Bone Marrow Transplantation (2004) 33, 1169–1172 & 2004 Nature Publishing Group All rights reserved 0268-3369/04 $30.00 www.nature.com/bmt

Review Non-ABO red cell alloantibodies following allogeneic hematopoietic stem cell transplantation

M Franchini, G Gandini and G Aprili

Servizio di Immunoematologia e Trasfusione, Azienda Ospedaliera di Verona, Verona, Italy

Summary: and minor blood group incompatibility but, not rarely, more than one type of mechanism is involved.1 Immune-mediated is a well-recognized occur- Alloimmune hemolytic anemia (AHA) following major rence which complicates the period following a bone and minor ABO-mismatched allogeneic hematopoietic stem marrow transplant (BMT). However, although many cell (HSC) transplantation is one of the most common and studies have investigated the hemolytic anemia following dangerous immunohematological complications of this ABO-incompatible BMT, data regarding the occurrence procedure.2 Less frequently, other RBC antigen systems, of alloantibodies against (RBC) antigens in most cases those of the Rh system, have been implicated other than ABO in patients undergoing hematopoietic in the development of AHA.1 However, although the stem cell transplantation are limited. In this review, we hemolytic complications following ABO-incompatible briefly analyze the most important non-ABO red blood BMT have been investigated by several authors,2 only few cell (RBC) antigen systems involved in the development of reports, almost anecdotally, have described the immuno- post-BMT alloimmune hemolytic anemia, paying parti- hematological complications following non-ABO incompa- cular attention to the pathogenic mechanisms and the tible transplants. In this review, we briefly report the most clinical significance of the alloantibodies involved. Among important non-ABO RBC antigen systems implicated in the non-ABO RBC antigens, RhD antigen is the one most post transplant AHA and analyze their clinical significance. frequently implicated in the development of post-BMT alloimmune hemolytic anemia. Although less frequent than hemolysis following transplants with ABO incompat- ibility, non-ABO-incompatible allograft hemolysis may Incidence of non-ABO RBC alloantibodies after allogeneic severely complicate the post-BMT period creating difficult BMT clinical management issues. For this reason, we advise careful pre-transplant donor and recipient checks for the Only few data are available in the published literature on most important RBC antigen systems and close post- the frequency of non-ABO red cell alloimmunization in the BMT immunohematological monitoring in those patients post transplant setting.3–7 Ting et al3 described the undergoing allogeneic hematopoietic stem cell transplant production of non-ABO red cell alloantibodies in 13 of with RBC antigen incompatibility. 150 patients (8.7%) after BMT. However, examining the Bone Marrow Transplantation (2004) 33, 1169–1172. series carefully, only nine of the 150 (6%) had non-ABO doi:10.1038/sj.bmt.1704524 alloantibodies that had developed during the post-BMT Published online 19 April 2004 period. Abou-Elella et al4 found that two of 45 patients Keywords: hematopoietic stem cell transplantation; red (4.4%) who received an allogeneic BMT developed non- blood cells; alloantibodies; hemolysis ABO alloantibodies after the transplantation. De la Rubia et al5 recently reported a similar frequency (3.7%) in a series of 217 patients undergoing allogeneic hemopoietic Hemolysis is a well-recognized complication of allogeneic peripheral cell transplantation and also identified ABO bone marrow transplantation (BMT) and may be caused by incompatibility and patient’s age as the only two variables immune and nonimmune mechanisms. Post transplant significantly associated with the development of non-ABO immune-mediated hemolysis may be the result of auto- RBC alloantibodies. In a retrospective analysis of the blood immune effects, passenger lymphocyte syndrome, major bank records of 427 allogeneic HSC transplant recipients seen between 1994 and 1999, Young et al6 observed a very low incidence (nearly 1%) of post-BMT non-ABO/RhD red cell alloantibodies. If the incidence of such alloanti- bodies in the post-BMT period is low, the frequency with which they cause clinically significant immune hemolysis Correspondence: Dr M Franchini, Servizio di Immunoematologia e seems to be even much lower. In fact, Hows et al7 found Trasfusione, Ospedale Policlinico, 37134 Verona, Italy; E-mail: [email protected] that only one out of the four patients with post-BMT anti- Published online 19 April 2004 Rh alloantibodies developed clinical hemolysis. However, Non-ABO RBC alloantibodies and BMT M Franchini et al 1170 Table 1 Non-ABO red blood cell group antigen systems involved in the development of post-BMT alloimmune hemolytic anemia

