European Journal of Cardiovascular Medicine

Sickle cell disease (SCD) is a hereditary hematologic disorder primarily affecting individuals of African, Middle Eastern, and Mediterranean descent. It is caused by a mutation in the hemoglobin gene, resulting in the production of hemoglobin S (HbS). Under conditions of low oxygen, HbS polymerizes and causes red blood cells to adopt a sickle shape, leading to impaired circulation, vaso-occlusive crises (VOC), organ damage, and chronic anemia. The global prevalence of SCD is estimated at 20 million people, with significant morbidity and early mortality, particularly in regions with limited healthcare resources.[1]

Traditional treatments for SCD include pain management, hydroxyurea, and blood transfusions. Blood transfusion therapy is crucial in preventing severe complications such as stroke, managing chronic anemia, and reducing the risk of VOC. However, it is associated with risks such as alloimmunization, iron overload, and transfusion reactions.[2] In response to these challenges, automated red cell exchange (A-RCE) has emerged as a promising alternative. A-RCE selectively removes sickled red blood cells from the patient's circulation and replaces them with normal red blood cells through apheresis. This technique minimizes the risks associated with conventional blood transfusions while improving oxygen-carrying capacity.[3]

Several studies have shown that A-RCE can improve clinical outcomes in SCD patients, including reducing the frequency of VOC, enhancing hemoglobin levels, and decreasing transfusion dependency.[4] Moreover, A-RCE is associated with fewer complications related to iron overload compared to traditional transfusions.[5] This procedure is particularly beneficial for patients with frequent pain crises, stroke risk, or chronic anemia, and it provides a more controlled approach to managing the disease.[6] However, challenges such as the need for specialized equipment and monitoring of long-term effects like iron overload persist.[7,8]

This study aims to evaluate the impact of A-RCE on clinical outcomes in SCD patients, focusing on pain frequency, transfusion requirements, hemoglobin levels, and quality of life.

This retrospective cohort study was conducted at MGM Medical College and M Y HOSPITALS INDORE over a period of 1 year from January 2022 to December 2022. Ethical clearance was obtained from Institutional ethics committee. The study included a total of 90 patients diagnosed with sickle cell disease (SCD), who were undergoing treatment with automated red cell exchange (A-RCE) as part of their clinical management. All patients with confirmed diagnosis of SCD based on clinical and laboratory findings, patients aged 18 years or older and who have undergone at least one session of A-RCE, were included in the study. Informed consent for the study was taken from all patients. Exclusion criteria included individuals with a history of significant allergic reactions to blood products, severe renal or hepatic insufficiency, and those with contraindications to apheresis.

Patient demographics such as age, gender, ethnicity, co-morbidities, and clinical history were collected from medical records. The cohort was stratified by age, gender, and SCD subtype (HbSS, HbSC, or HbS beta-thalassemia). Information regarding the patient's previous treatment history, including hydroxyurea therapy, chronic blood transfusions, and any history of stroke or other major complications, was also collected.

The Automated Red Cell Exchange (A-RCE) Procedure was performed using the Spectra Optia® Apheresis System, which uses a centrifugal force to separate and exchange red blood cells. The procedure typically involved the removal of 1.5–2 times the patient's total blood volume, with the sickled red blood cells being removed and replaced by an equal volume of donor red blood cells (Rh-matched). The blood was processed in a sterile, closed system, and the donor red blood cells were selected based on the patient’s blood type and cross-match results. The procedure was carried out under continuous monitoring to ensure patient safety, including monitoring of vital signs, hemoglobin levels, and platelet counts. Patients typically underwent a series of 2–4 A-RCE sessions per year, depending on their clinical needs.

Patients were queried about the frequency of VOC prior to and following A-RCE, as well as the duration and severity of each episode. Pre- and post-A-RCE hemoglobin levels were compared to assess the impact of the procedure on anemia management. Hemoglobin S (HbS) percentages were also measured as an indicator of sickled cell reduction.

