The clinical implications of platelet transfusions associated with ABO or Rh(D) incompatibility

The Clinical Implications of Platelet Transfusions Associated With ABO or Rh(D) Incompatibility Miguel Lozano and Joan Cid Despite the time elapsed since their development, and substantial human and economical efforts searching for alternatives, platelet transfusion, continues to be the main therapeutic measure available for the management of patients suffering from quantitative and qualitative platelet disorders. However, there are still aspects of their use that are not completely established. One of these is ABO and/or Rh(D) compatibility. A major ABO group incompatibility appears to decrease the response to a platelet transfusion, whereas a minor ABO incompatibility can be associated with, sometimes lethal, acute hemolytic transfusion reactions in the recipient. Other detrimental effects on the recipient of a minor ABO incompatibility have also been reported. In con-

p

LATELET TRANSFUSIONS are about to commemorate their 50th year since their introduction in therapeutics. It is then a bit surprising to see, that despite reaching this respectful age, we have not been able to definitely establish all the aspects related to their use. One such facet is platelet transfusion when ABO and/or Rh(D) incompatibility exists. In some cases, the existence of guidelines or consensus conferences help to resolve the situation, but in many other there are no unanimous recommendations and a wide variety of practices can be found. In this article, we present a review of the available data around ABO and/or Rh(D) incompatibility and platelet transfusions. ABO GROUP AND PLATELET TRANSFUSIONS

Since the early days of platelet transfusions, it became apparent that ABO group incompatibility did not preclude a normal response to a platelet transfusion. 1 So, whole-blood-derived platelet concentrates (PC) were transfused without regard of ABO. 2 In the subsequent years, it became apparent that not only can ABO-group incompatibility affect the efficacy of platelet transfusions but also have measurable effects on the recipient. ABH Group Antigens on Platelets Antigens specificity of ABO blood group system resides in oligosaccharide structures, which are the products of several glycosyltransferases that act subsequentially on 2 types of precursor oligosaccharide chains called paraglobosides. Differences

trast, the main problem associated to a Rh(D) incompatible platelet transfusion is the development of alloimmunization of a Rh(D)-negative woman in childbearing age or younger. Factors like degree of patient immunosuppression and red blood cell content in the piatelet concentrate significantly modulate the risk of alloimmunization. New clinical studies are needed to define clearly the current risk associated to ABO- and/or Rh(D)incompatible platelet transfusions, and such defined risks would help establish the most cost effective measures to prevent the appearance of the potential complications related to platelet use. Copyright 2003, Elsevier Science (USA). All rights reserved.

are caused by type of linkage of the terminal galactose substrate,/3(1-3) for type 1 and/3(1-4) for type 2. The H gene encodes a fucosyltransferase that attaches a fucose via an cff 1-2) linkage to the terminal galactose of type 2 chains. The Se (secretor) gene encodes a fucosyltransferase that acts similarly on type 1 paragloboside chains. Individuals whose cells have no sugars added, other than fucose by the H transferase, are denoted blood group type O and express the H antigen. In group A, another glycosyltransferase adds an additional N-acetyl-galactosamine to the terminal galactose, whereas in B group individuals the B gene encodes a B enzyme that adds another galactose via a cffl-2) bond. The rare individuals lacking the H fucosyltransferase (resulting in the hh or Bombay phenotype) cannot express the A and B antigens. ABH antigens found intrinsically on red blood cells (RBCs) are of the type 2 chains, mostly on membrane glycolipids and glycoproteins, whereas

From the Department of Hemotherapy and Hemostasis, Biomedical Diagnostic Center, Agusff Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Cl(nico of Barcelona, University of Barcelona, Barcelona, Spain, and the Blood Transfusion Center and Tissue Bank, Tarragona, Spain. Address reprint requests to Miguel Lozano, MD, Hospital Cl{nico Barcelona, Department Hemotherapy and Hemostasis, Villarroel 170, 08036 Barcelona, Spain. E-mail: mlozano@ clinic, ub. es Copyright 2003, Elsevier Science (USA). All rights reserved. 0887- 7963/03/1701-0004535.00/0 doi: 10.1053/tmrv.2003.50003