RBC antigen Antibodies Mechanism of hemolysis system

Rh system Anti-D, -C, -c, -E Delayed hemolytic anemia,13,21,32 which may be severe after major Rh-mismatched grafts.15 Passenger lymphocyte syndrome7 and chronic hemolysis (in the case of persistence of mixed chimerism)8 have also been described Kell system Anti-Kell Delayed hemolytic anemia25,28 Kidd system Anti-JKa, -JKb Severe acute hemolytic anemia with intravascular hemolysis (passenger lymphocyte syndrome),6,29 delayed hemolytic anemia25 MNSs system Anti-M, -N, -S, -s Delayed hemolytic anemia6,25 Lewis system Anti-Lewisa, -Lewisb Passenger lymphocyte syndrome26

although rare, hemolytic episodes have often been de- patients undergoing BMT with incompatibilities involving scribed as severe.1,7 the RhD system should receive prophylaxis with infusion of Table 1 summarizes the most important non-ABO RBC Rh-negative blood or anti-RhD immunoglobulins. An anti- group antigen systems involved in the development of RhD antibody does not necessarily pre-exist, since it may clinically significant post-BMT alloimmune hemolytic be produced during the BMT due to the mismatch between anemia. the donor and recipient. A RhD-positive bone marrow recipient may develop anti-RhD antibodies following transplant if the donor is RhD negative. The recipient’s Incompatibility involving the Rh system residual RBC (RhD positive) may be sufficiently numerous to stimulate the donor’s engrafted lymphocytes.1 However, Among the non-ABO red cell antigen systems, the Rh this event occurs only rarely since the donor-related system is the one most frequently implicated in the primary immune response usually starts about 6 months development of post transplant AHA.1,8 Mismatching of after BMT and after this period, if recipient bone marrow is the Rh system has different features from ABO mis- 100% of donor origin, residual RhD-positive recipient matches.9 In fact, as the anti-Rh alloantibody does not RBC are no longer detectable.19 It is also unlikely that the occur naturally, we consider a major or minor Rh reverse situation (RhD-negative recipient and RhD-posi- incompatibility only when either the recipient or the donor tive donor) may develop a de novo anti-RhD antibody, has antibodies following a previous exposure (eg pregnancy since the recipient lymphocytes (the only cells capable of and/or transfusions). Although bone marrow transplants producing anti-RhD antibody) are destroyed by the with Rh incompatibility involving C, c and E antigens have conditioning treatment. However, if mixed erythrocyte been described in the medical literature,7,10,11 most reports chimerism persists after the BMT, severe hemolytic anemia regard the D antigen.12–16 Like ABO incompatibility, RhD due to the development of autoantibodies with donor– incompatibility can cause hemolytic anemia after BMT.9 A antirecipient specificities for non-ABO system RBC anti- major RhD incompatibility between donor and recipient of gens may complicate the post transplant period.8 Another a BMT may lead to a severe delayed hemolytic anemia.15 occurrence in the BMT setting is alloimmunization, in Panhypoplasia was observed in a patient following a major patients receiving RhD-negative bone marrow transplants, RhD incompatible BMT with marrow recovery after the against concentrates from RhD-positive donors. subsequent spontaneous reduction in the anti-RhD titer.17 This event seems to be not uncommon: the incidence of A minor RhD incompatibility can cause both immediate anti-RhD antibodies in oncohematologic patients who and delayed hemolysis, the former being due to anti-RhD underwent autologous BMT and received platelet transfu- alloantibodies produced by lymphocytes infused with the sions seems to be nearly 20%.20 For this reason, some donor marrow (passenger lymphocyte syndrome) and the authors suggest prophylaxis with intravenous anti-RhD latter being due to anti-RhD alloantibodies produced by immunoglobulins during platelet transfusions in such donor engrafted lymphocytes.7 A simultaneous mismatch patients in order to prevent alloimmunization against involving both ABO and Rh systems can also occur and RhD.21 Conversely, other authors found a low incidence may cause hemolysis and/or pure red cell aplasia in the post of anti-D alloimmunization in hematologic patients receiv- transplant period.7,18 RhD incompatibility is treated in the ing D-incompatible platelet transfusions.22–24 same way as ABO incompatibility, in order to prevent post A BMT recipient with a pre-existing anti-RhD alloanti- transplant hemolysis.9 Thus, in the case of RhD major body must be transfused with RhD-negative RBC until the incompatibility (alloimmunized RhD-negative recipient disappearance of the alloantibody has been documented by and RhD-positive donor), RBC must be removed from the indirect antiglobulin test (IAT) and the cross-match the donor’s bone marrow by sedimenting substances such with RhD-positive RBC becomes negative.9 as hydroxyethyl starch (HES). Other strategies include Alloantibodies directed against other components of recipient plasma exchange, in order to reduce the anti-D the Rh system include anti-C, anti-c and anti-E anti- titer. In the case of RhD minor incompatibility (ie, when bodies.3,8,11 Usually, these antibodies are not isolated but the donor plasma contains anti-RhD antibodies against are associated with anti-D or antibodies against other red recipient red blood cells), plasma must be removed from the cell antigen systems,3 and may trigger or worsen a donor’s bone marrow. It has also been proposed that hemolytic picture.

