|Year : 2019 | Volume
| Issue : 1 | Page : 34-40
Comparative study of alloimmunization against red cell antigens in sickle cell disease & thalassaemia major patients on regular red cell transfusion
Keyuri Jariwala, Kanchan Mishra, Kanjaksha Ghosh
Surat Raktadan Kendra and Research Centre, Surat, India
|Date of Submission||07-Jun-2017|
|Date of Web Publication||22-Apr-2019|
Dr Kanjaksha Ghosh
Surat Raktadan Kendra & Research Centre, 1st Fl. Udhna Khatodara Urban Health Centre, Udhna Magdalla Road, Nr. Chosath Joganio Mata Temple, Surat 395 002, Gujarat
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background & objectives: Sickle cell disease (SCD) patients require red cell transfusion during different clinical complications of the disease. Such patients are at a high risk for developing alloantibody against red cell antigens. From India, there are limited data available on alloantibody formation in multiply transfused SCD patients. The present study was thus undertaken to fill up this lacunae by looking at the development of red cell alloantibodies in SCD and β-thalassaemia patients on regular transfusion.
Methods: All sickle cell disease patients undergoing red cell transfusion between 2008 and 2016, were included. During this period, a large number of β-thalassaemia major patients also underwent regular red cell transfusion. These thalassaemia patients were also included to compare the tendency of antibody formation between SCD and β-thalassaemia major patients. All patients before regular transfusion were regularly assessed for the development of red cell antibody. Red cell antigen, antibody screen crossmatch and antibody identification were done using the standard technique.
Results: A total of 138 patients with SCD aged between 4 and 53 yr (mean 17.6 yr) consisting of 83 males and 55 females (male:female, 1.5:1) along with 333 transfusion-dependent β-thalassaemia patients were studied. Over the last eight years, 15 patients with SCD and four patients with thalassaemia developed alloantibody (P <0.001). Antibody specificity of their alloantibodies was against Rhc, RhE, Kell, Fya and Fyb only. Sickle cell disease patients with and without alloantibody required on the average 11.8 and 8.6 units of red cell concentrate, respectively (P <0.05).
Interpretation & conclusions: About 11 per cent of the transfused sickle cells patients developed alloantibodies. The antibody specificity was restricted to Rh, Kell and Duffy blood group systems. Extended antigen matching involving Rh, Kell and Duffy antigens may prevent alloantibody in such patients.
Keywords: Alloantiboy - antibody specificity - multitransfused patients - red cell transfusion - sickle cell disease - thalassaemia
|How to cite this article:|
Jariwala K, Mishra K, Ghosh K. Comparative study of alloimmunization against red cell antigens in sickle cell disease & thalassaemia major patients on regular red cell transfusion. Indian J Med Res 2019;149:34-40
|How to cite this URL:|
Jariwala K, Mishra K, Ghosh K. Comparative study of alloimmunization against red cell antigens in sickle cell disease & thalassaemia major patients on regular red cell transfusion. Indian J Med Res [serial online] 2019 [cited 2021 Sep 24];149:34-40. Available from: https://www.ijmr.org.in/text.asp?2019/149/1/34/256710
Patients, who get multiple red cell transfusions develop alloantibodies against one or many red cell antigens,. There are many modifiers for the development of alloantibodies following red cell transfusion and some of them can be summarized as follows: (i)absence of a given red cell antigen in the recipient but its extensive presence in donor population, (ii)antigenicity of the given antigen against which alloantibody is formed, for example, RhD and Kell are strongly antigenic. This also includes the prevalence of red cell antigen mismatch between donor and recipient population, (iii) nature of underlying disease for which the transfusion is initiated, (iv) number of red cell units transfused, (v) leucodepleted or non-leucodepleted red cells (this is important for the development of anti-HLA antibody which may alro altect red cell survival), (vi)the racial differences in blood group antigen distribution between donor and recipient population, (vii)age at which the transfusion is initiated, (viii)average lifespan of the patient with the disease, (ix)recipient's inflammatory state at the time of transfusion and (x) concomitant medication, immune suppression which may be given alongside red cell transfusion, (e.g., chemotherapy, immunosuppressants, transfusion of IV Ig and splenectomy). Many complications of sickle cell disease (SCD) require red cell transfusion, and therefore a large proportion of these patients require regular red cell transfusion or exchange transfusion. India is home to estimated 1.5×105 sickle cell disease patients. There is no limited information from India, on the occurrence of red cell alloantibodies in these patients except a few including case reports,. The present retrospective study was an attempt to address this question by assessing the occurrence of red cell alloantibodies in patients with SCD on regular transfusion in a tertiary care centre in Gujarat, India.
| Material & Methods|| |
Consecutive patients having sickle cell disease, who attended regular transfusion service of Surat Raktadan Kendra and Research Centre, Surat, India, between 2008 and 2016, were included in this study. For comparison, transfusion-dependent thalassaemia major patients were also included in this study. The records of these patients were evaluated for any adverse transfusion reaction.