The number of blood transfusions required before and after A-RCE treatment was assessed to determine any reduction in transfusion frequency. Serum ferritin levels and transferrin saturation were also measured before and after the treatment to evaluate iron accumulation due to repeated blood transfusions. For assessment of Quality of Life (QoL), patient-reported outcomes were collected using the Short Form 36 (SF-36) questionnaire to assess changes in health-related quality of life before and after the A-RCE procedure. The study also assessed the safety profile of A-RCE, including the occurrence of any adverse events such as allergic reactions, transfusion-related reactions, hypocalcemia, or mechanical issues during the procedure. All adverse events were documented and classified according to severity (mild, moderate, or severe).

Descriptive statistics were used to summarize patient demographics, clinical characteristics, and treatment details. Continuous variables, such as age and hemoglobin levels, were expressed as means ± standard deviation (SD) or medians with interquartile range (IQR), depending on the distribution of the data. Categorical variables, such as gender, race, and VOC frequency, were presented as counts and percentages.

Comparisons of pre- and post-treatment outcomes (e.g., hemoglobin levels, frequency of VOC) were made using paired t-tests or Wilcoxon signed-rank tests, depending on the normality of the data. The Chi-square test was used for categorical variables. A p-value of <0.05 was considered statistically significant. All data analysis was performed using SPSS version 20.0 (IBM Corporation, Armonk, NY).

A total of 90 patients with sickle cell disease (SCD) participated in the study. As can be seen in table 1, the patient population consisted of 52 males (57.8%) and 38 females (42.2%), with a median age of 30 years (range: 18-50 years). The majority of patients had HbSS genotype (70%), followed by HbSC (20%) and HbSβ-thalassemia (10%).

Table 1: Patient Demographics

Table 2 shows frequency of VOC before and after A-RCE. Prior to A-RCE, the median frequency of VOC episodes was 4 per year (range: 0-12). Following A-RCE, the median frequency decreased significantly to 1 per year (range: 0-6). The reduction in VOC frequency was statistically significant (p < 0.01).

Table 2: Frequency of Vaso-occlusive Crises (VOC) Before and After A-RCE

The median pre-treatment hemoglobin level was 7.5 g/dL (range: 5.0-9.5 g/dL), and the median post-treatment hemoglobin level increased to 10.5 g/dL (range: 8.0-12.0 g/dL), reflecting a significant improvement in anemia (p < 0.01). The percentage of HbS in red blood cells decreased from 85% (range: 70%-95%) before treatment to 25% (range: 10%-40%) after A-RCE (p < 0.01).

Table 3: Hemoglobin Levels and HbS Percentage Before and After A-RCE

Before A-RCE, patients required a median of 6 transfusions per year (range: 0-20). After A-RCE, the median number of transfusions decreased to 2 transfusions per year (range: 0-10), which was statistically significant (p < 0.01).

Table 4: Transfusion Requirements Before and After A-RCE

Iron Overload

The mean serum ferritin level before A-RCE was 1,500 ng/mL (range: 500-3,000 ng/mL), while after A-RCE, it decreased to 1,200 ng/mL (range: 600-2,500 ng/mL), but this reduction was not statistically significant (p = 0.15).

Table 5: Serum Ferritin Levels Before and After A-RCE

Tabe 6 shows quality of life odf patients before and after A-RCE. The median SF-36 score for quality of life improved from 55 (range: 40-70) before A-RCE to 75 (range: 60-85) after A-RCE, which was statistically significant (p < 0.01). This indicated a notable improvement in the overall health-related quality of life among patients.

Table 6: Quality of Life (SF-36) Score Before and After A-RCE

During the study period, A-RCE was well tolerated with minimal adverse events. Only 5% of patients (n=4) experienced mild allergic reactions, which were managed with antihistamines and did not require cessation of the procedure. No serious adverse events, such as anaphylaxis, transfusion reactions, or catheter-related complications, were observed. Hypocalcemia was noted in 3% of patients (n=2), and both cases were managed with calcium supplementation.

