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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 4  |  Issue : 1  |  Page : 74-78

Red cell alloimmunization in multi-transfused, oncology patients: Risks and management


Department of Transfusion Medicine, Sri Balaji Action Medical Institute, New Delhi, India

Date of Web Publication22-Apr-2019

Correspondence Address:
Dr. Sadhana Mangwana
Department of Transfusion Medicine, Sri Balaji Action Medical Institute, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/GJTM.GJTM_11_19

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  Abstract 


Introduction: Repeated blood transfusion can result in the development of alloantibodies against one or more red cell antigens. Risk of alloimmunization is high in patients receiving multiple transfusions in hemoglobinopathies, hematologic malignancies, and cancer patients receiving chemotherapy. Materials and Methods: A study was undertaken to know risk of alloimmunization in multi-transfused, oncology patients and its management in a tertiary care oncology hospital over 3 years' period receiving multiple transfusions and subjected to antibody screening by 3-cell panel and antibody identification by 11 or 14 cell panels, wherever required, using solid phase red cell adherence technology. Results: 8115 units of leukodepleted, packed red blood cells (RBCs) were given to 5886 admissions. Of these, 18 patients (0.30%) developed red cell alloimmunization. Of these, 17 (94.5%) were female and only 1 (5.5%) was male patient, with 78% (14) solid organ malignancies and 22% (4) hematological malignancies. Three patients (16.6%) had concurrent warm autoantibodies with alloantibodies while 5 patients (28%) had multiple alloantibodies. About 68% of alloantibodies belonged to Rh blood group system followed by Duffy, Kidd, Kell, and MNS systems. Maximum alloantibodies (36%) were anti-E alloantibody. Conclusion: It is vital to detect the appearance of new alloantibodies or disappearance of old alloantibodies to prevent hemolytic transfusion reaction during or after allogeneic transfusion. Regular screening for the development of alloantibodies in multi-transfused patients and providing leukoreduced, Rh phenotyped and antigen-matched blood is recommended for better management of these patients. The prevention of RBC alloantibody formation in multi-transfused patients extends life expectancy and reduces the requirement of blood transfusion.

Keywords: Alloantibodies, alloimmunization, multi-transfused, oncology


How to cite this article:
Mangwana S, Kacker A, Simon N. Red cell alloimmunization in multi-transfused, oncology patients: Risks and management. Glob J Transfus Med 2019;4:74-8

How to cite this URL:
Mangwana S, Kacker A, Simon N. Red cell alloimmunization in multi-transfused, oncology patients: Risks and management. Glob J Transfus Med [serial online] 2019 [cited 2019 May 21];4:74-8. Available from: http://www.gjtmonline.com/text.asp?2019/4/1/74/256736




  Introduction Top


The transfusion of serological safe blood is an essential requirement in patient blood management in blood transfusion services. The discovery of blood group system by Karl Landsteiner in 1900 and development of Anti-globulin Test by Coombs, Mourant, and Race in 1945 led to the marked reduction in fatalities associated with blood transfusion and identification of various alloantibodies. Recently, 15 blood group antigens have been added to eight of the blood group systems as recognized by the International Society of Blood Transfusion making a total of 360 blood group antigens of which 322 are clustered within 36 blood group systems.[1]

Blood transfusion, although life-saving is associated with inherent risk of alloimmunization to red blood cell (RBC) antigens. Repeated blood transfusion can result in the development of alloantibodies against one or more red cell antigens. The risk of alloimmunization is high in patients receiving multiple transfusions such as patients having thalassemia major, aplastic anemia, sickle cell disease, hematologic malignancies, chronic renal failure, and cancer patients receiving chemotherapy. The most important determination for any transfusion is to exclude the presence of clinically significant alloantibodies in the patient's blood before selecting RBC for transfusion.