Investigations:All patients were investigated just before the next red-cell transfusion. Standard immuno-haematological techniques as described in the American Association of Blood Banks (AABB) manual were followed, along with the instructions in the packet insert of individual cell panels used in this study. Since DiaMed (DiaMed AG, Switzerland) 3-cell panel may not include all the red-cell antigens pertinent to the Indian population, a locally made (Tulip Diagnostics, India) 3-red cell panel was also used for screening the atypical antibodies. The patients' ABO, RhD antigen status, antibody screening was done by DiaMed 3-cell panel and a 3-cell panel by Tulip diagnostics using gel technique. In addition to the above, a LISS (low ionic strength solution)-indirect Coombs test, a standard cross matching and a DiaMed 11-cell panel was used for the identification of positive a typical antibodies.
The study was approved by the Institutional Review Board (SRKRC/RP/4/2017). As it was a retrospective data analysis and screening for alloantibody against important red cell antigens and the identification of antigen(s) against which the antibodies were formed was a requirement for safe transfusion, the patients were not identified and the consent forms from individual patients were not obtained.
Transfusion: All patients on regular transfusion received Coombs cross-matched red cells and in case of positive antibody screen, antigen-negative red cells which were thrice saline washed. At this transfusion centre, extended phenotype matched red cell transfusion was not routinely practiced.
Statistical analysis: For statistical analysis of data λ2 test with Yates correction was used for non-parametric data and Student's (unpaired) t test for parametric data.
| Results|| |
A total of 138 patients with SCD received between 1 and 61 units of packed red cell transfusion (total 1234 units with a mean of 8.9 units/patient) over eight years. During the same period, 333 β-thalassaemia major patients received on the average 246 ml/kg of packed red cell/kg/year (mean 17.6 units of packed red cells/patient/yr). The age group of sickle cell disease patients was much broader (4-53 yr) with a male:female ratio of 1.5:1 whereas for transfusion-dependent β-thalassaemia major patients the age range was narrower between 4 and 26 yr with a male:female ratio of 1.3:1. The amount of red cell transfusion in thalassaemia patients was 15-16 times more than that of SCD patients. Of the 138 patients with sickle cell disease, 15 (11%) developed alloantibodies compared to 4 of 333 (1.2%) thalassaemia major patients (P <0.001). The number of transfusions given to alloimmunized SCD patients (11.8±16.6 units) when compared to those who did not get alloimmunized (8.6±15.26 units) were not significantly different. There was no difference in reactivity between DiaMed and Tulip screening red cells for the patients screened.
Of the 15 patients with SCD who developed alloantibodies, 12 developed alloantibody on receiving 10 or less number of red cell units. For both the SCD as well as thalassaemia major patients, Rhc and E were the most common antigens involved, additional Kell, FYa and FYb (1 patient each) [Table 1] antigens were involved in SCD patients receiving multiple transfusion. Number of red cell units received by thalassaemia patients was significantly more (P <0.001) compared to that of SCD patients. Comparison of alloantibody formation in multitransfused SCD patients in the global studies is shown in [Table 2],,,,,,,,,. The comparison of alloantibody generation in thalassaemia patients in the present study with other studies on multitrans fused patients in India is presented in [Table 3],,,,,,,,,,,,,,.
