Immunoprophylaxis for D− patients receiving platelet transfusions from D−donors?

The current edition of the AABB Standards for Blood Banks and Transfusion Services (21st edition, 2002) requires that transfusion services have a policy for the use of D+ RBC-containing components in D− recipients (Standard 5.14.2.1).1 Approximately 30 to 40 percent of immunocompetent D− patients exposed to 0.5 to 1.0 mL D+ cells develop anti-D. For D− patients exposed to one unit of D+ blood, the alloimmunization risk exceeds 80 percent. Previously published reports indicate that as many as 19 percent of D− patients given platelet transfusions from D+ donors develop anti-D,(12-14) although some studies found that alloimmunization did not occur in patients with hematologic disorders.5,6 Platelets have ABH antigens on their surface, but not Rh system antigens. As such, D alloimmunization may occur in response to exposure to RBCs present in platelet concentrates. Ideally, D− patients should receive concentrates donated by D− donors. In practice, inventory constraints exacerbated by the limited 5-day dating period for platelet concentrates result in periodic platelet shortages with resultant pragmatic decisions to provide platelet concentrates obtained from D+ donors to D− patients. The number of RBCs per platelet transfusion varies considerably. Platelet concentrates derived from whole blood or prepared by apheresis methods contain trace to small numbers of RBCs: 0.3 to 0.5 mL per whole blood-derived platelet concentrate and 0.0002 to 0.007 mL per contemporaneous plateletpheresis components. Platelet concentrates obtained from buffy coats contain a mean of 0.59 mL RBCs per concentrate. In contrast, platelet concentrates prepared by apheresis methods in the 1970s and early 1980s contained up to 3 mL RBCs. On the basis of “evidence from well-designed, nonexperimental studies such as comparative and correlational descriptive and case studies” or Level IV evidence, American Society of Clinical Oncology Clinical Practice Guidelines state that “anti-D immunoprophylaxis should be considered for Rh D-negative children (particularly girls) and for women of child-bearing age.”7 This organization indicated further ‘there is little or no significant empirical evidence for their recommendation’, level D. Two articles in this issue of TRANSFUSION provide some empirical evidence about the risk of D alloimmunization in children and adults transfused with platelet concentrates donated by D+ donors.8,9 Molnar et al. conducted a retrospective analysis involving 42 pediatric oncology patients given WBC-reduced apheresis platelets.8 The patients had various oncologic diagnoses and received 745 D-mismatched platelet transfusions, of which 79 percent were ABO matched. The RBC content of each plateletpheresis component was approximately 0.00017 mL. Almost two-thirds of the patients had six or more exposures to transfusions from D+ donors. More than one-half of these transfusions were given at least 90 days apart, thereby potentially triggering an anamnestic response, and more than 60 percent of nontransplanted patients were followed for more than 90 days. None of the patients developed anti-D over a 2-week to 5-year follow-up interval. As a result, these investigators concluded that D immunoprophylaxis is unnecessary in pediatric oncology patients receiving WBC-reduced platelets because of the low level of RBCs present in concentrates and the immunosuppressed status of the patients studied. Cid et al. conducted a prospective study in Spain, involving 22 D− adult patients with hematologic diseases who received transfusions of platelets from D+ donors.9 The patients, mean age 56 years, received whole blood-derived pooled platelet concentrates prepared by the buffy coat method, containing 0.59 ± 0.25 mL RBCs per platelet concentrate or 4.17 ± 1.74 mL per transfusion. Ninety-one percent of the patients received immunosuppressive therapy and 41 percent died within 7 weeks of observation. None of the 22 patients developed anti-D, leading the authors to conclude that the level of immunosuppresion was more important than the RBC exposure dose. This finding is similar to that of Lichtiger et al. who reported that, in the early 1980s, none of the 30 D− oncology patients given transfusions of pooled whole-blood derived random donor and apheresis platelets containing 17.28 mL (range: 7.93-25.15 mL) D+ RBCs developed anti-D.5 These investigators contrasted their results with those of Goldfinger and McGinniss, who found that 7.8 percent of 102 D− oncology patients receiving pools of platelet-rich plasma and platelet concentrate transfusions containing a total average dose of 25 to 30 mL RBCs during the course of platelet transfusion therapy became alloimmunized.2 Lichtiger et al. postulated that the more intense chemotherapeutic regimens available in the early 1980s impaired the response to D antigen presentation.5 However, Baldwin et al.3 found when reviewing the records of D− oncology patients transfused between 1979 and 1983 that 18 percent of those given a combination of pooled whole blood-derived platelet concentrates and apheresis platelets containing 2.6 to 481.2 mL RBCs from D+ donors developed anti-D. Thirty-two percent of these patients developed HLA alloimmunization. The authors concluded that the timing of exposure to various antigens and differences in cancer diagnosis, stage, and treatment may have contributed to differences in responses to HLA and Rh system antigens, but D− patients treated with 1980s-era chemotherapy remained at risk for D alloimmunization. Another report involving patients who received transfusion in the 1990s suggests that the risk of alloimmunization may not be related solely to dose.6 None of 24 D− patients with hematologic disorders given pooled whole blood-derived platelets (approx. 