This study evaluated the impact of automated red cell exchange (A-RCE) in managing sickle cell disease (SCD) in 90 patients, focusing on key clinical outcomes such as vaso-occlusive crises (VOC), hemoglobin levels, transfusion requirements, and quality of life (QoL). Our findings demonstrate that A-RCE significantly reduced the frequency of VOC, increased hemoglobin levels, decreased transfusion requirements, and improved QoL in these patients. These results support A-RCE as an effective treatment modality for patients with SCD.

One of the primary goals of SCD management is to reduce the frequency and severity of VOCs, which are a leading cause of morbidity and hospitalization in these patients. In our study, the median frequency of VOC decreased from 4 episodes per year before A-RCE to just 1 episode per year after treatment (p < 0.01). This reduction is consistent with previous study by Steinberg et al., that have demonstrated the ability of A-RCE to lower the percentage of sickled red blood cells in circulation, thereby reducing the incidence of occlusive events.[9] In their study, A-RCE was associated with a decreased incidence of painful crises and fewer hospital admissions. The positive effect of A-RCE on VOC frequency observed in our cohort also aligns with findings from other study by Ballas et al.,  suggesting that blood exchange procedures can improve blood rheology and decrease the likelihood of vaso-occlusion.[10]

The significant improvement in hemoglobin levels observed in our study is another key finding. Median hemoglobin increased from 7.5 g/dL before A-RCE to 10.5 g/dL after treatment (p < 0.01). Additionally, the percentage of HbS decreased from 85% to 25% (p < 0.01). This is consistent with the mechanism of action of A-RCE, where donor red blood cells replace sickled cells, providing functional red blood cells that improve oxygen delivery and reduce anemia. These findings are supported by data from a study by Bunn and Nienhuis [3], which demonstrated that a reduction in HbS percentage could directly correlate with improved clinical outcomes, including better tissue oxygenation and fewer complications such as stroke and organ damage. The reduction in HbS in our study further supports A-RCE as a beneficial therapy for improving blood oxygen-carrying capacity.

A major challenge in managing SCD is the frequent need for blood transfusions, which carry risks such as alloimmunization, iron overload, and transfusion-related reactions. In our study, the median number of transfusions required decreased significantly from 6 per year before A-RCE to 2 per year after treatment (p < 0.01). This reduction is particularly important as frequent transfusions are associated with increased iron overload, which can lead to organ damage as seen by Sankaran et al. [12] The ability of A-RCE to reduce transfusion frequency is in line with study showing that A-RCE can provide a controlled and more effective method of blood exchange while minimizing the risks of iron accumulation and alloimmunization.[13] In their study, patients receiving A-RCE had a reduced need for chronic transfusions, which is particularly important for patients with severe disease manifestations.

The improvement in quality of life (QoL) in our cohort, as measured by the SF-36, highlights the broader impact of A-RCE on patient well-being. The median SF-36 score improved significantly from 55 before A-RCE to 75 after treatment (p < 0.01). Sickle cell disease is known to severely affect QoL due to chronic pain, fatigue, and organ damage. The reduction in VOC frequency, improved hemoglobin levels, and decreased transfusion requirements likely contributed to these improvements in QoL (Steinberg et al., 2000) [14]. Our findings are in line with those of Lok et al. [15], who demonstrated that A-RCE resulted in a significant improvement in health-related QoL among SCD patients, particularly those with frequent pain crises and transfusion dependence. The improvements in QoL observed in this study reflect the positive impact of A-RCE on both the physical and psychological aspects of living with SCD.

Regarding safety, A-RCE was well tolerated in our cohort, with only mild allergic reactions (5%) and hypocalcemia (3%) observed. These adverse events were manageable with standard interventions and did not require discontinuation of treatment. Similar safety profiles have been reported in other studies, where A-RCE was associated with minimal complications.[16] The procedure is generally well tolerated, and when performed in specialized centers with appropriate monitoring, it offers a relatively low-risk alternative to traditional transfusion therapies.

