|Year : 2021 | Volume
| Issue : 2 | Page : 171-177
Alloimmunization to erythrocyte antigens in patients receiving multiple blood transfusions: Clinico-immunohematological and demographic risk factors and impact of extended red cell phenotyping
Sudipta Sekhar Das, Rathindra Nath Biswas, Mahammad Safi, Rafique Uz Zaman
Department of Transfusion Medicine, Apollo Gleneagles Hospitals, Kolkata, West Bengal, India
|Date of Submission||21-Jun-2021|
|Date of Decision||19-Aug-2021|
|Date of Acceptance||17-Sep-2021|
|Date of Web Publication||30-Nov-2021|
Dr. Sudipta Sekhar Das
Department of Transfusion Medicine, Apollo Gleneagles Hospitals, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
Background and Objectives: The risk of red blood cell (RBC) alloimmunization is always a concern for multi-transfused patients. Various factors have been found to be associated with alloimmunization. Alloimmunization rates were reported from 4% to 50%, 1.9% to 13% and 1.27% to 13.1% in thalassemic, onco-hematology and renal patients respectively. Transfusion of extended phenotype-matched blood was found to reduce rate of alloimmunization. This study investigated the various risk factors associated with RBC alloimmunization and the impact of transfusing phenotype-matched PRBC to multi-transfused patients. Methods: The retrospective observational study included 4350 multi-transfused patients of hemoglobinopathies, onco-hematological diseases and chronic renal failure (CRF). Pre-transfusion testing that included ABO and Rh(D) typing, antibody screening and crossmatching were performed following departmental standard operating procedure (SOP). Rh (C, c, E, e) and Kell (K) antigen phenotyping of blood donors as well as patients were performed by recommended techniques. Statistical analysis was done using the SPSS statistical package. Results: The mean age of multi-transfused patients was 41.4 years with a female preponderance. A total of 122 alloantibodies with various specificities were found in the 4350 patients (2.8%). Anti-E was the most frequent alloantibody (27.87%) followed by anti-c (11.48%). Frequency of alloimmunization in patients with hemoglobinopathies receiving phenotype-matched blood was 1.89% which was significantly lower than those receiving phenotype-unmatched blood (p=0.0019). Gender, age, splenomegaly status, number of PRBC unit transfused, phenotype-matched status, and transfusion duration in years were independent risk factors of alloimmunization. Conclusion: Alloimmunization to red blood antigens challenge the proper management of multi-transfused patients. Based on the present results we suggest considering antibody screening as an important tool of pre-transfusion testing to ensure safe blood transfusion. It will be prudent to adopt a transfusion policy that provides at least the Rh-Kell phenotype-matched blood to minimize red cell alloimmunization among multi-transfused patients.
Keywords: Alloantibody, alloimmunization, multiple transfusion, phenotype-matched, risk factor
|How to cite this article:|
Das SS, Biswas RN, Safi M, Zaman RU. Alloimmunization to erythrocyte antigens in patients receiving multiple blood transfusions: Clinico-immunohematological and demographic risk factors and impact of extended red cell phenotyping. Glob J Transfus Med 2021;6:171-7
|How to cite this URL:|
Das SS, Biswas RN, Safi M, Zaman RU. Alloimmunization to erythrocyte antigens in patients receiving multiple blood transfusions: Clinico-immunohematological and demographic risk factors and impact of extended red cell phenotyping. Glob J Transfus Med [serial online] 2021 [cited 2022 Jan 18];6:171-7. Available from: https://www.gjtmonline.com/text.asp?2021/6/2/171/331617
| Introduction|| |
Blood component transfusion is an integral part of patient management in modern medicine. Packed red blood cell (PRBC) transfusion is required regularly in transfusion-dependent patients such as hemoglobinopathies, oncohematology, and renal ailments such as chronic renal failure (CRF). The risk of erythrocyte or red blood cell (RBC) alloimmunization is always a concern for patients receiving frequent PRBC transfusions. RBC alloimmunization or the formation of antibodies against non-self antigens on transfused RBCs may occur through exposure of blood transfusion or pregnancy. Various causes of alloimmunization such as genetic, immunological, demographic immunohematological, and clinical have been described by previous authors.,,,
Alloantibodies may be clinically significant, leading to haemolytic transfusion reaction, acute or delayed or serologic transfusion reactions, leading to decrease survival of transfused RBCs or hemolytic disease of the fetus and newborn. Such antibodies often cause difficulty in finding compatible blood for transfusion, and managing inventory in the face of extended cross-matching further posees serious challenges.
