Alloimmunization in Patients with Sickle Cell Disease and Thalassemia: Experience of a Single Centre in Oman
Received: October 9, 2016
Accepted: January 9, 2017
Mediterr J Hematol Infect Dis 2017, 9(1): e2017013 DOI 10.4084/MJHID.2017.013
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Blood transfusion is an integral part of the supportive care for
patients with sickle cell disease (SCD) and thalassaemia. The hazard of
red cell alloimmunization, however, is one of the main complications of
Development of anti-RBC antibodies (alloantibodies and autoantibodies) can significantly complicate transfusion therapy.[5-7] Furthermore, some of these alloantibodies being haemolytic, can cause haemolytic transfusion reactions, and thereby limit the utility of further transfusion, whereas others are clinically insignificant. Erythrocyte autoantibodies appear less frequently, but they can result in clinical hemolysis and difficulty in cross-matching compatible blood units. Patients with autoantibodies may have a higher transfusion rate and often require immunosuppressive drugs, splenectomy or alternative treatments to maintain an adequate level of haemoglobin.
Despite the recognition of antibodies as a transfusion-associated risk,[7,10-13] little is known about the extent and causes of these phenomena among thalassaemia and sickle cell disease patients from the Sultanate of Oman or the most appropriate methods of preGenetic blood disorders survey in the Sultanate of Omanvention. Approaches for prevention or treatment of alloimmunizations are under debate and include the provision of RBCs matched for all the major antigens associated with clinically significant antibodies, or to only give blood matched for antibodies that have already been detected. The reason for such a controversy may lie in the fact that many alloantibodies are not harmful and that expensive prevention methods may, therefore, benefit only some patients. In addition, donor feasibility and the cost of RBC matching could impact on these approaches as also the own local guidelines regarding this issue. Furthermore, a better knowledge basis of the potential harmful antibodies among the thalassaemia and sickle cell disease patients can assist in considering the appropriate transfusion strategy to use. Our objective was to assess the prevalence of alloimmunization among our multiply transfused patients with thalassaemia and sickle cell anaemia.
Materials and Methods
Thalassemia patients: Clinical features and transfusion records of 129 thalassaemia patients, aged 5-32 years, 44 males, 85 females, who received regular transfusion were analysed. These patients were attending the day care unit at SQUH for regular transfusions.
Sickle cell anaemia patients: 133 sickle cell disease patients [113 SS and 20 S-beta thal] who were admitted to SQUH haematology wards (30 males and 103 females) and who received regular transfusion were analysed. The transfusion records of all the patients including those transfused for their first time were examined for the presence of alloimmunization and antibody specificity, age, gender and ethnicity.
Donors: Blood donors from the SQUH blood bank were identified for their racial background, and RBC phenotype was performed for the following antigens C, c, D, E, e and Kell. The donor’s ethnic origin was classified into Arabs and non-Arabs.[Data not shown]
Laboratory protocol. Antibody screening: Detection of alloantibodies was performed on a fresh blood sample using the indirect antiglobulin test by the column agglutination method. The gel card centrifugation technique was used (DiaMed AG, Cressier sur Morat, Switzerland). All patients were screened before any transfusion.
Antibody identification: Antibody specificity was determined using a standard panel of red cells reacting to known antigens using column agglutination and gel centrifugation (ID-DiaPanel and ID-DiaPanel-P, DiaMed AG). The indirect antiglobulin test and enzymatic papain–treated RBC test at 370C were performed when necessary and elution of antibodies was done to help in identification. Detection of alloantibodies masked by autoantibodies required the use of adsorption techniques using Polyethylene glycol [PG], or albumin or low-ionic strength saline [LISS] to identify the underlying antibody by the indirect antibody test [IAT].
The rate of alloimmunization in adults (aged 13-32 years) was higher at 14.4% as compared to 4% in children (aged 5-12 years).