Transfusion Medicine Reviews, Vol 17, No 1 (January), 2003: pp 57-68

57

58

the plasma antigens are type 1 chains, located predominantly on glycolipids. Platelet express ABH antigens on their surface. 3 The origin of ABH antigens in platelets has been studied using different approaches. Dunstan et al, 4 using a 2-stage assay with radiolabeled mouse monoclonal antihuman immunoglobin (Ig) G, showed that the ABH antigens on human platelets are a mixture of both intrinsic (type 2) and extrinsic (type 1) absorbed from the plasma. 4 Other investigators using monoclonal antibody-specific immobilization of platelet antigen technique, radioimmunoprecipitation, and immunoblotting have been able to show that the A and B determinants are present on intrinsic platelet glycoproteins (GP) IIa, IIIa, and Ib (GPIIa being the most prominent among them). Interestingly, binding of IgG anti-A was only detected with platelets of A1 individuals but not (or only very weakly) to those of A 2 individuals. 5 This observation could explain the fact that refractory patients with high titer IgG antibodies to group A responded to platelet transfusion of A2 group donors. 6 In contrast, in a Japanese group of healthy donors, Ogasawara et al 7 using immunoprecipitation found that GPIIb bore the greatest amount of A and B antigen expressed on the surface of platelets, whereas GPIIa seemed to bear the greatest amount of antigen per molecule. 7 Likewise from these experiments, it was concluded that ABH substances are covalently bound to these GPs, ~ although this does not exclude that additional ABH antigen are expressed on platelet membrane glycolipids as had been shown before. 8 The expression of ABH antigens on platelets is not homogenous. According to the results of an enzyme-linked immunosorbent assay test designed to quantify the amount of A and B antigens expressed on platelet, the population studied by Ogasawara et al 7 could be classified as either low-expression and high-expression (measured absorbance exceeded the mean plus 2 standard deviation) phenotype. Totally, 7% of all the donors examined belonged to the high-expression phenotype of either A or B antigens. None of the group AB donors showed high expression of both A and B antigens at the same time. The level of high expression of antigens A and B correlated with the level of serum glycosyltransferase activity but not with the secretor (Se) or nonsecretor phenotypes. Family studies suggested the possibility that the high-expression phenotype could be inherited after

LOZANO AND CID

an autosomal dominant pattern. 7 These findings have been confirmed by others. 9 Moreover, in the same individual, the expression on platelets of A and B antigen is not homogenous. Dunstan and Simpson, 1~ using fluorescence flow cytometry, found on platelets a great variation in the expression of A and B antigens (and also for I, Le a, and P antigens) in comparison to the more homogeneous distribution of human platelet antigen la and human platelet antigen 3a. 1~

How ABO Incompatibility Affects Platelet Transfusion To review the effects of ABO incompatibility on platelet transfusions, it is appropriate to divide them into 2 groups: (a) major ABO incompatible transfusions in which the recipient is exposed to a ABH antigen not present on his/her RBC, and (b) minor ABO group incompatible platelet transfusions in which an alloantibody is infused with the transfusion to the recipient. A third possibility would be when both situations coexist. There are 2 sources of data regarding the effect of ABO group incompatibility on platelet transfusion: from survival studies with radiolabeled platelets in healthy volunteers and the analysis of patient responses to matched and unmatched platelet transfusions in different groups of recipients. Aster, ll in a group of healthy volunteers, found that the transfusion of AI platelets to group O recipients resulted in a reduction of in vivo recovery to one third of that observed with ABO compatible transfusion.ll Similar data were reported by Pfisterer et a112 and Kelton et al. 13 The studies with chromium-51 labeled platelets indicated that a fraction of ABO incompatible platelets are removed from the circulation within the first 10 to 30 minutes after transfusion, whereas the remaining platelets usually disappear from the circulation with a normal survival curve of 7 to 8 days. 11.13This biphasic pattern contrasts with that reported for HLA antibody-mediated destruction in which the posttransfusion kinetics show essentially continuous rapid destruction of infused platelets. Dunstan and Simpson 1~ suggested that this pattern could be explained, in part, by the heterogeneous distribution of ABH antigens on platelets, with those platelets with a high density of antigen sites rapidly removed from the circulation followed by a relatively normal survival for those platelets that possess only a few antigen sites.

PLATELET TRANSFUSION AND ABO/Rh(D)

