Transfusion Support During Hematopoietic Cell Transplantation

Blood products are essential during the peritransplant period. Patients receiving hematopoietic cell transplantation (HCT) require extensive transfusion support until appropriate platelet and red blood cell (RBC) engraftment ensures. The platelet lineage is considered engrafted when a patient’s platelet count is at least 20,000/µL after 3 consecutive days without platelet transfusion; neutrophil engraftment is defined by when the absolute neutrophil count (ANC) reaches > 500/µL for 2 consecutive days; and RBC engraftment (more difficult to assess) is declared by the appearance of 1% reticulocytes in the peripheral blood or on the day of the last RBC transfusion, with no transfusion given the following 30 days. Several factors are predictive for increased transfusion requirement during the peritransplant period including: ABO incompatibility, conditioning intensity, CD34+ cell dose, source of the stem cells, and presence of acute graft-versus-host disease (GVHD).

Human leukocyte antigen (HLA) matching has become a very distinguished predictor of success in HCT. Similarly to pursuing an HLA compatible donor to decrease the risk of GVHD and nonrelapse mortality (NRM), administering ABO compatible blood products is important to lessen potential complications from antigenic blood incompatibility. In the present review, we will discuss the transfusion support of patients undergoing HCT, common transfusion-related complications, and the measures to address and prevent these potential complications.

Red Blood Cell Concentrates

In general, one unit of RBC should increase the hemoglobin level of an adult by 1 g/dL. In children, a formula is applied as follows:

\begin{matrix} Volume (mL of RBC) : target Hgb after transfusion (g/dL) \\ - pretransfusion Hgb (g/dL) \\ \times 4 \times weight (Kg) . \end{matrix}

$\begin{matrix} Volume (mL of RBC) : target Hgb after transfusion (g/dL) \\ - pretransfusion Hgb (g/dL) \\ \times 4 \times weight (Kg) . \end{matrix}$

Over the last decades many studies have favored a restrictive RBC transfusion threshold of 7 to 8 g/dL hemoglobin for hemodynamically stable adult patients, and a level of 8 g/dL for patients with preexisting cardiovascular disease. A randomized clinical trial compared the use of a liberal strategy (hemoglobin < 9 g/dL) versus a restrictive strategy (hemoglobin of < 7 g/dL) between day 0 and day 100 in patients undergoing HCT. While HCT-associated outcomes and quality of life assessment were similar in both groups, there was a trend toward a lower number of RBC units transfused in the restrictive strategy group, supporting the use of this strategy.

Platelet Concentrates

Most platelet concentrates arise from the collection of four to five units of whole blood from “random donors.” Platelets are stored at 20°C to 24°C for up to 5 days. ABO antigens are intrinsic to platelets, and ABO incompatibility can reduce the survival of transfused platelets and be a cause of platelet refractoriness. On the other hand, Rh antigens are not present on the platelet surface, however, some RBCs contained in the platelet concentrate can lead to alloimmunization, thus Rh compatibility must be considered for these effects. The 1-hour posttransfusion platelet count is an important predictor of effective platelet transfusion.

The adequate use of prophylactic platelet transfusions in the transplant setting has been evaluated. The first prospective randomized clinical trial (PLADO trial) addressing this issue evaluated 1272 HCT recipients (children and adults) who received a prophylactic platelet transfusion when the morning platelet count fell below a 10,000/µL (10 K) or 20,000/µL (20 K) threshold. The number of prophylactic and therapeutic transfusions and the incidence of minor and major bleeding were comparable between the two groups, and the prophylactic approach was considered to be safe. In an age-group analyses of the PLADO trial, children had a significantly higher risk of bleeding than adults when receiving a low dose platelet transfusion.

The TOPPS trial randomly assigned patients who were receiving chemotherapy or HCT to receive prophylactic platelet transfusions for counts less than 10,000/µL (prophylaxis group) or when clinically indicated (no-prophylaxis group). A total of 600 patients were included; 70% who received autologous HCT (auto-HCT); 12% allogeneic HCT (allo-HCT) with reduced-intensity conditioning; and 1% allogeneic HCT with myeloablative conditioning (MAC). A significant number of patients had bleeding despite prophylaxis; however, patients in the no-prophylaxis group had more days with bleeding and a shorter time to the first bleeding episode. Another large prospective trial randomized patients with acute myeloid leukemia (AML) receiving chemotherapy and patients undergoing auto-HCT to the prophylactic or therapeutic strategy. While there was no increased risk of major hemorrhage in patients who had autologous transplantation, for those with AML, the risk of nonfatal grade 4 (mostly central nervous system) bleeding was increased. The results of these studies supported the continued use of prophylaxis with platelet transfusion in patients undergoing HCT.

