Transfusion support is one of the major supportive care procedures performed for hematologic malignancies and patients with benign hematologic diseases. Hematopoietic stem cell transplantation (HSCT) is a curative therapy for these patients and requires human leukocyte antigen (HLA) matching, which is a major barrier to donor selection. Rigorous matching is associated with favorable outcomes [1]. ABO and Rh matching statuses are not considered before HSCT, but crossing the ABO and Rh barrier has caused complications after HSCT and difficulties in selecting optimal transfusion products [2]. In this review, we discuss the various aspects of transfusion support before, during, and after HSCT.

ABO antigens are multiple sugar chains or oligosaccharides that are attached to the surface of red blood cells (RBCs) or N-glycans or O-glycans. ABO antigens are assembled by attaching sugars to an enzyme that can add sugar to a preexisting sugar molecule (Fig. 1A). The A and B blood antigens are formed by the sequential attachment of sugars (Fig. 1B) [3]. In the final step, the ABO gene located on chromosome 9q34 encodes a glycosyltransferase that adds A- or B-specific sugars at the end of the H antigen [4-6]. These antigens are located in the RBCs, platelets, and endothelium of vascularized organs.

These ABO blood group antigens are not a prerequisite for T cell sensitization for the production of antibodies and are poor inducers of T cell-specific response [7-10]. ABO antibodies are mostly IgM or IgG, which are formed by extrafollicular B-1 cells, whereas antipeptide antibodies are formed by follicular B-2 cells [11-13].

The ABO blood group is important in solid organ transplantation and can cause hyperacute rejection via preexisting isoagglutinin (anti-A and/or anti-B). The importance of ABO blood group matching status is less critical in HSCT than in organ transplantation, such as the kidney or liver [8, 9]. However, ABO-incompatible HSCT can cause some transfusion-related issues.

RhD incompatibility should also be considered. If RhD antigens differ between donors and recipients, the HSCT would be a RhD blood group antigen mismatch. The presence of anti-RhD antigens in donors or recipients before HSCT is incompatible with the RhD blood group antigen (Table 1) [14-16]. A minor RhD mismatch can be defined as a negative donor with a RhD-positive recipient. A major RhD mismatch can be defined as RhD-positive donors with RhD-negative recipients. Several studies showed that alloimmunization of RhD or anti-D production occurred in 9% of minor RhD mismatch HSCT, whereas 1% occurred in major RhD mismatch HSCT RhD blood group mismatch [17, 18].

RhD-negative blood is recommended for transfusion unless both the donor and recipient have RhD blood antigens. Because RhD-negative blood is rare in some regions, an alternative strategy may be considered. For RhD-positive recipients and RhD-negative donors, RhD-positive blood can be transfused until RhD antigens are weakened. For RhD-negative recipients and RhD-positive donors, RhD-negative blood should be selected until the RhD antigen appears to some degree, and then RhD-positive blood should be selected. In the case of platelets, anti-RhD should be administered before RhD-incompatible transfusion [17, 18].

HLA molecules are located on the short arm of chromosome 6 (6p21.3) with diverse polymorphic features. Class I HLA molecules (HLA-A, -B, and -C) are expressed in platelets and all nucleated cells, except neurons, corneal epithelial cells, trophoblasts, and germinal cells [19-21]. Only trace amounts are expressed in RBCs, designated as the Bg^a (HLA-B7), Bg^b [HLA-B17 (B57, B58)], and Bg^c [HLA-A28 (A68, A69)] blood groups [3, 4]. Class II HLA molecules (HLA-DR, HLA-DQ, and HLA-DP) are expressed in lymphocytes, monocytes, macrophages, dendritic cells, the intestinal epithelium, and early hematopoietic stem cells. Under certain conditions, endothelial cells or resting T cells can be induced to express HLA [3, 4].

These molecules are closely located and inherited en bloc, with one haplotype from the paternal and the other from the maternal side. This inheritable pattern results in a 25% chance of matching siblings. This close location also results in linkage disequilibrium, indicating that certain pairs of HLA molecules are more frequently found [20, 21-23].

Because HLA molecules are immunogenic factors, the HLA locus should be matched to overcome the histocompatibility barrier. As HLA matching status is the main criterion for donor selection and HLA genes are inherited independently from the ABO gene, 40–50% of HSCT procedures are performed across the ABO blood group [24-26].