Sickle cell anaemia: Out of 133 patients, 42(31.5%) developed positive antibody screen in whom 46 IgG alloantibodies were detected (95%CI, 24.87-40.66). Seven patients (16.6%) showed NSA, 23(54.7%) developed one antibody; 10(24%) developed two antibodies, and two patients had developed three antibodies. The specificities and frequencies of the alloantibodies in Omani patients with SCD are shown in Table 1 and Figure 1a. 38(83%) of the alloantibodies were Rh and Kell antibodies. The rate of alloimmunization among males was 30% and among females 33%.
|Table1. Type and frequency of antibodies identified in Thalassemia and SCD patients|
|Figure 1. Number (%) of specific antibodies in SCD (Figure 1a) & Homozygous Thalassaemia Major patients (Figure 1b).|
Furthermore, in the eight patients who had a non-specific antibody, we observed that PG-IAT detected clinically significant antibodies like anti-E, anti-C, anti-D, anti-Jk(a), anti-c, anti-e, anti-s that were masked by an autoantibody in our cohort of multi-transfused patients. PG-IAT was superior in detecting clinically significant allo- antibodies in the presence of masking autoantibodies as compared to the other techniques employed.
This study shows that the prevalence of alloimmunization in Omani homozygous thalassaemia patients was 20% (n=26; 95%CI, 13.9-27.6). Comparing the rate of alloimmunization in Omani thalassaemia patients with that of other populations, it was similar to several countries namely, 16.32% from Iran, and 22% from California and 19% from the CDC data in the USA on Asian and Caucasians patients. But in general, there is a reduction of the frequency of alloimmunization when the patient receives blood from the same ethnic groups like those living in Hong Kong and in Saudi Arabia. The low incidence of immunization found in an old Italian cooperative study of 1984 (5/68;5.4%), could have the same explanation since this study included only thalassaemic patients living in Italy and receiving blood from the same ethnic group. The higher rate of alloimmunization in adults as compared to children is in keeping with other studies where age is a significant factor. The incidence of alloimmunization in transfused Omani patients with SCD was found to be 31.5% (n=42, 95%CI, 24.87-40.66). This rate is similar to that reported in USA, France, Holland, and patients of Asian descent in Brazil.[23-27] It was also noticed that most of the alloantibodies were to Rh and Kell, antigens and that the E antibody had a higher rate.
The Omani population, for historical reasons, is known to be a mixture of more than one ethnic group. So it was expected to detect some antigenic differences among the Omani donors themselves. Also, 10% of donors are non-Omani, so patients receiving blood transfusions will be further exposed to “foreign” antigens. The frequency of alloantibodies may be reduced by limiting the transfusion from donors with the same ethnic origin.
It was noticed that patients with sickle cell anaemia showed a slightly higher rate of alloimmunization (31.5%) than thalassaemia patients (20%). This datum is consistent with observations by other studies as well. One reason for this observation could be because thalassemia patients are usually transfused at a younger age and regular intervals. The immune system response will be affected by the patient’s age at their first transfusion and number of blood units the patient received. It is believed that transfusions at an early age may offer some immune tolerance and protection against alloimmunization. The relation between the number of blood units transfused and antibody formation is unknown in thalassemia, but it is a major factor for increased alloimmunization in patients, including SCD, who receive multiple transfusions. However it should be taken into account that SCD is a chronic inflammatory state, and pro-inflammatory stimuli promote alloimmunization.[28,29] Furthermore, age is a significant factor, so children with SCD, who are chronically transfused, might have less inflammation, which could explain their lower rate of alloimmunization.[30,31] However, some antigen-negative patients may not produce antibodies at all or may form only one antibody despite exposure to antigen-positive cells. Studies have suggested at least in SCD patients, that genetic makeup is very relevant to the development of antibodies mainly altered Rh or Kell alleles, and perhaps acquiring these antibodies may be genetically driven.[32,33] In Omani population further studies will be needed to assess the effect of the number of transfusions on the immune response, the effect of the age at which the patient is first transfused, and the genetic makeup of recipients and donors on alloimmunization.