In a group of 91 HLA alloimmunized thrombocytopenic patients, Duquesnoy et a114 reported that the mean 24-hour recovery of platelets after an apheresis platelet transfusion from histocompatible donors and from donors selectively mismatched for cross-reactive HLA antigens was decreased by approximately 23% if the donor typed for blood group A and/or B not found in the recipient. These investigators concluded that this reduction would no contraindicate transfusion of ABO mismatched platelets. 14 Lee and Schiffer 15 studied the effect of ABO compatibility in platelet transfusions prepared from whole-blood donations. They randomly assigned patients to receive alternatively ABO matched or ABO mismatched for their first 4 platelet transfusions. In 40 evaluable patients, there was no significant difference between the 10 minutes posttransfusion corrected count increments (CCI) of the initial transfusion of the ABO-matched and ABO-mismatched platelet transfusions. In contrast, the second matched transfusion was significantly better than the second mismatched transfusion (mean CCI 14.9 v 9.5, P = .0007). Interestingly, also in this setting, although the recovery was significantly affected, the survival was not altered because the ratio of 18-hours to 10-minutes posttransfusion CCI was the same for both ABOmatched and ABO-mismatched platelet transfusions. 15 A similar finding was reported in 1987 by Heal et al,16 in a group of patients refractory to platelet transfusions. They found that platelet transfusions that were crossmatch negative in an enzyme-linked antiglobulin assay had a 41% reduction in CCI when platelets were major ABO incompatible. Interestingly, they also reported an intermediate degree of reduction in platelet recovery (18%) when the transfusion represented a minor ABO incompatibility. 16 Moreover, the detrimental effect on posttransfnsion CCI of providing nonidentical ABO platelet transfusion was cumulative: after three or more a significant lower CCI was obtained compared with those transfused with identical ABO platelets. ~7 In other clinical settings, (eg, hematopoietic stem cell transplantation), the negative impact of major ABO incompatibility in platelet transfusions (35% reduction in CCI, P = .0058) has also been reported. ~8 In contrast, in a cardiovascular surgery setting, no effect of ABO incompatibly in the first 2 platelet transfusions could be found. The authors suggest that for pa-

59

tients not requiring long-term platelet therapy, the use of ABO-nonidentical platelets in surgery settings is an acceptable and safe practice. 19 The reason for the shortened platelet survival in major ABO-incompatible platelet transfusions is presumable related to IgM and IgG anti-A and anti-B in the recipient interacting with A and B substance on the transfused platelets. The fact that after an ABO mismatched platelet transfusion, the decrease in the response to subsequent mismatched transfusion correlated with an significant increase in the anti-A or -B isoagglutin titers would support this view. is The cause for tile suboptimal response in the case of minor ABO incompatibility is less apparent. Heal et al2o proposed that this could be caused by the formation of immune complexes between the patient's soluble ABH antigens and the alloantibodies present in the plasma. Platelets might then be destroyed by the binding of immune complexes to platelet FCy receptor or to the C3b/ iC3 or Clq complement binding proteins. 2~

How an ABO Mismatched Platelet Transfusion Can Affect the Recipient Acute hemolytic reactions. In addition to affecting the yield of the transfusion, an ABO-mismatched platelet transfusion can also be associated with other untoward effects, mainly an acute hemolytic reaction, but adverse effects on recipient's disease course have also been reported. Despite the presence of isohemagglutinins in the plasma, a minor ABO-mismatched platelet transfusion is considered safe practice. Nevertheless, there is a sort of contradiction. For example, the Standards of the American Association of Blood Banks clearly indicate that in the case of plasma component transfusions, the plasma unit should be ABO compatible with recipient's RBCs, although it allows the transfusion of the plasma present in a PC, which in the case of an apheresis PC can reach over 400 mL. 21 Thus, especially some ABO group patients (B or AB) can receive a significant amount of ABO-incompatible plasma. One possible reason for not recommending plasma reduction for minor ABO mismatched PCs is that the additional centrifugation step needed to reduce the volume of incompatible plasma would cause the loss of 35% to 55% platelets in such a P C Y Although this loss can be minimized to 15% if centrifugation conditions are set to 580 • g for 20 minutes, 23 most guidelines limit volume reduc-

60

LOZANO AND CID

tion in the case of a minor ABO-mismatch platelet transfusion to children and neonates. 21,24 Over the past 25 years, there are several reports of severe acute hemolytic reactions after minor ABO-mismatched platelet transfusions 25-36 (Table 1) that led to the death of the recipient in 2 cases. Moreover, there is the recognition that the rate of underrecognition and/or the underreporting of this complication is probably very significant; as is exemplified in the report by Murphy at a131 in which a first episode of acute hemolysis after a minor ABO-mismatched apheresis platelet transfusion had gone unnoticed. Only after the second platelet transfusion from the same donors, 25 days after, was the complication identified. 31 Mair and Benson 32 have estimated the risk of clinically significant acute hemolysis as 1 per 46,176 platelet transfusions or 1 per 9,000 minor ABO-mismatched platelet transfusions. Nevertheless, at the present time the risk is probably higher as the transfusion of PC collected by apheresis is more c o I I u n o n ,24,37 and the plasma from a single donor present in a minor ABO-mismatched unit is 4 to 8 times higher compared with a PC derived from a whole-blood donation. As indicated recently, 36 there are sharp differences in opinion on the need to remove plasma from PC units. Moreover, small amounts of ABOincompatible plasma (25-30 mL) such as is present in a dry platelet concentrate (PC collected by