Granulocytes Transfusions

Several studies in the 1970s suggested improved survival in neutropenic patients with gram-negative bacteremia who received granulocyte transfusion (GXT); however, their use took a pause when the use of recombinant granulocyte colony-stimulating factor (G-CSF) was approved by the U.S. Food and Drug administration (FDA) in the early 1990 s. The Resolving Infection in people with Neutropenia with Granulocytes (RING) study was a 5-year randomized controlled trial that addressed the utility of G-CSF mobilized GXT in patients with neutropenia caused by chemotherapy or HCT who had proven or probable bacterial or fungal infection. Because of slow accrual criteria, it was expanded after 31 months to include the concept of “presumed infections” and nonmalignant conditions. The study did not show significant benefit on the patients treated with GTX, but a post hoc analysis in the GXT arm demonstrated improved outcomes in those who received high-dose GTX (≥ 0.6 × 10 ⁹ × Kg) versus low dose (<0.6 × 10 ⁹ × Kg) with an efficacy of 59% versus 15%, respectively. Nevertheless, GTX remains controversial because of the lack of evidence confirming efficacy, the logistic hurdles that involve the collection and prompt infusion of granulocytes given their short half-life (window of 6–7 hours), and potential adverse events such as HLA alloimmunization and transfusion-associated volume overload.

Fresh Frozen Plasma, Cryoprecipitate, and Fibrinogen

Fresh frozen plasma (FFP) is separated from whole blood and placed at –18°C or lower within 8 hours of collection. FFP is not considered to have RBCs and thus can be administered without regard of Rh type; however, it does contain ABO antibodies and must be compatible with the recipient’s red cells. Cryoprecipitate is considered the cold-insoluble portion of FFP that is thawed at 1°C to 6°C and stored at 18°C or below, for up to 1 year. Cryoprecipitate contains factor VII, von Willebrand factor, and fibrinogen. Fibrinogen concentrate is recommended for fibrinogen level < 100 mg/dl, although in cases of hemorrhage or bleeding a goal of > 150 mg/dL has been used.

Peritransplant Consideration

Before transplant, patients may be immunocompromised from their primary malignancy and associated therapies, or immunocompetent (i.e., patients with thalassemia, aplastic anemia, or sickle cell disease). Immunocompetent recipients are able to mount an immune response to transfusions with antibodies against HLA leading to alloimmunization, translating in an increased need for blood products and decreased donor T-cell chimerism. Thus, we minimize blood products in this patient population, unless clearly necessary. When indicated, the use of leukoreduced products decreases the risk of alloimmunization. A similar approach should be used in immunocompromised patients, even though they are less likely to become sensitized to these antigens. Another important consideration is to avoid providing blood products from family members, as these relatives may become a potential donor, and this may sensitize the recipient against their potential donor. Most of the patients, using or not using MAC regimens, will need some degree of blood product support throughout their transplant. The AABB (formerly American Association of Blood Banks) recommends adhering to a restrictive transfusion strategy (7–8 g/dL) transfusing irradiated RBC units in a hemodynamically stable and otherwise asymptomatic patient. The evidence also suggests the use of prophylactic platelet transfusion for a goal of > 10,000/µL platelets.

Transfusion-Related Complications

Standard transfusion-related complications, such as allergic or febrile nonhemolytic reactions, are common in patients heavily transfused. Other complications arise when lymphocytes within the transplant are activated against the recipient, leading to transfusion-associated graft-versus-host disease (TA-GVHD) and passenger lymphocyte syndrome (PLS), or pure red cell aplasia (PRCA) when a patient’s residual antibodies attack the graft.

Transfusion-Associated Graft-Versus-Host Disease

This is a rare complication that tends to be fatal. It is caused by the transfusion of viable T cells present in blood products that are not rejected by the recipient. Usually, in immunocompetent hosts, these viable T lymphocytes are destroyed by the recipient's immune system; however, in immunocompromised patients, these lymphocytes are not recognized nor destroyed, thus they mount an immunologic response against the host.

The incidence of TA-GvHD is relatively low, but 10 to 20 times higher in populations with less HLA diversity, such as in the Japanese population. Signs and symptoms begin 2 to 30 days after transfusion, and include an erythematous, maculopapular rash, fever, elevated liver enzymes (with or without hepatomegaly or jaundice), diarrhea, nausea, vomiting, and bone marrow (BM) failure, which progressively develops with death secondary to infection and/or bleeding complications. Diagnosis can be supported by biopsies (skin, liver, or bowel) taking into account the clinical context.