One of the biggest problems in a conventional hospital blood bank is finding the appropriate antigen-negative blood for the allo-immunised patients. Numerous reports show that transfusion of phenotype-matched RBCs (Rh and Kell) can reduce the risk.[19,34] However, there are still few reports revealing that the risk of alloimmunization is still high even when the donor blood is Rh and Kell matched with the recipient.[12,13]
BCSH transfusion guidelines also state that all patients with sickle cell disease and thalassaemia have their full phenotype tested at diagnosis and are given matched blood for C, c, E, e and K.[35,36] Moreover, extended red cell phenotype matching, although useful in preventing the formation of most alloantibodies, may prove impractical to provide adequate and timely donors for these patients. At present, we too follow this standard recommendation and hope to decrease the rate of alloimmunization. In our hospital it is estimated that the cost of one year of phenotyping for Rh and Kell antigens is about 12,500 OMR ($32,400) for all the donated units in our blood bank, raising the question whether it is cost effective to phenotype all of these units routinely. Nevertheless, DNA-based phenotyping can overcome certain limitations of serological studies and is beneficial in patients recently transfused or with interfering allo- or autoantibodies.
AcknowledgementWe wish to thank the hospital administration for the use of hospital material for this study.
- Al-Riyami A, Ebrahim GJ, Genetic
blood disorders survey in the Sultanate of Oman. J Trop. Pediatr.
2003 Jul; 49 suppl 1: i1-20
- Al-Riyami AA, Sulieman AJ, Afifi M, Al-lamki ZM, Daar S, A community- based study of common hereditary blood disorders in Oman. East Mediterr. Health J 2001 Nov; 7(6):1004-11
- Alkindi S, Al Zadjali S, Al Madhani A, Daar S, Al Haddabi H, Al Abri Q, Gravell D, Berbar T, Pravin S, Pathare A, Krishnamoorthy R. Forecasting hemoglobinopathy burden through neonatal screening in Omani neonates. Hemoglobin. 2010; 34: 135-44. http://dx.doi.org/10.3109/03630261003677213
- Wayne AS, Kevy SV, Nathan DG, Transfusion management of sickle cell disease. Blood 1993; 81:1109-23
- Hmida S, Mojaat N, Maamar M, Bejaoui M, Mediouni M, Boukef K, Red cell alloantibodies in patients with haemoglobinopathies. Nouv Rev Fr Hematol 1994 oct; 36 (5): 363-6.
- Spanos T, Karageorga M, Ladis V, Peristeri J, Hatziliami A, Kattamis C. Red cell alloantibodies in patients with thalassaemia. Vox Sang 1990; 58( 1): 50-5. http://dx.doi.org/10.1111/j.1423-0410.1990.tb02055.x
- Rosse WF, Gallagher D, Kinney T, Castro O, Dosik H, Moohr J,Wang W, Levy PS, Transfusions and alloimmunization in sickle cell disease. The cooperative study of sickle cell disease. Blood 1990 Oct.1; 76(7): 1431-7.
- Aygun B, Padmanabhan S, Paley C, Chandrasekaran V. Clinical significance of RBC alloantibodies and autoantibodies in sickle cell patients who received transfusions. Transfusion 2002 Jan; 42(1): 37-43. http://dx.doi.org/10.1046/j.1537-2995.2002.00007.x
- Wayne AS, Kevy SV, Nathan DG, Transfusion management of sickle cell disease. Blood, 1993 Mar 1; 81(5): 1109-23.
