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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 35  |  Issue : 1  |  Page : 34-40

Red-blood cell alloimmunization in a cohort of multitransfused β-thalassemic patients in Menoufia Governorate, Egypt


1 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Pediatrics, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission29-May-2021
Date of Decision08-Jul-2021
Date of Acceptance11-Jul-2021
Date of Web Publication18-Apr-2022

Correspondence Address:
Amira S Elmaghraby
Shebein El Kom, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_106_21

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  Abstract 


Objective
We aimed to find out the frequency of alloimmunization in multitransfused β-thalassemic patients, the most common alloantibodies involved, factors contributing to their development, and their impact on severity of the disease.
Background
Thalassemia is a major health problem in Egypt. It is an inherited hemolytic disorder. Blood transfusion, despite being a life-saving process, it is associated with inherent risks of alloimmunization against red-blood cell antigens.
Patients and methods
Blood samples from 200 multitransfused β-thalassemic patients who were regularly transfused with leukodepleted packed red-blood cells, matched only for ABO-Rh (D) antigens, were analyzed. The antibody screening and identification were performed by column-agglutination method. To detect autoantibodies, autocontrol and direct antiglobulin test was carried out in all patients. Adsorption test was not employed as there were not autoantibodies detected in any patient.
Results
Alloantibodies were detected in 18/200 (9.0%) patients. The most frequent alloantibodies were anti-Kell system (50%), Rh system (anti-D and anti-E are 16.75% for each). Alloimmunization significantly differed with gender, ABO and Rh blood group, frequency of blood transfusion, age at first transfusion, the number of blood units transfused, and serum ferritin (P < 0.01).
Conclusion
Alloimmunization was detected in 9.0% of patients. Most alloantibodies were anti-Kell followed by anti-Rh system. Serum ferritin level was significantly high in alloimmunized patients, which impacts on the severity of the disease. Antibody screening has to be done before each transfusion and extended red-cell phenotyping must be performed once diagnosed to prevent complications.

Keywords: alloimmunization, antibody identification, multitransfused, thalassemia


How to cite this article:
Essa ES, El-Hawy MA, Ahmedy IA, Elmaghraby AS. Red-blood cell alloimmunization in a cohort of multitransfused β-thalassemic patients in Menoufia Governorate, Egypt. Menoufia Med J 2022;35:34-40

How to cite this URL:
Essa ES, El-Hawy MA, Ahmedy IA, Elmaghraby AS. Red-blood cell alloimmunization in a cohort of multitransfused β-thalassemic patients in Menoufia Governorate, Egypt. Menoufia Med J [serial online] 2022 [cited 2024 Mar 29];35:34-40. Available from: http://www.mmj.eg.net/text.asp?2022/35/1/34/343089




  Introduction Top


Thalassemia is considered the most common genetic disorder worldwide. Eighty–ninety (1.7%) million people of the global population, are now carrying β-thalassemia alleles in their genetic makeup. Up to 60 000 children show clinical symptoms and require hospital care [1].

In Egypt, the carrier rate varies between 5.5% and more than 9%. It is rated that there are 1000/1.5 million per year live births born with β-thalassemia [2].

Lifelong red-blood cell (RBC) transfusion is still the main treatment for severe forms of thalassemia [3].

Alloimmunization to RBC antigens is an immune response often stimulated by transfusion of RBC products. After exposure to foreign RBCs, antibodies, which are usually immunoglobulin G, will be produced. These immunoglobulin G antibodies will sensitize the transfused red cells in the patient blood and may cause their damage. Antibodies to many of red cells could be clinically significant, as they can enhance accelerated destruction of RBCs carrying the corresponding antigen and these antibodies can be retained for years [4].

One of the most important adverse reactions to blood transfusion is the development of alloimmunization in the recipient to the antigenic components of the transfused blood [5]. Generally, 10–30% of multitransfused patients have red-cell antibodies [6].

Furthermore, clinically significant RBC antibodies shorten the survival of transfused red cells [7].