The estimation of the effect of HLA mismatch is complicated by the diversity of HLA alleles and the occurrence of a mismatch from different loci with different allele combinations. These variables were simplified and yielded averaged results for many variables. A speculated hazard ratio of HLA-A, HLA-B, HLA-C, and HLA-DRB1 mismatching compared to perfect matching resulted in overall mortality as follows: 1.17 to 2.20; 1.16 to 1.90; 1.13 to2.12 and 0.97 to 1.81, respectively [23-26].

HSCT is a curative treatment for certain hematologic diseases. The type of HSCT can be classified as autologous, related, or unrelated allogeneic, HLA-matched, or mismatched allogeneic depending on the donors [26-28]. Autologous HSCT procedures were performed for plasma cell myeloma (50%) and lymphoma (40%), and allogeneic HSCT is performed for malignant diseases, including acute myeloid leukemia (40%), acute lymphoid leukemia (15%), and others (35%) [19]. HSCT using stem cell sources can be classified as bone marrow, peripheral blood stem cells, and cord blood. For patients lacking suitable donors, a haploidentical donor from a first-degree related donor can be used for HSCT [25, 29].

The advantages and disadvantages of peripheral blood HSCT include rapid engraftment compared to bone marrow transplantation and the incidence of chronic graft versus host disease (GVHD) has increased compared to bone marrow transplantation, respectively. For cord blood transplantation, rapid collection and administration of grafts are possible with lower infections and GVHD and less stringent HLA matching criteria, whereas engraftment has been delayed, and graft rejection and relapse have increased [30].

Transfusion support is a critical supportive method for the patient before (Phase I), during (Phase II), and after (Phase III) HSCT [3, 10]. The general principle of transfusion is to transfuse cells or plasma that exactly matches the donor and recipient. However, these circumstances are usually unmet for patients undergoing HSCT. Therefore, additional principles are required to ensure a safe transfusion. If exact matching is unavailable, transfusion should be performed on the recipient using a product expressing fewer antigens and antibodies. For example, packed red blood cells (PRC) with blood group O can be transfused into recipients with an AB blood group. As antibodies are an important factor for transfusion with abundant plasma components, platelets, fresh frozen plasma, or cryoprecipitate with blood group AB can be transfused to a recipient. Determination of ABO and Rh typing is important for transfusion. Cell typing and serum typing results should be considered when determining blood groups [3-6].

A restrictive RBC transfusion threshold of 7 g/dL hemoglobin is recommended for hemodynamically stable adults. The recommended transfusion threshold is 8 g/dL for patients with underlying diseases such as cardiovascular disease, evidence of end-organ damage, acute brain injury, anemia-related symptoms, or unexplained hypotension [9, 31]. Platelets should be transfused for nonbleeding, non-febrile adult patients with a platelet count ≤10×10⁹/L. Active bleeding and febrile adult patients might be transfused at platelet count ≤20×10⁹/L or higher depending on the patient status. For patients scheduled for invasive procedures, a platelet count threshold of ≤50×10⁹/L is recommended, and for patients scheduled for procedures involving closed anatomical spaces, a platelet count threshold of ≤100×10⁹/L is recommended [29-31]. Implementation of the PBM program substantially decreased the transfusion of PRC and PLT products. Warner et al. [29] reported that, before PBM implementation, 80.7% (284/352) patients received PRC, whereas 63.2% (225/356) received PRC after implementation (P<0.001). Among PLT products, 73.4% received PLT, whereas 48.8% received PLT after implementation (P<0.001) [9, 29]. For patients scheduled for induction chemotherapy or HSCT, Leahy et al. [32] reported that PRC and PLT quantities decreased from 111 units to 72 units and from 121 units to 78 units, respectively, from 2010 to 2015. PBM of fresh frozen plasma or cryoprecipitate is beyond the scope of this review [33-37]. It has been reported that peritransplantation RBC transfusion is associated with increased acute GVHD and higher mortality, which might be triggered by minor blood antigens in RBC and platelets or inflammation after transfusion [38]. Transfusion should be carefully planned during HSCT to maximize transfusion effects and minimize adverse events.

Patients with hematologic diseases or undergoing HSCT require transfusion products that are incomparable to those of other patients with chronic disease, and ABO or RhD barriers hinder the selection of the blood group [9, 29]. The institutional transfusion officer or PBM team could intervene in the selection of optimal blood products before, during, and after HSCT. In addition, PBM programs for HSCT could reduce transfused blood products without adverse clinical outcomes [29].