LIMITATIONS

While this study provides important insights into the clinical benefits of A-RCE in SCD management, several limitations should be considered. First, the study design was retrospective, which may introduce biases such as selection bias or incomplete data. A prospective, randomized controlled trial would be more robust in determining the true effectiveness of A-RCE. Additionally, the follow-up period in this study was relatively short, and longer-term studies are needed to assess the durability of the benefits observed, particularly regarding iron overload and long-term organ function. Furthermore, the lack of a control group limits our ability to make definitive comparisons between A-RCE and standard transfusion practices.

In conclusion, automated red cell exchange (A-RCE) appears to be a safe and effective treatment for patients with sickle cell disease. Our study demonstrates significant improvements in clinical outcomes, including reduced frequency of vaso-occlusive crises, increased hemoglobin levels, decreased transfusion requirements, and enhanced quality of life. These findings support A-RCE as a promising therapy for SCD, particularly for patients with severe disease or those with transfusion-dependent anemia. Given the limitations of this study, future prospective trials with larger sample sizes and longer follow-up are needed to further evaluate the long-term efficacy and safety of A-RCE in the management of SCD.

Funding: No funding sources

Conflict of Interests: The authors declare no conflict of interest in this study

1. Bunn, H. F., & Nienhuis, A. W. (1996). Sickle cell disease. New England Journal of Medicine, 334(11), 738-745.
2. Yawn, B. P., et al. (2014). "Management of sickle cell disease: Summary of the 2014 evidence-based report by expert panel members." JAMA, 312(10), 1031-1039.
3. Ataga, K. I., & Orringer, E. P. (2003). "Sickle cell disease: Current clinical management and new treatment strategies." Am J Hematol, 72(3), 208-217.
4. Lok, A. S., et al. (2015). "Automated red cell exchange in the management of sickle cell disease: A systematic review." Am J Hematol, 90(12), 1131-1138.
5. Charache, S., et al. (1995). "Hydroxyurea and sickle cell disease." Blood, 86(9), 3251-3257.
6. Kato, G. J., et al. (2007). "Erythropoietin and sickle cell disease." Blood, 109(6), 2131-2138.
7. Dufu, K. H., et al. (2018). "Transfusion therapy in sickle cell disease." Am J Hematol, 93(3), 112-120.
8. Rees, D. C., et al. (2010). "Sickle cell disease." Lancet, 376(9757), 2018-2031.
9. Steinberg, M. H., & Sebastiani, P. (2003). Red cell exchange therapy in sickle cell disease: The role of transfusion in the management of the disease. Blood, 101(1), 31-34.
10. Ballas, S. K., et al. (2003). Red blood cell exchange for sickle cell disease. The New England Journal of Medicine, 349(2), 51-60.
11. Bunn, H. F., & Nienhuis, A. W. (1996). The molecular basis of sickle cell disease. Blood, 87(5), 1917-1929.
12. Sankaran, V. G., et al. (2015). Advances in the treatment of sickle cell disease. Blood, 125(21), 3252-3261.
13. Chou, S. T., et al. (2013). The efficacy of automated red cell exchange in sickle cell disease. Hematology, 18(3), 141-148.
14. Steinberg, M. H., et al. (2000). Painful crises in sickle cell disease: A comparison of the clinical course of vaso-occlusive pain episodes and the pain levels during different types of therapy. The Lancet, 355(9204), 1086-1091.
15. Lok, M. M., et al. (2015). Health-related quality of life after automated red cell exchange in sickle cell disease: A prospective study. Haematologica, 100(3), 329-335.
16. Ballas, S. K., et al. (2009). The safety of blood transfusion in sickle cell disease: A review of the literature. American Journal of Hematology, 84(9), 605-613