Hemolytic transfusion reactions due to non-ABO antibodies have been the second or third leading cause of transfusion-associated death reported to the FDA over the last 5 years; in addition to mortality, RBC alloantibodies may lead to morbidity in the form of bystander hemolysis and renal failure. Patients with multiple RBC alloantibodies or antibodies against high-incidence antigens may experience complications of anemia due to lengthy delays prior to the location of compatible RBC units for transfusion; some may even die if compatible RBCs cannot be detected [8].

Antibody screening and identification are fundamental for selection of suitable blood for transfusion as multiple blood exposure contributed to the problem of alloimmunization [9].

Therefore, our goal in this study was to detect the frequency of alloimmunization, factors contributing to its development, and its impact on severity of the disease. So that our current transfusion policies can be reviewed and modified accordingly.


  Patients and methods Top


This study was conducted at the blood banking unit of Menoufia University Hospital during the period of April 2018 and August 2020 after informed consent was obtained from each subject or his or her legal guardians before enrollment in the study and after approval of the Menoufia University Research Ethics Committee, which is a member of Egyptian Network Research Ethics Committee.

EDTA blood (fresh nonhemolyzed samples) of 200 multitransfused β-thalassemic patients was withdrawn. Patients were with age from 3 to 24 years old. Patients were regularly transfused with leukodepleted packed RBCs of more than 10 U of packed RBCs. Data that included patients' age, sex, blood group, age at the start of transfusion, the number of blood units received, and status of spleen and ferritin level, were collected.

Using standard blood banking methods, plasma was separated and analyzed to detect antibodies to RBC antigens. Plasma was tested for the presence of alloantibodies using commercial three-cell panel, SeraScan Diana3 (Diagnostic Grifols, Barcelona, Spain) with homozygous expression of the antigens. Autocontrol and direct antiglobulin test were done parallel with antibody screening test by using microtube gel card with polyspecific anti-human globulin (Diagnostic Grifols) to detect the presence of any autoantibodies. Any sample with positive antibody screen was subjected to antibody identification. A commercial Identisera Diana (Diagnostic Grifols) 1–11, with known antigens against the patient's sample, performed the antibody-identification test. The tests were done using the gel card method, as per the manufacturer's guidelines. Adsorption by autogenic RBCs was not needed to be employed to remove autoantibodies as dual positivity of antibody screening and autocontrol was not detected in any sample.

Statistical analysis

Data were statistically analyzed using SPSS (Statistical Package for Social Science) program, version 19, for Windows (SPSS Inc., Chicago, Illinois, USA), and for all analyses, a P value less than 0.05 was considered significant (S), P value less than 0.01 was considered highly significant (HS), and P value more than 0.05 was considered nonsignificant. Data were shown as mean, median, range, frequency, and percent. χ2 test was done for qualitative-variable analysis. Student t test was done for normally distributed variables. A two-way analysis of variance is used to assess how the mean of a quantitative variable differs according to the levels of two categorical variables. Use a two-way analysis of variance when we want to know how two independent variables, in combination, affect a dependent variable.


  Results Top


Out of the 200 patients, 111 (55.5%) were males and 89 (44.5%) were females; their ages ranged from 3 to 24 years with a mean age of 9.77 ± 4 years. The ABO blood groups of the patients were as follows: 90 (45.0%) patients had blood group A, 68 (34.0%) had blood group O, 29 (14.5%) had blood group B, and 13 (6.5%) had blood group AB. The Rh blood group of patients were 195 (97.5%) positive, and five (2.5%) D negative. In a total of 200 patients, 167 (83.5%) were β-thalassemia major and 33 (16.5%) were β-thalassemia intermediate. With regard to the spleen state, 52 (26.0%) patients were splenectomized and 148 (74.0%) were not. As regards the frequency of blood transfusion, the mean frequency was 12 U/year, patients who transfused with more than or equal to 12 U/year were 167 (83.5%), and patients who transfused with less than 12 U/year were 33 (16.5%) [Table 1].
Table 1: Distribution of the studied patients as regards general data