apheresis and resuspended in a platelet additive solution) have been shown to be capable of causing an acute hemolytic reaction in the 2 recipients of a double unit collected by apheresis from the same donor and leading to the death of one of the recipients. 35 A possible approach to deal with this situation would be to return to the use of a concept from the 1950s when group O whole blood was transfused to A or B group recipients (the dangerous universal donors, ie, O group donors with high titer anti-A or anti-B isohemagglutinins). 38 At that time, group O donors were systematically screened using different methods to identify those with high anti-A or anti-B isohemagglutinins titers and those with high titers were labeled as dangerous universal donors, not to be used for whole-blood transfusions to A or B recipients. When the separation of whole-blood donation into components began and the transfusion of RBC concentrates with small amounts of residual plasma was the general rule, this practice was stopped. Several authors have proposed to return to this practice and perform screening on all donors to avoid the transfusion of minor ABO-mismatched PC from donors with high isohemagglutinin titers. 2. Unfortunately, there is not a unanimous agreement as to the definition of the critical titer to define a dangerous donor. 34 Depending on the titer

Table 1. Acute Hemolytic Reactions After a Platelet Transfusion Recipient Author, Year

Age

ABO group

Platelet Product Type

leohemagglutinin Titer ABO group

Saline

AHG

HemoglobinDrop (%)

NR

NR

10,240 NR 32,000 16,384 > 4,000 4,096 1,024 NR NR NR NR 2,048 4,096

42.8 NR 50.4* 42.6 26 g/L 53.9 47.3 3O.9 NR 29.8 t 37.2 39.7* 22.5 15.3

Zoes, 197725

44

AB

Random donor pool

O

McLeod, 198226 Conway, 198427 Pierce, 198526

45 15 2.5 58 66 56 30 28 72 44 51 16 36 45

A A A B A B A A AB A A A A A

Apheresis Apheresis Apheresis Random donor Random donor Apheresis Apheresis Apheresis Apheresis Apheresis Apheresis (dry platelet)

O 0 0 O O O O O O O O

anti-A: 256 anti-B: 64 1,280 8,192 512 512 256 NR 256 128 NR 16,384 > 8,000

Apheresis Apheresis

O O

NR NR

Ferguson, 198820 Reis, 19893o Murphy, 199031 Mair, 199832 MacManigal, 199933 Larsson, 200034 Valbonesi, 200035 Anonymous, 200236

Abbreviation: NR, not reported; AHG, antihuman globulin. *Led to the death of the recipient. tDrop measured after receiving 2 RBC units.

PLATELET TRANSFUSION AND ABO/Rh(D)

used, the prevalence of dangerous donors in O group donors varies between 10% to 20%. 34 Impact on clinical outcome. Several authors have reported the deleterious effect of using ABOmismatched platelet transfusions on the clinical course of a patient's disease. Heal et aP 7 in 1994 reported on 34 leukemic patients randomized to receive ABO identical or ABO-mismatched platelet transfusions. Among those achieving a complete remission, a longer survival for recipients of ABO-identical platelets compared with recipients of ABO-mismatched recipients (25 months v 13 months, P = .02) was observed. Moreover, in multifactorial analysis, the receipt of ABO-identical platelets was the best predictor of prolonged survival (P = .038). The authors speculate about the possible role of increased levels of circulating immune complexes in the immune defenses against leukemia. 17 Benjamin and Antin 39,4~ in 1999, reported in a group of allogeneic non-T-cell-depleted bone marrow transplant recipients suffering from acute myelogeneous leukemia and mylodysplastic syndrome, who had received either major or minor ABO-mismatched transplants, an increased risk (relative risk, 1.85) of dying of multiple organ failure and infection within 100 days of transplant, an effect ascribed to regimen-related toxicity. 39 This finding was in contrast to previous reports that did not find any effect of ABO incompatibility between donor/recipient in the survival of bone marrow transplant patients. The authors suggested that the cause of this effect was because, "Our transfusion policy was unusual, in that we did not deplete platelet transfusions of incompatible plasma. ''4~ According to the authors, the infusion of incompatible plasma may exacerbate regimenrelated toxicity in susceptible subgroups of patients and lead to increased early mortality. In other clinical settings, such as cardiovascular surgery patients, there are contradictory reports. Blumberg et a141 reported in 2001 that in 153 patients undergoing primary coronary artery bypass graft or coronary valve replacement surgery by 2 surgeons and receiving at least 1 ABO-mismatched pool of platelets, a statistically significant longer hospital stay, more days of fever, greater total hospital charges, and more RBC transfusions were found. However, to remove the possible bias caused by the tendency that patients receiving more transfusion would be both more likely to