0.3 mL RBCs/adult therapeutic dose) and apheresis platelets (approx. 0.005-0.007 mL RBCs/dose) developed anti-D, compared with eight of 59 (13.5%) contemporaneously transfused D− patients with nonhematologic disorders (p = 0.06). At least one-quarter of the transfusions given in both groups were pooled, whole blood-derived platelet concentrates. The observed differences did not reach statistical significance, the exact dose of RBCs given to patients in each subset was not provided, and it was not possible to determine the proportion of patients exposed to potentially immunizing doses of D+ cells in either subgroup. Hence, the 13.5 percent alloimmunization rate in the patients without hematologic disorders may reflect the low risk of immunization that results from plateletpheresis transfusions containing a paucity of RBCs. The overall impression gleaned from these studies is that the incidence of alloimmunization is significantly lower than that expected among D− patients exposed to more than 0.5 mL D+ RBCs. Why? Some possible explanations are: Chemotherapy impairs the immune system and current chemotherapeutic regimens are more immunosuppressive than those used previously. However, this is uncertain. For example, the observed rate of HLA alloimmunization in ‘control’ leukemia patients (45%) enrolled in the Trial to Prevent Alloimmunization to Platelets10 in the 1990s is not lower than the 31 percent rate observed in leukemia patients in the 1970s (88% of patients with aplastic anemia in a study conducted in the 1970s developed HLA antibodies).11 The current level of RBCs in apheresis-derived platelet concentrates is several logs lower than in the concentrates given decades ago (and is below levels traditionally considered immunizing). A combination of the above. The protective effect associated with the transfusion of ABO- and Rh-mismatched RBCs. However, this is unlikely given the high incidence of ABO-matched transfusions given in the studies reported. WBC reduction. This affects the rate of HLA alloimmunization, but should not alter the impact of alloantigen presentation via RBCs. Observation interval after transfusion. This may have played a role in the results reported by Cid et al. Forty-one percent of the patients did not survive 7 weeks, an interval perhaps insufficient for detectable antibody formation in immunosuppressed patients. Sensitivity of antibody screening tests. The role of this factor is uncertain in the absence of data directly comparing the tests used throughout the past three decades. Should we alter current practice regarding immunoprophylaxis for D− patients receiving platelet transfusions from D+ donors on the basis of the data presented in the current issue of TRANSFUSION? We had additional data demonstrating that the risk of D alloimmunization is low when D− patients have hematologic disorders and are given platelet concentrates not visibly containing RBCs. We have some additional information that intrinsic and/or chemotherapy-associated factors have an ameliorating effect on alloimmunization risk among patients receiving RBC doses sufficient to cause alloimmunization in immunocompetent patients. In deciding to administer immunoprophylaxis, potential benefits include prevention of HDN should a female patient become pregnant with an D+ fetus, and reduction in the frequency of positive antibody screening tests, which cause potential transfusion delays and costs. Potential downsides include the remote risks of infection transmission and hematoma formation associated with IM injections in thrombocytopenia patients. Of note, RhIg preparations prepared from human plasma undergo cold alcohol fractionation, and ultrafiltration and/or SD treatment, in principle abrogating the risk of known transmissible agents. Currently, hematoma formation is avoided by giving RhIg approved for IV use, 18-25 μg per mL transfused RBCs,12 via IV transfusion rather than IM injection. On balance, little benefit derives from administering RhIg to D− men or D− women physically incapable of conception who have hematologic disorders and receive platelets from D+ donors. The relative safety of RhIg administering to women with childbearing potential suffering hematologic disorders compared with the apparently very low risk of alloimmunization remains a matter of medical judgement. Bearing in mind the extremely reduced risk of alloimmunization in patients with hematologic disorders who receive platelet transfusions with trace amounts of RBCs, transfusion services now have additional information and more empirical observations for making policy decisions about the use of D+ RBC-containing components in D− recipients. We conduct quality control testing to determine the residual WBC count in WBC-reduced plateletpheresis preparations. As an aid for making this decision, it might be helpful to measure the residual RBC content of plateletpheresis components from D+ donors that are given to selected D− patients. If the level is below an immunizing dose of 0.1 mL, clinical judgement would suggest that RhIg is not necessary.