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By using antibody screening tests and autocontrol, alloantibodies were detected in 18/200 (9.0%) patients. Out of 18 alloimmunized patients, anti-Kell was detected in nine (50%) patients followed by anti-Rh (D) and anti-Rh (E), each was in three (16.75% for each) patients, anti-duffy in one (5.50%) patient, one patient with both anti-CW and anti-KPa (5.50%), and another patient with anti-CW, anti-KPa, and anti-Luth (5.50%). The results of autocontrol were negative, so autoantibodies were not detected in any patient [Table 2].
Table 2: Distribution of alloantibodies and autoantibodies in the study group

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Regarding the age of patients, we stratified our patients into three age groups, the first was less than 6 years old, the second was from 6 to 12 years old, and the third was more than 12 years old, and we detect that the frequency of alloimmunization in each group was in the following order, respectively: 11.1, 55.6, and 33.3% (P > 0.05). Regarding gender, out of eighteen alloimmunized patients, 12 were females, 66.7%, and six were males 33.3% (P < 0.01). About blood grouping, there was a highly significant difference with alloimmunization (P < 0.01). Among alloimmunized patients, blood group O represented (44.4%) followed by group A (38.8%) and anti-D was detected in three out of 18 alloimmunized patients who were Rh negative. As regards the spleen state, there was no significant association with alloimmunization (P > 0.05). The age at first transfusion significantly differed with alloimmunization as the frequency of alloimmunization appeared to be greater in patients who started transfusion therapy after 1 year of life, 88.9%, than patients who started transfusion therapy before 1 year of life, 11.1% (P < 0.01) [Table 3].
Table 3: Comparing qualitative data as regards alloimmunization

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As regards severity of the disease, alloimmunization frequency was significantly higher in β-thalassemia-major patients 14/18 (77.8%) than β-thalassemia intermediate 4/18 (22.2%). Regarding the total number of RBC units transfused, alloimmunized patients showed significantly higher mean of RBC units, transfused 154 U, than nonalloimmunized patients, 108 U (P < 0.01). In alloimmunized patients, the range of the total number of RBC units transfused were 56–330 U, with mean and median, 154 and 112, respectively. Among the 18 alloimmunized patients, 13 (72.2%) had received more than median 112 U compared with five (27.2%) who had received less than median 112 U. Furthermore, ferritin level was significantly higher in alloimmunized patients than nonalloimmunized patients (P < 0.01) [Table 4],[Table 5],[Table 6].
Table 4: Comparison between alloimmunized and nonalloimmunized patients with different data

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Table 5: Total number of red-blood cell unit transfused incidence in alloimmunized patients

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Table 6: Relation between alloimmunization and ferritin in different types of thalassemia

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  Discussion Top


In this study, we investigated 200 thalassemic patients for alloimmunization. Patients were regularly transfused with leukodepleted packed RBCs. Our results revealed that 18/200 (9.0%) patients were alloimmunized, 16/200 (8.0%) patients develop one alloantibody, 1/200 (0.5%) patients develop two alloantibodies, and 1/200 (0.5%) patients develop three alloantibodies. The most frequent alloantibody was anti-Kell followed by Rh (anti-E and anti-D).

Our findings were in accordance with many reported studies in which alloimmunization were Bashawri et al. [10], 11%, Haslina et al. [11], 8.6%, both Shamsian et al. [12], Ho et al. [13], 7.4%, and Karimi et al. [14], 5.3%.

However, Sadeghian et al.[15] recorded a lower frequency of alloimmunization in thalassemic patients, 2.87%. This center had succeeded in reducing the rate of alloimmunization because it adopted the policy of D-antibody conformation on all RBC units labeled Rh negative.

Some studies done in countries with variable ethnic groups had shown a higher percentage of alloimmunization. Singer et al. [3], in the United States, reported an alloimmunization percentage of 20.8%. Abdel Gader et al. [16], on thalassemic and sickle-cell patients, reported 22%. According to Ameen et al. [17], in Kuwait, it was 30%, and according to Hassan et al. [18], it was 22.7% in Pakistan.