Treatment of TA-GVHD is largely palliative and aimed at improving the recovery of the recipient's immune system and BM failure. Prevention becomes of vital importance. Majority of cases of TA-GVHD are attributed to cellular, nonirradiated, nonleukoreduced components that are stored for less than 10 days. Irradiation (with at least 2500 cGy) of blood products and pathogen reduction can abrogate in some degree the risk of TA-GVHD. RBC, platelet, and granulocyte units all carry risk for TA-GVHD, while FFP is not considered to increase the risk. Any blood component from relatives is considered to be at higher risk because of shared HLAs, and should be avoided.

ABO Incompatibility

ABO incompatibility occurs in more than 30% of cases. ABO mismatch HCT does not seem to adversely affect survival, TRM, or severe acute GVHD (aGVHD); nonetheless it carries the risk of complications that should be identified and managed accordingly by the transplant physician. The nature and degree of the complication depend on whether the incompatibility was considered a major or minor mismatch. Minor ABO incompatibility is characterized by the ability of donor B lymphocytes to produce antirecipient isoagglutinins; in contrast, a major ABO-incompatibility is characterized by the presence of preformed antidonor isoagglutinins. In bidirectional ABO incompatibility, a combination of both the major and minor ABO blood group barriers must be overcome ( Table 6.1 ).

Table 6.1

ABO Mismatching in Allogeneic Hematopoietic Cell Transplant

ABO Mismatch	ABO Blood Type		Potential Consequences	Etiology	Potential Interventions
	Recipient	Donor
MAJOR	O A B	A, B, or AB AB AB	- Acute hemolytic anemia - Delayed RBC, granulocyte and platelet engraftment - PRCA	- Transfusion of incompatible RBCs - Presence of recipient antidonor isohemagglutinins	- RBC reduction of stem cell product - Plasma exchange in recipient before transplant (to reduce isohemagglutinins, rarely used in the United States) - Erythropoietin administration
MINOR	A B AB	O O O, A or B	- Acute hemolytic anemia - Delayed hemolysis secondary to PLS	- Donor plasma with high isohemagglutinin titers - Passenger lymphocytes producing isohemagglutinins	- Plasma reduction - Monitoring hemolysis parameters
BIDIRECTIONAL	A B	B A	- Combination of major/minor consequences	- Combination of major/minor causes	- Combination of major/minor interventions

PLS , Passenger lymphocyte syndrome; PRCA , pure red blood cell aplasia; RBC , red blood cell.

Major ABO Incompatibility

Immediate and Delayed Transfusion Reactions : Major ABO incompatibility complications include hemolysis at the time of graft infusion, delayed RBC engraftment, or PRCA. ²⁸ The source of stem cells is of importance: approximately 1000 mL of BM product can contain up to 450 mL of RBCs. Cord blood units (100 mL total volume) may contain proportionately large volumes of RBCs; however, the process of prestorage tends to reduce the RBC content. Peripheral blood progenitor cell (PBPC) collection has low RBC volume but greater content of lymphocytes that may increase the risk of delayed hemolysis and aGVHD. The risk of hemolysis can be decreased by reducing the RBC content of the graft or alternately by reducing the recipient isoagglutinin titers by plasma exchange, in vivo immunoadsorption, or infusion of donor-type RBCs.

Pure Red Cell Aplasia: The incidence is about 16% of ABO incompatible patients and is frequently seen with group O patients receiving a group A transplantation or with bidirectional mismatches. The presence of activated recipient antibodies directed against donor RBCs leads to a delay in erythroid recovery, which is reflected by a lack of erythroid precursors in BM and peripheral reticulocytopenia that can persist for months to years after transplantation. Patients require continuous RBC support and are at risk for transfusion-associated side effects. Therapy has been limited to the results of small studies and case reports, and includes tapering immunosuppression, steroids, donor lymphocyte infusions (DLI), rituximab, bortezomib, or daratumumab to suppress antibody-producing B-cells, or plasmapheresis to eliminate isohemagglutinins. Nevertheless, these treatments have been used with varying degree of success and there is no defined standard of care.

Minor ABO Incompatibility

Passenger Lymphocyte Syndrome : This phenomenon, described in both solid transplant and HCT, is caused by transient antibody production from passenger immunocompetent donor lymphocytes against the recipient's erythrocytes, which may cause delayed hemolysis, 5 to 15 days after allo-HCT. It may manifest with a precipitous drop in hemoglobin, along with positive hemolysis parameters. A positive direct antiglobulin testing or direct Coombs (which may become negative if all the antibody-bound cells have already lysed) and measurement of antibodies against the recipient's RBC antigens may provide a useful hallmark for the diagnosis of PLS. Risk factors include the use of unrelated donors, pairing group A or group AB recipients with group B donors, and the use of calcineurin without methotrexate for GVHD prophylaxis. Treatment may involve the use of steroids, rituximab, plasma exchange or red cell exchange.

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