Packed RBC, leukocyte-reduced RBC, packed platelet, single donor-derived platelet, fresh frozen plasma, cryoprecipitate, and granulocytes are some of the most commonly transfused products. Most of the products are irradiated with gamma rays or X-ray irradiators (25–50 Gy) to prevent GVHD and leukoreduction (leukocyte <1×10⁶/unit), except for granulocyte products [39, 40]. The British Society of Hematology recommends that irradiated components should be continued until all the following criteria are met [41]:

As patients might have GVHD, administration of immunosuppressants, different HSCT conditions, underlying diseases, and previous treatments, usually, lifetime use of irradiated blood administered as immunological reconstitution status is difficult to confirm [42].

ABO incompatibility could be classified as major, minor, or bidirectional incompatibility (Table 2). Major incompatibility can be defined as the recipient having preformed antibodies or isoagglutinin against the donor RBCs or graft. This occurs in recipients with O blood type with donors with non-O blood type and recipients with A or B blood group with donors with AB blood group [2, 43].

The clinical complications of major incompatibility include hemolysis, delayed RBC engraftment, pure red cell aplasia (PRCA), and delayed granulocyte or platelet engraftment. To prevent hemolytic anemia (HA) complications, erythrocytes can be depleted using bone marrow-derived grafts. Isoagglutinins can be removed from recipients if the titer is greater than or equal to 1:128 via plasmapheresis or extracorporeal immunoadsorption. The prevention or treatment of sinusoidal obstruction syndrome or veno-occlusive syndrome can be performed using ursodeoxycholic acid or defibrotide, respectively [44, 45].

HA associated with HSCT could be associated with an underlying disease, infection, drug-induced HA, and passive transfer of ABO antibodies. After HSCT, acute HA due to isoagglutinin, thrombotic microangiopathy, and autoimmune HA should be excluded [44-47]. PRCA is a complication associated with major or bidirectional incompatibility after HSCT and is characterized by anemia, reticulocytopenia, and the absence of erythroid progenitors. Other causes of RBC depletion, such as infection, hemolysis, relapse, and drug effects, should be excluded [44, 45]. Reduced-intensity conditioning, cyclosporine administration for GVHD prophylaxis, high initial isoagglutinin levels, sibling donor as stem cell sources are the known risk factors [46, 47]. Treatment of PRCA includes plasmapheresis, transfusion support, high-dose erythropoietin, donor lymphocyte infusion, anti-thymocyte globulin, rituximab, and steroids [47, 48]. In addition, an increase in transfusion amount was noted for major and bidirectional incompatibilities compared to minor incompatibilities [47, 49].

Minor incompatibility can be defined as a donor with antibodies or isoagglutinin against the recipient RBCs. This occurs in recipients with A, B, or AB blood groups and donors with O blood group or recipients with AB and donors with A or B blood groups. Clinical complications of minor incompatibility include acute HA or passenger lymphocyte syndrome (PLS), which causes delayed hemolysis [3-6].

PLS is an unpredictable complication usually occurring at 1–3 weeks after HSCT and is caused by hemolysis of recipient RBCs produced by donor lymphocytes. GVHD prophylaxis by sole cyclosporine or reduced-intensity conditioning is common in PLS in patients with the A blood group receiving stem cells from the O blood group. When antibodies are produced against the ABO blood group, hemoglobin and haptoglobin levels decrease, whereas laboratory parameters associated with intravascular hemolysis increase. Elevated lactate dehydrogenase, aspartate aminotransferase, indirect bilirubin, and urine hemoglobin levels have been reported [2, 43].

Alloimmunization against minor red blood cell antigens can occur and persist for several years [3, 5]. These antibodies are known to be either produced by the donor or recipient immune system against residual RBCs. The incidence of alloantibody formation against minor ABO antibodies is from 2.1% to 3.7% [44, 45].

Prevention of clinical features for minor incompatible cases includes alleviating PLS by a selection of a graft from peripheral blood stem cells, administration of calcineurin inhibitors, or exchange of donor RBCs before HSCT. Treatment strategies applied to autoimmune HA, such as intravenous immunoglobulin therapy or rituximab administration, can be considered [45]. Late engraftment of leukocytes has been noted for minor incompatibility compared to major and bidirectional incompatibility [46, 47].