Bone Marrow Transplantation Non-ABO RBC alloantibodies and BMT M Franchini et al 1171 Incompatibility involving other blood group antigens complications may develop even many years after BMT.32 Immunohematological follow-up is also important for Pre-transplant clinical consideration is usually given only to monitoring marrow engraftment and disease status. In ABO and RhD compatibility between donor and recipient. fact, following an ABO-matched BMT, it is possible to Although immune hemolysis due to ABO or RhD- identify a chimeric antigen of Rh or other red cell group mismatched marrow transplants is the most frequent systems whose appearance/disappearance in the post immunohematological post-BMT complication, occurring transplant period gives the opportunity to evaluate the in approximately 10–15% of such transplants,6 other RBC marrow engraftment. Furthermore, whereas persistence of antigen systems have been implicated less frequently in the recipient’s blood group antigens in the post transplant alloimmunization after allogeneic transplantation.25–30 period suggests that the conditioning regimen failed to However, the medical literature reports many cases of eradicate the patient’s marrow, the reappearance of the hemolysis after BMT caused by alloantibodies directed recipient’s blood group antigens may indicate a relapse of against the Kidd, MNSs and Kell antigen systems.6,25,28–30 the disease.1 Since these data are very important for the The hemolysis may be severe if several alloantibodies are hematologist, close cooperation between clinical and simultaneously involved.25 We have previously described28 laboratory staff in a BMT unit is warranted. an episode of mild hemolytic anemia 1 month after BMT due to a major Kell incompatibility (recipient with anti- Kell alloantibodies, donor Kell negative). Of the non-ABO/ References Rh alloantibodies, those directed against the Kidd antigen system are among the more frequently observed and are 1 Klumpp TR. Immunohematologic complications of bone often associated with severe intravascular hemolysis.25,29,30 marrow transplantation. Bone Marrow Transplant 1991; 8: They may cause acute hemolysis through a passenger 159–170. lymphocyte mechanism25,29 or, if mixed erythrocyte chi- 2 Rowley SD, Liang PS, Ulz L. Transplantation of ABO- merism persists, they can be responsible for a delayed incompatible bone marrow and peripheral blood stem cell hemolytic anemia.29 Young et al6 described two cases of components. Bone Marrow Transplant 2000; 26: 749–757. et al. post transplant acute intravascular hemolysis due to anti- 3 Ting A, Pun A, Dodds AJ Red cell alloantibodies a produced after bone marrow transplantation. Transfusion Jk antibodies produced by donor-derived passenger 1987; 27: 145–147. lymphocytes, successfully treated in one case with plasma 4 Abou-Elella AA, Camarillo TA, Allen MB et al. Low exchange and in the other case with steroids and red cell incidence of red cell and HLA antibody formation by bone exchange. The Lewis antigen system needs particular marrow transplant patients. Transfusion 1995; 35: 931–935. consideration. In fact, while a successful BMT leads to 5 De la Rubia J, Arriaga F, Andreu R et al. Development of the appearance of donor-type red cell antigen systems such non-ABO RBC alloantibodies in patients undergoing allo- as ABO, Rh, Duffy, Kell, MNSs, donor erythrocytes geneic HPC transplantation. Is ABO incompatibility a predis- continue to express recipient-type Lewis antigens even posing factor? Transfusion 2001; 41: 106–110. during the post transplant period because the cells do not 6 Young PP, Goodnough LT, Westervelt P, DiPersio JF. Immune hemolysis involving non-ABO/RhD alloantibodies synthesize these antigens but adsorb them from plasma.1,31 5,26 following hematopoietic stem cell transplantation. Bone There are reports of post transplant hemolytic anemia Marrow Transplant 2001; 27: 1305–1310. due to acquired anti-Lewis antibodies in Lewis-mismatched 7 Hows J, Beddow K, Gordon-Smith EC et al. Donor-derived 27 bone marrow transplants. Some authors postulated that red cell antibodies and immune hemolysis after allogenic bone Lewis incompatibility may contribute to the renal failure marrow transplantation. Blood 1986; 67: 177–181. complicating allogeneic BMT. 8 Sokol RJ, Stamps R, Booker DJ. Posttransplant immune- mediated hemolysis. Transfusion 2002; 42: 198–204. 9 Friedberg RC. Transfusion therapy in the patients undergoing Conclusions hematopoietic stem cell transplantation. In: Mintz PD (ed.) /Oncology Clinics of North America. I Patients undergoing non-ABO mismatched allogeneic . WB Saunders Company: Philadelphia, 1994; pp 1105–1116. BMT are at risk of developing alloantibodies against 10 Heim MU, Schleuning M, Eckstein R et al. Rh antibodies non-ABO RBC antigens. Although rarely, the antibody against the pretransplant red cells following incompatible bone formation may complicate the post transplant period by marrow transplantation. Transfusion 1988; 28: 272–275. causing clinically significant hemolysis. If hemolysis occurs, 11 Tasaki T, Sasaki S, Gotoh K et al. Multiple red blood cell it is often severe. antibodies produced by donor B lymphocytes after ABO- For this reason, we advise pre-transplant donor and matched allogeneic bone marrow transplantation. Transf Sci recipient checks of Rh phenotype and of the other 1999; 20: 121–127. erythrocyte antigen systems involved in post-BMT alloim- 12 Esteve J, Alcorta I, Pereira A et al. 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