Role of therapeutic automated red cell exchange in patients with sickle cell crisis: Report of six cases from an Indian tertiary care center

INTRODUCTION

Sickle-cell anemia (SCA) represents the most severe and clinically significant form of sickle-cell disease (SCD), arising when an individual inherits two copies of the sickle b-globin variant (bS). SCD encompasses a group of hereditary hemoglobinopathies caused by mutations in the b-globin gene.^[1] In SCA, a single nucleotide substitution (A→T) in codon 6 of the b-globin gene results in the replacement of glutamic acid with valine, producing sickle hemoglobin S (HbS), which polymerizes under deoxygenated conditions and induces characteristic structural and functional alterations in RBCs.^[2,3] People with SCA often suffer significant health issues from both immediate and long-term complications. Without sufficient care, the most critical instances might pose a life-threatening risk during the early years.^[4] It is predominantly observed in individuals of Arabian, African, as well as Indian descent.^[5] SCD prevalence in India varies significantly by region. In North-eastern India, it ranges from 0% to 18%, while in Western India, it varies between 0% and 33.5%. Central India exhibits a higher prevalence, from 22.5% to 44.4%; in Southern India, it ranges from 1% to 40%.^[1,5,6] Earlier, blood transfusion was the primary method for treating sickle cell anemia, assisting in sustaining a hemoglobin (Hb) concentration of 9-9.5 g/dL.^[7] However, frequent blood transfusions can expose patients to risks such as alloimmunization, iron overload, and the potential for transmission of infectious diseases. Therefore, red cell exchange (RCE) is being done. In our article, we discuss six cases of SCD where an automated apheresis system was utilized for RCE.

MATERIALS AND METHODS

Automated RCE was performed for the six cases at our tertiary care center between May 2021 and June 2024. Blood samples have been received in our blood center for blood grouping, including extended phenotyping for Rh and Kell antigens, and antibody screening. Blood grouping was performed through gel column agglutination technique utilizing Bio-Rad DiaClon for all patient samples. Antibody screening and identification were conducted utilizing the Bio-Rad ID Dia cell I, II, III Asia (Mia+) 3-cell panel and the Bio-Rad ID Dia panel 11×4. None of the six cases exhibited the presence of any alloantibody. All the patients were diagnosed with sickle cell disease (SCD). Other relevant investigations, including serum electrolytes, liver function tests, complete blood count, as well as Hb electrophoresis, were also done. Hematologist’s opinion was sought, and as per their advice, it was decided that automated RCE would be performed on these patients. It was based on the clinical indications specified by the American Society for Apheresis (ASFA) Guidelines 2023. All six procedures were performed on the COM.TEC (Fresenius Kabi, Germany) apheresis machine along with a specific PL1 kit from the same manufacturer.

The automated apheresis system, powered by proprietary software (Version 04.03.08, COM.TEC), is designed for performing RCE procedures. To start the process, the required patient details, such as sex, height, body weight, and hematological values, are input into the machine. As per the ASFA guidelines, the target HbS level is used to determine the volume of RBCs to be exchanged. With a goal HbS level of <30%, the software calculates the required volume of RBCs for the exchange. Using the “Red Blood Cell (RBC) calculator” feature integrated into the software, the machine receives data on the hematocrit and volume of each packed RBC (PRBC) bag. Based on these inputs, the software then estimates the expected post-procedure hematocrit and HbS percentage.

Donor blood units within 5 days of collection, HbS negative, Rh- and Kell-matched, leukoreduced, crossmatch-compatible PRBC units were chosen for the procedure. The number of units needed was decided based on the individual calculated RBC volume of each patient. A double-lumen 16F central catheter has been introduced into either the internal jugular or femoral vein of the patients for venous access for the procedure. Throughout the procedure, the patient’s vital signs – such as blood pressure, respiratory rate, heart rate, and oxygen saturation – were continuously monitored. To counteract the effects of citrate from the administration of acid citrate dextrose (ACD), a continuous infusion of 10% calcium gluconate (30 mL in 100 mL of normal saline) was provided at a rate of 60 mL/h. RBC priming of the entire kit was done before initiation of the procedure for patient 6, who had a hemoglobin level less than 7 g/dL.

RESULTS

Table 1 provides comprehensive details of each procedure, including patient complaints, total blood volume, the volume of blood processed, the number of RBCs transfused, the average hematocrit of the RBC units used, and the volume of the anticoagulant ACD infused to the patient during the procedure.

Table 2 depicts the laboratory parameters for the six patients, both before and after the procedure.

Table 3 depicts the association between the pre-procedural and post-procedural parameters.

Following one cycle of the procedure, there was a drastic reduction in the HbS% for all the patients. Furthermore, the patients felt significant relief from their existing symptoms. The reduction in HbS% of all 6 patients following the procedure has been depicted in Figure 1.