|Table 1: Alloantibodies in transfused sickle cell disease and β-thalassaemia patients|
Click here to view
|Table 2: Global literature on alloantibodies in sickle cell disease patients receiving transfusion|
Click here to view
|Table 3: Alloantibodies produced by red cell transfusion against diverse conditions in India where donor and recipient populations were similar|
Click here to view
| Discussion|| |
Several studies have recorded the development of alloantibodies in hospitalized patients and multitransfused patients with thalassaemia, and other conditions,,,,,,,,,,,,,,, from India and the prevalence of such antibodies varied widely between 0.49 and 18.8 per cent. One study compared the transfusion practice for sickle cell disease patients between a centre in India and a sickle cell management centre in Jamaica, though no assessment of alloantibody formation in Indian patients was made in that study. Majority of the data of alloantibody formation from Western countries in SCD patients receiving transfusion showed up to 76 per cent alloimmunization, and the prevalence across the world varied between 2.6 per cent in Jamaica to 65 per cent for ABO, RhD only matched red cells in Kuwait and 76 per cent in Jamaican sickle cell disease patients taking transfusion in the UK,,. [Table 2] provides the broad range of such data across the world. The increased prevalence of alloantibodies in transfused sickle cell disease patients in Western countries have largely been explained on the basis of racial mismatch of major red cell antigen system between blood donating Caucasian population and SCD patients from African, Indian-Arab populations,,,, the same argument was given by Moreira et al for Brazilian sickle cell disease population. However, a study showed that even when transfusion was made from donors from the same racially oriented population, high levels of alloantibodies were still produced, and this was explained by the high levels of Rh antigenic differences in ethnic African population.
In our study, majority of patients developed alloantibody with <10 units of red cell transfusion and some developed this complication even after one unit of transfusion. Early development of alloantibody in susceptible patient has also been described by others.
Certain alloantibodies may be difficult to detect; hence, techniques employed to detect such antibodies may be different and some evanescent antibodies may come and go; hence, the prevalence of the alloantibodies may not only be dependent on less or more sensitive techniques but also types of cell panel employed, zygosity of the particular antigen in the cell panel and time after transfusion when the testing was done to detect such antibodies.
It has been argued that centres which practice pre-storage leucodepletion or any type of leucocyte filtration may have less alloimmunization. The argument was found to be true for HLA alloimmunization; however, it has not been shown to be pertinent in development of antibodies against red cell antigens.
Alarif et al showed that HLA-B35 might be relevant for alloimmunization in sickle cell disease. Others have pointed out the role of various HLA-DRB1 alleles in the alloimmunity to red cell antigens in sickle cell disease. HLA antigen distribution was not studied in our patients will SCD who developed alloantibodies following red cell transfusion.
In our study SCD patient showed nine times more alloimmunization than those receiving more intense transfusions for thalassaemia major (11 vs. 1.2% for thalassaemia).
There are several reasons why sickle cell patients are alloimmunized more readily than other multitransfused patients. This has been extensively discussed by Yazdanbakhsh et al,. Very often sickle cell disease patients have ongoing inflammation which upregulates many of the genes in the immune system responding to danger signal associated molecular patterns released by ongoing tissue destruction and tissue necrosis as a result of sickle cell crisis. There is often racial mismatch between donors of the red cells and the recipients.
In Western countries, particularly in North European countries, where thalassaemia is rare, the prevalence of alloantibodies in thalassaemia patients is high, probably due to racial mismatch,. In India, studies in multitransfused patients with thalassaemia major have shown 1.5-8 per cent alloantibody formation [Table 3]. Only Jolly et al showed a high prevalence (15.5%) of alloantibody in multitransfused thalassaemia major patients.
Most studies on alloimmunization in SCD patients have shown that alloantibodies are formed against broad Rh locus antigens, i.e. e C e E D, Kell antigen and Duffy antigens. Hence, it has been suggested that extended phenotyping of blood involving all the Rh Kell and Duffy antigens may cut down this alloimmunization rate at least by 60-80 per cent. However, the time, finance and labour required to provide such a red cell unit may be worthwhile because of cost and time may increase several fold to find properly matched red cell units in a heavily alloimmunized patient. Moreover, such action also prevents the mortality and morbidity in these patients.
When the high throughput molecular typing of red cell antigens becomes available, it will be possible to provide improved matching of red cells for transfusion to sickle cell disease patient and prevent red cell alloimmunization to a large extent.
Acknowledgment: The authors acknowledge the help provided by Atilakshmi Transfusion Medicine Centre, Surat, India in compiling the data.
Financial support & sponsorship: None.
Conflicts of Interest: None.
| References|| |
Hoeltge GA, Domen RE, Rybicki LA, Schaffer PA. Multiple red cell transfusions and alloimmunization. Experience with 6996 antibodies detected in a total of 159,262 patients from 1985 to 1993. Arch Pathol Lab Med
Rosse WF, Gallagher D, Kinney TR, Castro O, Dosik H, Moohr J, et al.