- Castellino SM, Combs MR, Zimmerman SA, Issitt PD, Ware RE, Erythrocytes autoantibodies in paediatric patients with sickle cell disease receiving transfusions therapy: frequency, characterization, and significance. Br. J. Haematol 1999 Jan; 104(1): 189-94. http://dx.doi.org/10.1046/j.1365-2141.1999.01127.x
- Murao M, Viana MB, Risk factors for alloimmunization by patients with sickle cell disease. Braz J. Med. Biol Res 2005; 38: 675-682 http://dx.doi.org/10.1590/s0100-879x2005000500004
- Chou ST, Jackson T, Vege S, Smith-Whitley K, Friedman DF, Westhoff CM. High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors. Blood. 2013;122(6):1062-71. https://doi.org/10.1182/blood-2013-03-490623
- Miller ST, Kim H-Y, Weiner DL, Wager CG, Gallagher D, Styles LA, et al. Red blood cell alloimmunization in sickle cell disease: prevalence in 2010. Transfusion. 2013;53(4):704-9. https://doi.org/10.1111/j.1537-2995.2012.03796.x
- Wayne As, Schoenik SE, Pegelow CH, Financial
analysis of chronic transfusions for stroke prevention in sickle cell
disease. Blood 2000 Oct.1; 96(7):2369-72
- 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 1986, 38:178-183. http://dx.doi.org/10.1016/0090-1229(86)90136-4
- Vichinsky EP, Earles A, Johnson RA, Hoag MS, Williams A, Lubin B, Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood. N Eng J Med 1990, 322: 1617-21. http://dx.doi.org/10.1056/nejm199006073222301
- Davari K, Soltanpour MS. Study of alloimmunization and autoimmunization in Iranian beta-thalassemia major patients. Asian J Transfus Sci. 2016 Jan-Jun;10(1):88-92. http://dx.doi.org/10.4103/0973-6247.172179
- Singer ST, Wu V, Mignacca R, Kuypers FA, Morel P, Vichinsky EP Alloimmunization and erythrocyte autoimmunization in transfusion-dependent thalassemia patients of predominantly Asian descent. Blood. 2000;96:3369-3373.CrossRefMedlineWeb of ScienceGoogle Scholar
- Vichinsky E, Neumayr L, Trimble S, Giardina PJ, Cohen AR, Coates T, Boudreaux J, Neufeld EJ, Kenney K, Grant A, Thompson AA; CDC Thalassemia Investigators.Transfusion complications in thalassemia patients: a report from the Centers for Disease Control and Prevention (CME). Transfusion. 2014 Apr;54(4):972-81; quiz 971. http://dx.doi.org/10.1111/trf.12348
- Ho HK, Ha SY, Lam CK, Chan GC, Lee TL, Chiang AK, Lau YL. Alloimmunization in Hong Kong southern Chinese transfusion-dependent thalassemia patients. Blood.2001 Jun 15;97(12):3999-4000. PubMed PMID: 11405212
- Abdel Gader AM, Al Ghumlas AK, Al-Momen AM, Transfusion medicine in a developing country-alloantibodies to red blood cells in multi-transfused patients in Saudi Arabia. Transfus Apher Sci.2008 ;39:199-204. http://dx.doi.org/10.1016/j.transci.2008.09.013
- Sirchia G, Zanella A, Parravicini A, Morelati F, Rebulla P, Masera G, Red cell alloantibodies in thalassemia major: results of an Italian cooperative study. Transfusion 1985 Mar-Apr; 25(2)110-2. http://dx.doi.org/10.1046/j.1537-2995.1985.25285169198.x
- Vichinsky EP, Current issues with blood transfusion in sickle cell disease. Semin. Hematol 2001 Jan ; 38( 1 suppl 1): 14-22 http://dx.doi.org/10.1053/shem.2001.20140
- Moreira Junior G, Bordin JO, Kuroda A, Kerbauy J, Red cell alloimmunization in sickle cell disease, the influence of racial and antigenic pattern differences between donors and recipients in Brazil. Am. J Hematol 1996 Jul; 52(3) : 197-200. http://dx.doi.org/10.1002/(sici)1096-8652(199607)52:3<197::aid-ajh11>3.0.co;2-d