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Figure 1:

Case-wise reduction in hemoglobin S% values.

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DISCUSSION

Acute symptoms of SCD include vaso-occlusive crises, which encompass stroke, splenic sequestration, intrahepatic cholestasis, acute chest syndrome, renal failure, priapism, as well as bone marrow necrosis/fat embolism syndrome.^[8] Although simple transfusions have long been a primary treatment for sickle cell anemia, frequent transfusions may result in problems like iron overload and alloimmunization in individuals with SCD. RCE transfusions are an effective, but occasionally underutilized, treatment for addressing both chronic and acute problems of SCD.^[9] RCE entails the extraction of aberrant RBCs from a patient’s bloodstream and their substitution using RBCs from a healthy donor, accomplished either manually or by an automated cell separator. This process is frequently used to reduce HbS concentration in patients having SCD who are experiencing complications, provide immediate relief from symptoms, and reduce post-operative complications.^[9,10] A key advantage of RCE in SCD is its iron neutrality, as the iron content in the removed HbS is comparable to that in administered normal HbA.^[9,10] RCE has been considered more efficient than simple transfusion for managing patients with SCD, multiorgan failure, or respiratory failure. In a retrospective cohort of children with SCD and first acute stroke, Hulbert et al.^[11] found that initial treatment with simple transfusion was associated with a 57% rate of recurrent stroke, compared to 21% in those treated with RCE (risk ratio = 5.0, 95% confidence interval = 1.3-18.6; P = 0.02) while in acute chest syndrome, Saylors et al. (2013)^[12] found that upfront RCE (15 episodes) significantly reduced clinical respiratory scores and WBC counts, whereas patients initially receiving simple transfusion who later required exchange (15 episodes) experienced significant increases in CRS and WBC, a fall in platelet count, and were the only group requiring mechanical ventilation, although overall length of stay and hospital charges were similar.”^[11,12] According to Aneke et al.,^[13] after receiving RCE for acute chest syndrome, the duration necessary for peripheral oxygen saturation recovery in ambient air decreased significantly, varying between 6 and 96 h.^[13] RCE therapy can be done as both a manual process and an automated process with the use of an apheresis machine. Various studies elaborate on the benefits of automated RCE over manual RCE, which include effective reduction of HbS RBCs, maintenance of blood volume through isovolemic transfusion, and minimization of both iron overload and hyperviscosity, and a quicker increment in the hematocrit.^[6,14] Investigation done by Tsitsikas et al.^[15] shows automated RCE is a safe procedure with minimal alloimmunization risks and no associated iron loading. Significant improvements have been observed in patients with recurrent painful crises, with benefits typically developing over time. Patients with leg ulcers and recurrent priapism have also shown notable clinical responses, and those with pulmonary hypertension have experienced excellent outcomes.^[15] The ASFA guidelines recommend RCE for managing sickle cell crises, categorizing it as a category I indication.^[16] Automated RCE was conducted on our patients to reduce the sickle cell burden by removing sickle cells and replacing them with allogenic donor red cells. This helped to reduce acute complications of SCD and to improve laboratory parameters. The decision to perform automated RCE was dependent on the availability of proper intravenous access, apheresis services, as well as the availability of leukoreduced, Rh- and Kell-matched, crossmatch-compatible blood products. This procedure also allowed for continuous patient monitoring while ensuring comfort and safety.^[6] Providing automated RCE is a crucial aspect of any specialized service managing SCD. Establishing an apheresis service involves investing in the necessary equipment and hiring qualified staff. However, automated RCE proves to be a cost-effective intervention by decreasing the need for iron chelation therapy and lowering the frequency of emergency hospital visits.^[15] Although RCE has been generally a safe process, patients are susceptible to transfusion-related adverse effects as well as complications related to apheresis. Potential risks include central venous catheter thrombosis, hemorrhage, and issues related to central catheter placement.^[17] Given the numerous documented benefits observed after just one cycle of exchange, and the similar positive outcomes demonstrated in our study, centers that can offer this service should consider initiating automated RCE, particularly for patients experiencing acute vaso-occlusive crises having SCD.

CONCLUSIONS

Automated RCE demonstrates significant advantages in managing SCD, especially in acute vaso-occlusive crises. Our case series highlights the effectiveness of RCE in promptly alleviating symptoms and improving laboratory parameters, while also mitigating long-term complications such as iron overload. The procedure offers a substantial benefit over simple transfusions, including reduced risk of alloimmunization and avoidance of iron accumulation. Although initial setup necessitates investment in apparatus as well as personnel, RCE proves to be an economical intervention by reducing the necessity for iron chelation therapy and minimizing emergency hospital visits. Given positive outcomes observed, centers equipped with the necessary resources should strongly consider incorporating automated RCE into their treatment protocols for SCD, particularly for patients in acute crises. This method improves patient care as well as conforms to contemporary standards and recommendations for optimal management of SCD.