The frequency of alloimmunization in multitransfused patients has been observed to be variable in different studies. Alloimmunization rates were reported from 4% to 50%, 1.9% to 13%, and 1.27% to 13.1% in thalassemic, oncohematology, and renal patients, respectively.,,,, The most frequent alloantibodies in chronically transfused patients are those against antigens of the Rh and Kell systems. These findings have suggested the performance of RBC typing for at least the Rh (C, c, E, and e) and Kell antigens in both donors and recipients to reduce the rate of alloimmunization.,,,
Aims and objectives
This study investigated the various risk factors associated with red cell alloimmunization in patients receiving multiple blood transfusions, the frequency and specificity of alloantibodies in these patients, and the impact of transfusing phenotype-matched PRBC to multitransfused patients.
| Materials and Methods|| |
Study design and patient selection
The retrospective observational study from April 2015 to March 2020 included 4350 registered patients who received multiple transfusions in our tertiary care hospital. Due ethical clearance was obtained from the hospital Ethics committee to conduct the study. Three major pathological conditions needing multiple transfusions, namely, hemoglobinopathies (thalassaemia and sickle cell disease [SCD]), oncohematological diseases, and CRF were included in the study. Patients receiving more than two episodes of PRBC transfusion were defined as multitransfused. Patients with autoantibodies or alloantibodies due to pregnancy were excluded from the study. Details of each patient were obtained from the hospital information system and the blood center immunohematology register.
As patients of hemoglobinopathies (N = 600) received phenotype-matched blood (C, c, E, e, and K antigen) from October 1, 2017 as institutional policy, the total study period in this category was divided into two periods. The period from April 2015 to September 2017 (30 months) has been termed as phenotype-unmatched period and that from October 2017 to March 2020 (30 months) as phenotype-match period.
For patients requiring PRBC transfusion, complete blood requisition along with adequate blood samples in ethylenediaminetetraacetic acid and clotted vial was received in the hospital blood centre for pretransfusion testing. Pretransfusion testing that included ABO and Rh (D) typing, antibody screening, and crossmatching were performed following departmental standard operating procedure. The minimum interval between last transfusion episode and an antibody screen was 72 h. The various investigations included the following:
- ABO and Rh (D) typing was performed by column agglutination technology (CAT) (Ortho-Clinical Diagnostics, USA) following manufacturer's instructions
- Antibody screening for all patients and identification whenever required were performed by CAT using commercial cell panels and polyspecific Coombs gel cards (BIO-RAD, Cressier s/Morat, Switzerland)
- All cross matches were done by CAT using polyspecific Coombs gel cards (BIO-RAD, Cressier s/Morat, Switzerland)
- Rh (C, c, E, and e) and Kell antigen phenotyping of blood donors as well as patients with hemoglobinopathies were performed by CAT using special Coombs gel cards impregnated with the corresponding antibody (BIO-RAD, Cressier s/Morat, Switzerland)
- For patients carrying antibody/antibodies PRBC units negative for the corresponding antigen were selected using specific anti-sera (Ortho-Clinical Diagnostics, USA).
Statistical analysis was done using the SPSS statistical package (IBM, 2015, Armonk, New York, USA). All values were captured in the MS office excel sheet and statistically analyzed. Discrete categorical data were presented as n (%), and comparison of categorical data was made by Chi-square test. All reported P values were two-sided with a significance level < 0.05. Multivariate logistic regression was analyzed to identify independent significant risk factor by Odds Ratio.
| Results|| |
This study included 1506 (34.62%) males and 2844 (65.38%) females. The male: female ratio was observed to be 1:1.9. The mean age of multitransfused patients in the study was 41.4 years, with 1625 (37.36%) in 104 (2.39%) patients. Multiple (≥2) alloantibodies were observed in 15 (14.42%) alloimmunized patients. Out of 104 alloimmunized patients, 55 (52.9%) were ≤40 years with a mean age of 32.1 years. A mean age of 18.4 years was observed in the 30 alloimmunized hemoglobinopathy patients.