ABO blood group system is unique in that it is the only blood group system where reciprocal or antithetical antibodies are present with no prior exposure to antigens. It has “Naturally Occurring” antibodies. For this reason, ABO compatibility is so important in transfusion testing and provides the tools for ABO testing. Antibodies that are not naturally occurring will only be formed if an individual is exposed to red cells through transfusion or pregnancy, where the red cells transfused, contain antigens not present on that individual's own red cells. When an individual is exposed to this foreign red cell antigen, an individual may make an antibody, called an alloantibody.

Usually, blood banks provide only ABO- and Rh (D)-antigens matched blood, so the risk of alloimmunization to minor blood group antigens is very high. Patients who have warm autoantibodies (WAAs) in their serum have a higher rate of alloimmunization.[2],[3],[4] Exclusion of newly formed alloantibodies in patients requiring transfusion having WAAs is of primary concern. Monitoring of evidence of RBC destruction due to alloantibodies is difficult in patients, who already have autoimmune hemolytic anemia (AIHA).[5]

The most important irregular RBC alloantibodies are directed toward Rh (anti-D, -C, -E, -c, and -e), Kell (anti-K), Duffy (anti-Fy a and -Fy b), Kidd (anti-Jk a and -Jk b), and MNS (anti-M, -S, and -s) blood group systems.

The risk of the development of alloantibodies depends on number and frequency of transfusions, pregnancy, antigen immunogenicity, recipient's immune response, ethnicity of patient, and difference in the antigenic pattern of donor and recipient.

Antibody screening by 2–3 cells panel, as a part of pretransfusion testing, is not mandatory in India. Only few select centers are routinely doing antibody screening as pretransfusion testing. Although there are various studies of alloimmunization prevalence in multi-transfused patients in India and abroad.[6],[7],[8],[9],[10] However, to the best of our knowledge, data on the prevalence of red cell alloimmunization in multi-transfused, oncology patients is limited. In view of this, the study was undertaken in Tertiary Care Hospital of North India to assess the prevalence and risk of alloimmunization in multi-transfused, oncology patients, and its management.


  Materials and Methods Top


An observational study was conducted in a tertiary-care hospital with dedicated oncology setup in patients receiving repeated red cell transfusions over 3 years from September 2015 to August 2018 and was subjected to antibody screening by 3-cell panel using solid phase red cell adherence (SPRCA) technology. A total of 5886 oncology patients were screened for red cell alloimmunization in 3 years' period. Patients having a positive antibody screening were further tested for antibody identification by 11 or 14 cell panels on SPRCA.

Blood samples from patients, requiring transfusion, were collected in ethylenediaminetetraacetic acid tube for 3-cell antibody screen testing along with detailed clinical and transfusion history including diagnosis, blood group, recent transfusion date, history of pregnancy, abortion, any recent anti-D immunoprophylaxis in case of females, and history of drugs such as antibiotics. Three-cell antibody screen-positive samples were further investigated to identify the antibodies using commercial 16-cell panel of SPRCA (Capture, Immucor Inc., Norcross, GA, USA) and PanOCell 10 (Immucor Inc., Norcross, GA, USA). All testing and procedures are carried out as per guidelines of AABB.[11] Polyspecific direct antiglobulin test (DAT) was performed on all patients using 0.8% cell suspension of patient's RBC with antihuman globulin. Advance investigations such as adsorption and elution technique were also performed to identify the antibodies. A commercial warm autoantibody removing medium (W.A.R.M.; ZZAP) was used for the eluates and adsorbed sera to detect the specificity of the autoantibody. Adsorb sera was tested again with screen cells. Transfusion policy in our blood center is universal leukodepletion of packed RBCs (PRBCs). All donors are screened for antibody screening by pooled cell and extended phenotype for Rh and Kell antigens so that PRBC inventory is always maintained thus significantly reducing the turnaround time of issuing blood at the time of emergency. If pool cells show positivity in donors, then, 3-cell antibody screening is done. If 3-cell screen shows negative, then the unit is labeled as negative, and if 3-Cell screen shows positivity, then antibody identification of the donor is done. If blood is requisitioned, 3-cell antibody screening is done in all patients at the time of the first requisition and repeated after 72 h. If 3-cell screen is negative, then the patient is labeled as negative, and if 3-cell screen shows positivity, antibody identification is done. All oncology patients are issued Rh phenotype matched PRBCs. After antibody was identified, the corresponding antigen-negative unit was selected from inventory. If antibody other than Rh and Kell was identified, then the unit was typed for the corresponding antigen, followed by Coombs' crossmatch, and compatible unit was issued to the patient.