Bidirectional incompatibility can be defined as a recipient having A or B blood groups and a donor having B or A groups, respectively. Transfusion of RBCs can be performed using the O blood group, and for platelets and plasma transfusion, the AB blood group can be selected. Bidirectional incompatibility can have features of both major and minor incompatibilities [46-49].

The advantages of cord blood include lower immunogenicity and lower incidence, severity of chronic GVHD, whereas disadvantages include delayed engraftment, low cell dose, and increased infection risk [50]. HLA-matched, double CD34 cell dose was used for sufficient cell dose, which often results in two different ABO blood groups transplanted. Therefore, transfusion support is requested in some rare clinical situations. Cord blood HSCT in adults often requires two donors, and incompatible ABO blood groups are common in cord blood transplantation. Additionally, a patient undergoing a second HSCT with an incompatible ABO blood group from the first donor could be performed, in which RBCs of the O blood group and platelets or plasma of the AB blood group are usually selected [50, 51].

Granulocytes are white blood cells involved in the innate immune system. They perform phagocytosis, produce reactive oxygen species, release cytokines and chemokines, and are related to neutrophil extracellular traps [52-54]. Granulocyte transfusion (GT) can be administered to patients undergoing chemotherapy or HSCT for infection control. GT can cause logistic problems and difficulties in recruiting designated donors. The indications for GT are as follows [55, 56]:

As decreased granulocytes can provoke or sustain the microbial infection, GT can be a therapeutic option as a bridging therapy until the recovery of white blood cells [53-58]. However, there are various obstacles to GT. Recruiting designated donors at the time of GT requirements is difficult. Mobilization of granulocytes using G-CSF or dexamethasone could raise ethical problems and donor safety issues, and at least three days are required for the donor pre-transfusion test, mobilization, and collection of granulocytes using apheresis. The banned use of hydroxyethyl starch because of renal toxicity during the apheresis process could hinder the granulocyte dose from reaching a therapeutic level. Pooled granulocytes from approximately 10 units of whole blood can provoke alloimmunization by HLA molecules on leukocytes [55-57]. Additionally, the efficacy of GT differed by patient group, depending on organ function at the time of GT.

GT effectiveness was evaluated by risk factors composed of the area under the curve of leukocytes, secondary AML, prothrombin time, blood urea nitrogen, bilirubin, alanine aminotransferase, phosphorus, and lactate dehydrogenase [55]. There were four risk groups: lower, intermediate, high, and very high risk. The probability of 30-day survival and mean survival days for lower, intermediate, high, and very high was as follows: 87.6% (99/113), 27.5 d; 55.9% (33/59), 23.6 d; 21.1% (4/19), 13.9 d; 0% (0/19), 3.3 d, respectively [55]. Although this was not a prospective randomized controlled trial, administration of GT in the lower- or intermediate-risk group was statistically significant compared to the higher-risk group [55-57]. As GT is not a feasible treatment modality, the cost and benefit should be weighed before starting its administration. Adverse effects, including fever, alloimmunization, and pulmonary reactions, should be considered. Further studies, along with risk stratification of patients, could provide an impact on GT undergoing HSCT [58-60].

Red blood cell products contain about 2×10⁹ leukocytes, or 2×10⁶ leukocytes are present in platelet products [61]. Prestorage leukoreduced products could be administered, or a leukocyte reduction filter could be applied during transfusion. Leukocyte reduction through centrifugation or filtration reduces more than 99.9% of leukocytes, which results in a leukocyte count of less than 10×10⁶/unit. Transfusion-transmitted infections, such as HTLV-1, HTLV-2, CMV, herpesvirus, Epstein-Barr virus, and Trypanosoma cruzi could be prevented or reduced. Febrile non-hemolytic transfusion reactions and alloimmunization to leukocyte antigens including HLA could be mitigated [61]. The disadvantages of leukocyte reduction are extra cost and time, a 2% loss of RBCs, and a 10% loss of platelets. However, the benefit is higher than the disadvantages; therefore, leukocyte-reduced products are highly recommended for patients before, during, and after HSCT [61-64].

Transfusion support for HSCT is an essential part of supportive care and should be performed considering the patient and donor ABO blood group results. Local transfusion guidelines, hospital transfusion committees, and patient management should be considered for transfusions.