[Table 1] shows the specificity and frequency of alloantibodies in the patients. A total of 122 alloantibodies with various specificities were found in the 4350 patients (2.8%). Anti-E was the most frequent alloantibody (27.87%), followed by Anti-c (11.48%). The highest incidence of alloimmunization was detected against the Rh system (57.38%), followed by MNS system (13.92%). Anti-Ina was found in 2 (1.64%) patients suffering from thalassemia.
|Table 1: Specificity and frequency of alloantibodies in multi-transfused patients|
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Frequency of alloimmunization in patients with hemoglobinopathies receiving phenotype-matched blood was 1.89% which was significantly lower than those receiving phenotype-unmatched blood (P = 0.0019). Anti-E and anti-c were the common alloantibodies observed in both these groups of patients [Table 2].
|Table 2: Rh-Kell antibody specificity and frequency in patients with hemoglobinopathies receiving phenotype-matched and phenotype-unmatched blood (n=600)|
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[Table 3] summarizes the various factors associated with alloimmunization. Demographically, alloimmunization was significantly higher in females compared to males (2.9% vs. 1.33%, P = 0.0008), and it was noted more in patients with age ≤40 years (P = 0.0009). Immunohematologically, significant alloimmunization was observed in patients receiving >10 units PRBC transfusion (P = 0.0002), patients transfused with phenotype-unmatched blood (P = 0.0019), and patients with transfusion duration more than 5 years (P = 0.0188). On evaluating the clinical risk factors, significant alloimmunization was noted in patients with splenomegaly (P = 0.0002). Out of 4350 patients, 2450 (56.32%) suffered from oncohematological diseases, followed by 1300 (29.89%) with CRF. No significant association was found between the disease type and alloimmunization. Alloimmunization in hemoglobinopathy, oncohematology, and CRF patients was observed to be 5%, 2.25%, and 1.46%, respectively. Multivariate logistic regression analysis showed that gender, age, splenomegaly status, number of PRBC units transfused, phenotype-matched status, and transfusion duration in years were independent risk factors of alloimmunization [Table 4].
|Table 3: Demographic, clinical and immunohematological factors associated with alloimmunization in transfused patients (n=4350)|
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|Table 4: Multivariate logistic regression analysis to identify independent significant risk factors for alloimmunization (n=104)|
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| Discussion|| |
Factors affecting alloimmunization and frequency of alloimmunization in a population have been discussed globally. Data and statistics on alloimmunization varied regionally and nationally. A paucity of data on RBC alloimmunization in multitransfused patients from the eastern region of India has been observed. Therefore, we conducted this study to share an overall knowledge of alloimmunization in our multi-transfused patient population.
The prevalence of alloimmunization in the present study was 2.8% [Table 1] which could be compared with previous Indian studies. Agarwal et al. and Thakral et al. reported alloimmunization rate of 2.71% and 3.4%, respectively, in their transfused patient population., Other authors from different parts of India observed alloimmunization rate varying from 1.4% to 8.6%.,,,,,, Lower rate of alloimmunization in a patient population may be due to population homogeneity which explains the presumed high phenotypic compatibility between blood donors and the patients. Studies on alloimmunization in various European countries reported variable prevalence from 5% to 10%., Rate of alloimmunization up to 60%–70% of multitransfused patients was also reported before.,,
We found that the most common antibodies were against the Rh system (57.38%), which was similar to previous reports.,,,, While Anti-E was the most prevalent antibody (27.87%) followed by anti-C (11.48%), previous workers also reported anti-E as the most common.,,, On the contrary, Thakral et al. and Datta et al. reported anti-C prevalence of 38.8% and 28.57%, respectively, followed by anti-E., On obtaining a detailed transfusion history and pregnancy history from the alloimmunized patients, it was found that the seven Rh (D) negative patients who developed Anti-D had received transfusions in rural hospitals elsewhere on five to ten occasions. No documented laboratory and transfusion reports were available from these patients. High rate of alloimmunization in the Rh system may be explained by the fact that this system is the most immunogenic. The second most prevalent antibody was against MNS system (13.92%) which correlated with 11.1% prevalence reported by Thakral et al. In the MNS system, five antibodies were IgG type, two mixed type, and others were IgM type. The prevalence of anti-K was observed to be variable in the previous studies. We observed an Anti-K prevalence of 2.46%, which correlated with Cheng et al. Low prevalence of Anti-K in our study could be due to low frequency of Kell antigen in the Indian population as described by Basu et al. The current study observed anti-Duffy and anti-Kidd frequency of 6.56% and 7.38%, respectively, which correlated with Cheng et al. We observed Lewis alloantibodies in 11 (9.02%) patients with 6 of them clinically significant and optimally reactive at 37°C. Clinically significant IgG type or mix/high thermal amplitude Lewis alloantibodies were detected by previous workers carrying potentiality of hemolytic transfusion reaction., The current study observed anti-Ina in two thalassemia patients. Although the frequency of Ina antigen in the Eastern India population is unknown, previous authors reported an Ina antigen frequency of 3% in other Indian states., Anti-Ina identification was possible with the “O” negative Ina cells which were procured from another blood center.
