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 blood 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 hemolysis 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 red blood cell (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 platelet 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