Different factors could explain this heterogenicity in the rate of alloimmunization among B-thalassemic patients in many centers worldwide. First, the homogeneity of RBC antigens between the blood doners and recipients. Second, most of blood donors and recipients are from the same ethnic group, accordingly, reducing the racial differences between donors' and recipients' RBC phenotypes. Third, the young age of some patients affects the percent of alloimmunization as the transfusion at an early age (<1–3 years old) may generate some immune tolerance and guard against alloimmunization in thalassemia patients [19]. Last, leukodepletion reduces alloimmunization owing to the fact that removal of leukocytes reduces alloimmunization to allogenic blood products [3].

The immunomodulatory role of white-blood cells (WBCs) in donated blood could have participated in the high incidence of alloantibodies. WBCs in blood components may enhance B-cell function that may result in increased alloimmunization to RBC antigens [20]. However, the long-term storage of leukodepleted blood before transfusion can lead to alloimmunization due to apoptosis of residual WBCs with subsequent release of immunostimulatory white-cell antigens and soluble biologic mediators from the dying cells, such as nuclear matrix protein and CTLA-4 epitopes (cytotoxic T-lymphocyte antigen 4), resulting in sensitization of the recipients and therefore, lead to development of alloantibodies and autoantibodies. Therefore, storage time should be optimized for prevention of WBC apoptosis [21].

We investigated autoantibodies in our patients by autocontrol. We found no autoantibodies in any patient. However, Dahlia et al.[22] found autoantibodies in only one patient. The pathogenesis of RBC autoantibody production after transfusion is not well understood. However, it was assumed that alloantibody binding to RBCs could cause conformational changes of antigenic epitope that enhances the production of autoantibodies [11].

Regarding age, we classified our patients into three age groups, the first was less than 6 years old, the second was from 6 to 12 years old, and the third was more than 12 years old, and we detect that the frequency of alloimmunization in each group was in the following order, respectively: 11.1, 55.6, and 33.3% (P > 0.05). These findings were in accordance with Ho et al. [13], who found no significant difference.

As regards the gender, we found that alloimmunization was higher in females 66.7% than males 33.3%, which was in accordance with Haslina et al.[11] and Sadeghian et al. [15]. This is biologically plausible because females are more vulnerable to antibody formation than males as they are exposed to alloantibodies during pregnancy and childbirth. We do not know whether our findings suggest an unknown pathophysiologic mechanism or whether random variation in a small number of subjects produced the association. However, Bilwani and Kakapoto[23] and Ameen et al.[17] found no significant association between alloimmunization and gender.

In the current study, mean age at the start of transfusion of alloimmunized patients was 1.7 years. The rate of alloimmunization was significantly higher in these who started transfusion more than 1 year compared with those who started transfusion less than 1 year of age (88.9 vs. 11.1%), similar results were obtained by Sirchia et al.[24] and Spanos et al. [19], supporting the view that there is some form of immune tolerance induced by an immature immune system to repeated blood transfusions.

Regarding the types of antibodies, the most frequent alloantibodies detected are anti-Kell (9/18; 50%), anti-Rh (D) (3/18; 16.75%), anti-Rh (E) (3/18; 16.75%), anti-duffy (1/18; 5.50%), one patient with both anti-CW and anti-KPa (1/18; 5.50%), and another patient with anti-CW, anti-KPa, and anti-Luth (1/18; 5.50%).

These were in accordance with Karimi et al. [14], who found that the most common alloantibodies were anti-Kell (50%), Anti-Rh (D) (15.8%), and anti-Rh (E) (10.5%).

Shamsian et al.[12] detected red-cell alloantibodies in four of the patients, two of them were anti-K and the two others were anti-D. Moreover, in a study done in Bahrain by Bashawri et al. [10], the most common alloantibodies identified were those of the Rhesus (Rh) and Kell systems.

Ameen et al.[17] reported that the most common clinically significant alloantibodies were anti-Kell, Rh, Duffy, and Lua systems.

However, Haslina et al.[11] recorded that anti-E was most frequently seen, followed by anti-c (Rhesus system), anti-S, anti-N (MNS system), anti-Jka (Kidd system), and finally anti-K (Kell system).