Transfusion and alloimmunization in sickle cell disease. The cooperative study of sickle cell disease. Blood
Yazdanbakhsh K, Ware RE, Noizat-Pirenne F. Red blood cell alloimmunization in sickle cell disease: Pathophysiology, risk factors, and transfusion management. Blood
Colah R, Italia K, Gorakshakar A. Burden of thalassemia in India: The road map for control. Pediatr Hematol Oncol J
Dogra A, Sidhu M. A case of delayed hemolytic transfusion reaction in sickle cell disease patient. Asian J Transfus Sci
Daniel MJ, Muddegowda PH, Chezhiansubash, Lingegowda JB, Gopal N, Prasad K, et al.
Study of twenty one cases of red cell exchange in a tertiary care hospital in Southern India. J Clin Diagn Res
Roback JD, Grossman BJ, Harris T, Hillyer CD, editors. Technical manual of American Association of Blood Banks (AABB). Methods Section 3
ed. Bethesda, Maryland, USA: American Association of Blood Banks; 2011. p. 897-915.
Natukunda B, Schonewille H, Ndugwa C, Brand A. Red blood cell alloimmunizationin sickle cell disease patients in Uganda. Transfusion
Castro O, Sandler SG, Houston-Yu P, Rana S. Predicting the effect of transfusing only phenotype-matched RBCs to patients with sickle cell disease: Theoretical and practical implications. Transfusion
Bashawri LA. Red cell alloimmunization in sickle-cell anaemia patients. East Mediterr Health J
Sarnaik S, Schornack J, Lusher JM. The incidence of development of irregular red cell antibodies in patients with sickle cell anemia. Transfusion
Ameen R, Al Shemmari S, Al-Bashir A. Red blood cell alloimmunization among sickle cell Kuwaiti Arab patients who received red blood cell transfusion. Transfusion
Olujohungbe A, Hambleton I, Stephens L, Serjeant B, Serjeant G. Red cell antibodies in patients with homozygous sickle cell disease: a comparison of patients in Jamaica and the United Kingdom. Br J Haematol
Vichinsky EP, Earles A, Johnson RA, Hoag MS, Williams A, Lubin B, et al.
Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood. N Engl J Med
Moreira Júnior G, Bordin JO, Kuroda A, Kerbauy J. Red blood cell alloimmunization in sickle cell disease: The influence of racial and antigenic pattern differences between donors and recipients in Brazil. Am J Hematol
Aygun B, Padmanabhan S, Paley C, Chandrasekaran V. Clinical significance of RBC alloantibodies and autoantibodies in sickle cell patients who received transfusions. Transfusion
Jolly JG, Agnihotri SK, Choudhury N, Gupta D. Evaluation of haemotherapy in thalassaemias (20 years of Indian experience). J Indian Med Assoc
Shukla JS, Chaudhary RK. Red cell alloimmunization in multi-transfused chronic renal failure patients undergoing hemodialysis. Indian J Pathol Microbiol
Pradhan V, Badakere S, Vasantha K, Korgaonkar S, Panjwani S, Jajoo N. Antibody to red cells in beta thalassemia major patients receiving multiple transfusion - A short report. Indian J Haematol Blood Transfuse
Thakral B, Saluja K, Sharma RR, Marwaha N. Red cell alloimmunization in a transfused patient population: A study from a tertiary care hospital in North India. Hematology
Pahuja S, Pujani M, Gupta SK, Chandra J, Jain M. Alloimmunization and red cell autoimmunization in multitransfused thalassemics of Indian origin. Hematology
Gupta R, Singh DK, Singh B, Rusia U. Alloimmunization to red cells in thalassemics: Emerging problem and future strategies. Transfus Apher Sci
Chaudhari CN. Red cell alloantibodies in multiple transfused thalassaemia patients. Med J Armed Forces India
Makroo RN, Arora JS, Chowdhry M, Bhatia A, Thakur UK, Minimol A, et al.
Red cell alloimmunization and infectious marker status (human immunodeficiency virus, hepatitis B virus and hepatitis C virus) in multiply transfused thalassemia patients of North India. Indian J Pathol Microbiol
Makroo RN, Bhatia A, Hegde V, Chowdhry M, Thakur UK, Rosamma NL, et al.