We observed a significant reduction in alloimmunization in the phenotype-matched period (2017–2020) (P = 0.0019). Few previous studies showed no difference in alloimmunization rates on transfusing closer antigen-matched blood., However, many agree that extended red cell typing beyond the routine ABO/D typing has a beneficial effect on the incidence of alloimmunization in multi-transfused patients.,, Despite transfusing phenotype-matched PRBC units, patients in the current study developed antibody/antibodies against antigens that were absent in the transfused red cells. Such unusual immunogenic response may occur because production of RBC antibodies depends on genetic and acquired patient-related factors, antigen frequency in the population, dose and number of transfusions, immunogenicity of the RBC antigen, sensitivity of the test performed, and many more factors.
The current study observed a significant association between the rate of alloimmunization and patient's demographic, clinical, and immunohematological factors. Alloimmunization in females and those patients who were ≤40 years of age was significantly higher (P < 0.001). Previously published reports showed significant association of gender and age with RBC alloimmunization.,,, Higher rate of alloimmunization was observed in patients with splenomegaly, patients who received more than 10 units PRBC transfusions, patients of the phenotype-unmatched period (2015–2017), and those patients where transfusion duration was >5 years (P < 0.05).
RBC allosensitization is more likely in patients with increased frequency and duration of blood transfusion., Like our observation, Qidwai et al. reported a higher alloimmunization rate among patients who had splenomegaly. Uptake of transfused RBCs by splenic macrophages and dendritic cells, and subsequent presentation of RBC as immunogens under certain conditions, such as inflammation, results in allosensitization. In the present study, no significant association was observed between splenectomy and the development of alloantibodies. This may be due to less number of splenectomized patients in the study. While Pahuja et al. reported such association as insignificant; Singer et al. reported a higher alloimmunization rate among splenectomized thalassemics and attributed this to the absence of an efficient filtering system for removal of damaged or senescent red cells which may explore new antigens., Donor RBC phenotyping for Rh (D, C, E, c, and e) and Kell is necessary to avoid alloimmunization and stop unwanted clinical consequences in multi-transfused patients. Castro et al. reported a drop in the rate of alloimmunization from 3% to 0.5% when SCD patients were transfused only with phenotype-matched RBC. While previous authors reported significant alloimmunization in thalassaemia; we found no significant association between disease type and alloimmunization.,,,
We analyzed the predictors of alloimmunization through multivariate logistic regression and found factors such as gender, age, splenomegaly status, number of transfused red cell units, phenotype-matched status, and blood transfusion duration as independent predictors of alloimmunization in multitransfused patients (P < 0.05) [Table 4]. While gender was not a statistically significant independent predictor of alloimmunization in their multi-transfused SCD patients; however Murao and Viana. found that a higher number of transfusions and older age could independently predict alloimmunization in these patients.
| Conclusion|| |
Alloimmunization to red blood antigens challenges the proper management of multi-transfused patients. Most alloantibodies detected in the present study were clinically significant. Based on the present results and available literatures, we suggest considering antibody screening as an important tool of pretransfusion testing to ensure safe blood transfusion. As the most frequent alloantibodies were against Rh, Kell, MNS, and Lewis systems, therefore in resource-poor settings, it will be prudent to adopt a transfusion policy that provides at least the Rh-Kell phenotype-matched blood to minimize red cell alloimmunization among multi-transfused patients. We observed that patient age, gender, spleen status and other immunohematological factors carry increased risk of alloimmunization or may be independent predictor of alloimmunization. Further large and multi-centric studies for verification and explanation of these observed phenomenon are required which will help to formulate balanced, cost-effective, and universal guidelines that will help in minimizing alloimmunization in chronically transfused patients.
We would like to thank Dr. Sanmukh R. Joshi of Lok Samarpan Blood Bank and Research Centre, Surat, Gujarat, India, for his guidance and great support in procuring the Anti-Ina serum as well as “O” negative Ina cells.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]