- Sins JW, Biemond BJ, van den Bersselaar SM, Heijboer H, Rijneveld AW, Cnossen MH, Kerkhoffs JL, van Meurs AH, von Ronnen FB, Zalpuri S, de Rijke YB, Ellen van der Schoot C, de Haas M, van der Bom JG, Fijnvandraat K. Early occurrence of red blood cell alloimmunization in patients with sickle cell disease. Am J Hematol. 2016 Aug;91(8):763-9. http://dx.doi.org/10.1002/ajh.24397
- Norol F, Nadiahi J, Bachir D, Desaint C, Guillou Bataille M, Beajean F, Bierling P, Bonin P, Galacteros F, Duedari N, Transfusion and alloimmunization in sickle cell anemia patients. Transfus Clin Biol. 1994; (1): 27-34. http://dx.doi.org/10.1016/s1246-7820(05)80054-0
- Murao M, Viana MB, Risk factors for alloimmunization by patients with sickle cell disease. Braz J Med Biol Res 2005 May; 38(5) : 675-82. http://dx.doi.org/10.1590/s0100-879x2005000500004
- Yu J, Heck S, Yazdanbakhsh K. Prevention of red cell alloimmunization by CD25 regulatory T cells in mouse models. Am J Hematol. 2007;82(8):691–696. https://doi.org/10.1002/ajh.20959
- Hendrickson JE, Chadwick TE, Roback JD, Hillyer CD, Zimring JC. Inflammation enhances consumption and presentation of transfused RBC antigens by dendritic cells. Blood. 2007;110(7):2736–2743. https://doi.org/10.1182/blood-2007-03-083105
- Murao M, Viana MB. Risk factors for alloimmunization by patients with sickle cell disease. Braz J Med Biol Res. 2005;38(5):675–682. https://doi.org/10.1590/s0100-879x2005000500004
- Gill FM, Sleeper LA, Weiner SJ, Brown AK, Bellevue R, Grover R, Pegelow CH, Vichinsky E. Clinical events in the first decade in a cohort of infants with sickle cell disease: Cooperative Study of Sickle Cell Disease. Blood. 1995;86(2):776–783.
- Chou ST, Westhoff CM, Molecular biology of the Rh system: clinical consideration for transfusions in sickle cell disease. Am Soc Hematol Educ program 2009: 178-84. http://dx.doi.org/10.1182/asheducation-2009.1.178
- Boturao-Neto E, Chiba AK, Vicari P, Figueiredo MS, Bordin JO, Molecular studies reveal a concordant KEL genotype between patients with hemoglobinopathies and blood donors in Sao Paulo City Brazil. Haematologica 2008 sep;93(9): 1408-10. http://dx.doi.org/10.3324/haematol.12766
- Vichinsky EP, Luban NL, Wright E, Olivieri N, Driscoll C, Pegelow CH, Adams RJ, Prospective RBC Phenotype matching in a stroke –prevention trial in sickle cell anemia :a multicenter transfusion trail. Transfusion 2001 Sep; 41(9): 1086-92. http://dx.doi.org/10.1046/j.1537-2995.2001.41091086.x
- Guidelines for pre-transfusions compatibility procedures in blood transfusions laboratories-BCSH Blood Transfusions Task Force. Transfus Med. 1996 Sept; 6(3):273-83. http://dx.doi.org/10.1111/j.1365-3148.1996.tb00079.x
- Vichinsky EP, Ohene-Frempong K, Thein SL, Lobo CL, Inati A, Thompson AA, Smith-Whitley K, Kwiatkowski JL, Swerdlow PS, Porter JB, Marks PW, Transfusion and chelation practices in sickle cell disease: a regional perspective. Pediatr Hematol Oncol 2011 Mar; 28(2): 124-33. http://dx.doi.org/10.3109/08880018.2010.505506
- Castro O, Sandler G, Houston –Yu P, Rana S, Predicting the effect of transfusing only phenotype –matched RBC to patients with sickle cell disease: theoretical and practical implications. Transfusions 2002 Jun; 42:684-90. http://dx.doi.org/10.1046/j.1537-2995.2002.00126.x
- Fasano RM, Chou ST. Red Blood Cell Antigen Genotyping for Sickle Cell Disease, Thalassemia, and Other Transfusion Complications. Transfus Med Rev. 2016 Oct;30(4):197-201. http://dx.doi.org/10.1016/j.tmrv.2016.05.011
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