Antibody screening & Identification in the general patient population at a tertiary care hospital in New Delhi, India. Indian J Med Res
Dhawan HK, Kumawat V, Marwaha N, Sharma RR, Sachdev S, Bansal D, et al.
Alloimmunization and autoimmunization in transfusion dependent thalassemia major patients: Study on 319 patients. Asian J Transfus Sci
Elhence P, Solanki A, Verma A. Red blood cell antibodies in thalassemia patients in Northern India: Risk factors and literature review. Indian J Hematol Blood Transfus
Jain R, Choudhury N, Chudgar U, Harimoorthy V, Desai P, Perkins J, et al.
Detection and identification of red cell alloantibodies in multiply transfused thalassemia major patients: A prospective study. Indian J Hematol Blood Transfus
Datta SS, Mukherjee S, Talukder B, Bhattacharya P, Mukherjee K. Frequency of red cell alloimmunization and autoimmunization in thalassemia patients: A report from Eastern India. Adv Hematol
Dhar S, Basu S. Red cell alloimmunisation in oncology patients: A study from Eastern India. Transfus Apher Sci
Jain A, Agnihotri A, Marwaha N, Sharma RR. Direct antiglobulin test positivity in multi-transfused thalassemics. Asian J Transfus Sci
Mehta V, Mistry A, Raicha B, Italia Y, Serjeant G. Transfusion in sickle cell disease: Experience from a Gujarat centre. Indian J Pediatr
Campbell-Lee SA, Kittles RA. Red blood cell alloimmunization in sickle cell disease: Listen to your ancestors. Transfus Med Hemother
Chou ST, Jackson T, Vege S, Smith-Whitley K, Friedman DF, Westhoff CM, et al.
High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors. Blood
Sins JW, Biemond BJ, van den Bersselaar SM, Heijboer H, Rijneveld AW, Cnossen MH, et al.
Early occurrence of red blood cell alloimmunization in patients with sickle cell disease. Am J Hematol
Schonewille H, Brand A. Alloimmunization to red blood cell antigens after universal leucodepletion. A regional multicentre retrospective study. Br J Haematol
Alarif L, Castro O, Ofosu M, Dunston G, Scott RB. HLA-B35 is associated with red cell alloimmunization in sickle cell disease. Clin Immunol Immunopathol
Schonewille H, Doxiadis II, Levering WH, Roelen DL, Claas FH, Brand A, et al.
HLA-DRB1 associations in individuals with single and multiple clinically relevant red blood cell antibodies. Transfusion
Yazdanbakhsh K. Immunoregulatory networks in sickle cell alloimmunization. Hematology Am Soc Hematol Educ Program
Matteocci A, Pierelli L. Red blood cell alloimmunization in sickle cell disease and in thalassaemia: Current status, future perspectives and potential role of molecular typing. Vox Sang
Nickel RS, Hendrickson JE, Fasano RM, Meyer EK, Winkler AM, Yee MM, et al.
Impact of red blood cell alloimmunization on sickle cell disease mortality: A case series. Transfusion
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||Hydroxyurea and blood transfusion therapy for Sickle cell disease in South Asia: inconsistent treatment of a neglected disease
| ||Thamal Darshana,David Rees,Anuja Premawardhena |
| ||Orphanet Journal of Rare Diseases. 2021; 16(1) |
|[Pubmed] | [DOI]|
||An Overview on Thalassemia Diagnosis and Management Approach, Literature Review
| ||Tahani Mohammed Manea,Faris Suhail Abdalhameed Khan,Renad Mohammed Alsharyufi,Kholoud Mohammed Alghamdi,Manal Khalaf Alzahrani,Fawaz Mohammed Alzubaidi,Ali Abdulaziz Alghanmi,Turki Abdullah Almahdawi,Turki Mohammed Alhasani,Nermeen Nasser Alrajhi |
| ||International Journal Of Pharmaceutical Research And Allied Sciences. 2021; 10(2): 103 |
|[Pubmed] | [DOI]|
||Snapshot on physicians’ view on safe blood transfusion in multiply transfused patients in Nigeria
| ||ChilotaC Efobi,AngelaO Ugwu,EstherI Obi,EdmundN Ossai,Sunday Ocheni |
| ||International Journal of Medicine and Health Development. 2021; 26(1): 50 |
|[Pubmed] | [DOI]|