance with chelation therapy, and precise post-transfusion hemoglobin trends. These limitations highlight the exploratory nature of our findings. TIF’s recommendation for multi-center cohorts to overcome single-center limitations in rare disease research—which is crucial for validating genotype-phenotype correlations—directly informs the direction of our proposed future studies.

Conclusions

This observational study highlighted thalassemia genotype severity and RBC product type as independent determinants of intertransfusion intervals in pediatric TDT patients, while RBC storage duration showed no significant impact. These findings underscore the multifactorial nature of transfusion efficacy in TDT management. Future prospective studies with larger cohorts and comprehensive socioeconomic data are warranted to refine clinical guidelines and improve patient outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-423/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-423/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-423/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-423/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Children’s Hospital, Zhejiang University School of Medicine, National Children’s Regional Medical Center, National Clinical Research Center for Child Health (approval No. 2025-IRB-0166-P-01). Informed consent was waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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