  Results Top


In 3 years' period, 8115 units of leukodepleted, PRBCs were given to 5886 admissions of oncology patients. Of these, 18 patients (0.30%) developed red cell alloimmunization who were in the age ranging from 42 to 85 years. Of these 18 patients, 17 (94.5%) were females and only 1 patient (5.5%) was male. About 78% (14) patients were of solid organ malignancies while 22% (4) patients were suffering from hematological malignancies. In solid organ malignancies, the average age of patients was 62.5 years whereas in hematological malignancies, the average age of patients was 63.5 years. This difference is statistically insignificant. The frequency of solid organ malignancies is shown in [Figure 1]. Urogenital malignancies were the highest (50%) among solid organ malignancies while acute lymphoblastic leukemia and non-Hodgkin's lymphoma constituted 25% and 75%, respectively, of total hematological malignancies.
Figure 1: Frequencies of solid organ malignancies (with absolute values in inner circle)

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Three patients (16.6%) showed concurrent WAAs along with alloantibodies. Five patients (28%) had multiple alloantibodies. 68% alloantibodies belonged to Rh blood group system and remaining from Duffy, Kidd, Kell, and MNS systems [Figure 2]. Maximum alloantibodies (36%) were anti-E alloantibody. Of these 18 patients, 10 patients (55.5%) showed a positive direct antiglobulin test (DAT) while 8 patients (45.5%) showed negative DAT. There was no correlation of DAT positivity with age, sex, and diagnosis of the patients except that all patients having concurrent WAAs showed DAT positivity.
Figure 2: Alloantibodies prevalence in oncology patients

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  Discussion Top


The prevalence of alloimmunization in various populations studied varies depending on transfusion policy, time and frequency of testing, sensitivity of test methods, and technical expertise of transfusion laboratory. This study was carried out to look for prevalence and risk of alloimmunization in multi-transfused, oncology patients, and management of such patients.

There have been wide variations noted in rate of alloimmunization (2.9%–37%) among different studies due to clinical, methodological, and statistical heterogeneity of studies.[12] Our results in oncology patients revealed red cell antibody prevalence as 0.30% with maximum belonging to Rh blood group system (68%) followed by Duffy, Kidd, Kell, and MNS systems. In India, majority of data are from multi-transfused thalassemia patients [Table 1] which showed alloimmunization prevalence varying from 3.8% to 18.8%.
Table 1: Results of various studies on alloimmunization in multi-transfused thalassemia patients

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Antibody specificity E (36%) was highest in our study followed by C, Kp a, D, and c (14%, 14%, 9%, and 9%, respectively) which is similar to other studies where antibody specificity E was maximum, but their prevalence was found higher than in our study as 33%,[6] 36.4%,[13] 42.9%,[14] 32.9%,[17] and 52%.[18] In a study conducted by Hassab et al., on 200 thalassemic patients in Egypt showed antibody prevalence as 10.5% with antibody specificity, anti-E (23.8%), anti-D (19%), anti-K (19%), anti-E (14.3%) and each of anti-Fy (a), anti-Js (a), anti-Lu (a), anti-N, and anti-S in 1 patient (4.8%).[19] In a study conducted by Abe et al. on 331 pediatric patients in Japan showed antibody prevalence as 1.8% with age ranging from 7-month to 14-year-old and antibody specificity as anti-E (42.8%), anti-Jka (42.8%), and anti-M (14.4%).[20]

In a systematic review of red cell alloimmunization in transfusion-dependent thalassemia patients by Franchini et al., the main risk factors emerged as age, female gender, splenectomy, first transfusion before 2 years of age and RBC units received/duration of blood transfusion/transfusion frequency.[12] Abe et al. in their study, observed the development of antibodies at the age of 181 and 611 days which cannot exclude the possibility of “naturally occurring” anti-E and anti-M. They suggested that genetic background should be kept into consideration.[20] In our study, on oncology patients also, maximum of female patients (94.5%) developed red cell alloimmunization.