Ho et al.[13] found nine alloantibodies (three anti-E, three anti-Mi, one anti-HLA, one anti-BG, and one anti-BW22), only anti-E has been found to be clinically significant, causing a hemolytic transfusion reaction, caused by recipient–donor antigenic discrepancy.

Furthermore, Bhatti et al.[25] study reported that alloantibodies are mainly against Rh antigens although other antibodies such as anti-K, anti-Jsb, and anti-Jka were also found.

Hassan et al.[18] recorded that anti-Kpa antibodies were the most common, followed by anti-e, anti-E, and anti-K antibodies. Anti-k, CW, -Fyb, -Kpb, -Rh 'D,' and -c antibodies were observed in one patient.

We have noticed that the specificity of RBC alloantibodies in thalassemic patients was against Kell and Rh blood-group systems mainly. The high frequency of anti-Rh could be explained by transfusion of some RBC with rhesus D-incompatible blood due to false-negative results in weak D typing of blood donors, which stimulates the immune system for production of anti-D.

As regards clinical findings, we found out that there was statistically no significant difference between splenectomized and nonsplenectomized patients as regards the alloimmunization rate (13.5 vs. 7.4%, respectively, P > 0.05). This agreed with other studies, such as Ho et al.[13] in Hong Kong and Karimi et al.[14] in Iran. But this disagreed with Singer et al. [3], who reported a higher frequency of alloimmunization in splenectomized patients and explained this as the absence of spleen may further stimulate the immune response to the transfused foreign antigens that were not effectively filtered.

Alloimmunization frequency was significantly higher in β-thalassemia-major patients 14/167 (7%) than β-thalassemia intermediate 4/33 (2%), P value less than 0.05. Consequently, as regards the frequency of transfusion per year, there was a statistically significant difference between patients receiving less than 12 U/year who developed alloantibodies (22.2%) and patients receiving more than 12 U/year who developed alloantibodies (77.8%). This is in agreement with Spanos et al. [19]. Although some studies reported that there is no relation between alloimmunization and frequency of transfusion, Ho et al. [13]. Moreover, Beresntsen and Tionnfiord[26] reported that the interval between transfusions did not appear to play a significant role in antibody development as a similar interval was observed between all patients. However, the interval shortened after the development of the antibodies due to decreased survival of foreign RBCs.

The total number of the units transfused till the performance of our study was highly significantly associated with alloimmunization (P < 0.01). Among the 18 alloimmunized patients, 13 (72.2%) had received more than 112 U versus five (27.8%) who had received less than 112 U. This is in agreement with Joseph et al.[27] and Dogra et al. [28]. Whether exposure to such a large number of blood-donor units is likely to increase alloimmunization or the alloimmunization is the cause of an increased number of transfused units or both, this is to be further investigated.

Regarding blood group, we found out that the frequency of alloimmunization was higher in blood group O (8/18, 44.4%) followed by group A (7/18, 38.8%). However, Hassan et al.[18] disagreed with us who reported that red-cell alloimmunization was not significantly associated with ABO and Rh groups of the patients.

Alloimmunized patients showed a significantly higher serum ferritin level than the nonalloimmunized patients (P < 0.01). This agreed with Dahlia et al. [22], who showed that serum ferritin level was significantly higher with alloimmunization. Our results showed that, in β-thalassemia major, serum ferritin was significantly higher in alloimmunized patients than nonalloimmunized patients, and in β-thalassemia intermediate, serum ferritin was higher in alloimmunized patients than nonalloimmunized patients. This implicates that increased serum ferritin is related to alloimmunization rather than the type of β thalassemia.


  Conclusion Top


Alloimmunization to RBC antigens is a relatively frequent finding among Egyptian transfusion-dependent β-thalassemic patients (9.0%). The most frequent antibodies detected were against the Kell and Rh (E and D) groups, which are all clinically significant. Alloimmunization could complicate the general condition of these patients. Accordingly, it is recommended that antibody screening has to be done before each transfusion, providing phenotypically matched RBCs at least for Kell and Rh subgroups, and early institution of transfusion therapy after diagnosis are the means of decreasing alloimmunization.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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