The influence of ethnic and antigenic pattern differences between the blood-donor and recipient population has also been reported.[21],[22] Lower rates of RBC alloimmunization are reported in studies with more homogeneous donor and patient population whereas higher rates were observed in studies with ethnic/racial disparity between donors and recipients.[12]

In meta-analysis of multi-transfused thalassemia patients, increased antigen matching for Rh and Kell and use of leukoreduced RBC were found to have a protective effect.[12] Transfusion policy of our blood center, of universal leukodepletion of PRBCs and issuing of Rh-phenotype matched PRBCs to all oncology patients; resulted in very low frequency of red cell alloimmunization (0.30%) supporting the findings of Franchini et al. that use of antigen matching of Rh and Kell and leukoreduction are protective factors against alloantibody development.

Although red cell alloimmunization is one of the complications of multiple RBC transfusions, it causes difficulty in the interpretation of cell typing, obtaining compatible blood, antibody detection, and antibody identification. For the management of oncology patients, it is important to take a history of drugs specially daratumumab. Daratumumab is an immunoglobulin G1 kappa human monoclonal antibody targeting CD38 that has been shown to provide significant clinical benefit for the treatment of multiple myeloma and is approved in the United States and other regions for use in patients with previously treated multiple myeloma alone or in combination with other drugs. Because CD38 is expressed on human RBCs, daratumumab may interfere with indirect antiglobulin test by binding to endogenous CD38 present on the surface of RBCs causing panagglutination in blood compatibility tests leading to false-positive results on compatibility testing complicating the assessment of blood for safe transfusion.[23]

The management of red cell alloimmunization cases includes detection of antibodies, identification of antibodies, and providing antigen negative blood for transfusions. Because RBC adsorption techniques, frequently used to eliminate antibody interference, do not effectively negate daratumumab interference with antibody screening; alternative methods such as preventing daratumumab from binding to CD38 by treating reagent or donor RBCs with dithiothreitol or neutralizing interference by adding an anti-idiotype antibody or soluble CD38 to patient serum samples to disrupt the interaction between daratumumab and RBCs can be used to mitigate the interference.[23]

Usually, blood banks provide only ABO- and Rh (D)-antigens matched blood, so the risk of alloimmunization to minor blood group antigens is very high. Majority of alloantibodies are of Rh blood group specificity, extended antigen matching (C, E, c, e, K) can prevent RBC alloimmunization to great extent. Patients who have WAAs in their serum have a higher rate of alloimmunization. Monitoring of evidence of RBC destruction due to alloantibodies is difficult in patients, who already have AIHA.

It is vital to detect the appearance of new alloantibodies or disappearance of old alloantibodies to prevent hemolytic transfusion reaction during or after allogeneic transfusion. Regular screening for the development of alloantibodies in multi-transfused patients and providing leukoreduced, Rh phenotyped, antigen-matched blood would add toward the better management of these patients. In oncology patients, it is recommended to establish patients' blood-compatibility profiles before treatment, requiring them to carry blood type identification reports, and identifying appropriate mitigations methods, thus enabling the safe and timely delivery of transfusions. Blood banks with limited resources and technical facilities need to take these complications into consideration when planning the long-term transfusion support to transfusion-dependent patients. The prevention of RBC alloantibody formation in multi-transfused patients extends life expectancy and reduces the requirement of blood transfusion.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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