61

receive ABO-nonidentical platelets and more likely to have worse outcomes, only those patients receiving not more than 2 platelet transfusions were analyzed. Only for the number of RBC transfusions is the statistical significance preserved. Among those receiving ABO-mismatched platelet transfusions a tendency to a longer length of stay (mean 18 days v 14, P = .057), higher in hospital mortality (mean 8.6% v 1.9%, P = .10), more antibiotics days (14 v 4.4, P = .17), and more hospital charges ($55,900 v 42,900, P = .17) was still observed. In contrast, Lin et al, 19 in a group of 1,691 cardiovascular surgery patients, divided into 2 groups according to the compatibility of the first platelet transfusion (ABO identical and ABO nonidentical), found no differences in adverse clinical outcomes between the 2 groups. Differences were also not observed when subgroup analyses were done in patients receiving only 1 or 2 transfusions. 19 THE RH(D) ANTIGEN AND PLATELET TRANSFUSIONS In contrast to ABH, Rh antigens, which reside on glycoproteins involved in ammonia transport across cell membranes, 42 do not appear to be expressed on human platelets (neither are the Duffy, Kidd, Kell, and Lutherans antigens). 43 So, the only possible source of Rh(D) antigen in a PC are the RBC$ present in the concentrate. Thus, the transfusion of PC from D-positive donors can aUoimmunize D-negative receptors. In the following, we review the factors that influence the development of this complication of platelet transfusion. R B C Content in Platelet Concentrates

The RBC content per platelet transfusion varies considerably, being higher in whole-blood-derived PCs than those collected by apheresis. PCs derived from whole blood, either by the plateletrich plasma (PRP) or the buffy-coat method, contain similar amounts of RBCs. 44,45 Moreover, current PCs contain a similar amount of RBCs as PCs produced decades ago. Table 2 shows the reported RBC content in PCs, with no significant changes over time. Goldfinger and McGinniss 46 calculated the maximum RBC volume in 10 representative units of PRP in 1971 and reported that the RBC volume in PCs was 0.42 mL per PC. 46 Since then, other authors have reported similar RBC content.

62

LOZANO AND CID

Table 2. Summary of Studies Analyzing Anti-D Formation After Rh(D)-Incompatible Platelet Transfusions Author, Y e a r Goldfinger, 197145 Lichtiger, 198347 Baldwin, 198863 McLeod, 199064 Heim, 199248 Zeiler, 199469 Atoyebi, 200049 Molnar, 20025o Cid, 200246 Summary

RBC in WB-PC(mL) 0.42 0.53 0.20 0.42 0.30 NR 0.30 NR 0.59 --

RBC in A-PC(mL)

Anti-D Frequency

Anti-D >4 wk*

8/102 0/30 9/73 3/16 1/37 0/20 0/24 0/35 0/22 21/359

7/102 0/30 4/73 1/16 1/37 0/20 0/24 0/35 0/22 13/359

NR 3.00 2.00 1.50 0.80 0.75 0.005 0.00017 NR --

Follow-up (wk) (range) 36 14 16 3 27 22 8 27 8

(2-174) (2-97) (2-55) (2-12) (4-104) (12-52) (2-76) (2-223) (1-37) --

ABO Compatiblet NR 88.6% 90% NR NR NR NR 79% 89% --

Abbreviations: NR, not reported; WB-PC, whole-blood derived platelet concentrates; A-PC, platelet concentrates collected by apheresis. *Frequency of anti-D development more than four weeks after the first Rh(D)-incompatible platelet transfusion tPercentage of ABO compatibility in Rh(D)-incompatible platelet transfusions

The most recent report by Cid et aW in 2002 reported a mean RBC content of 0.59 mL per PC. In contrast, PCs prepared by apheresis methods contain only small numbers of RBCs, which have varied over time. In the early 1980s, Lichtiger et a148 calculated that 34 single-donor concentrates obtained by apheresis with the Haemonetics H-30 (Haemonetics, Braintree, MA) contained a mean of 3 mL of RBC (range, 2.1-5.0 mL) in a mean 300 mL PC (range, 280-400 mL). In 1992, Heim et a149 reported an RBC content of 0.8 to 1.8 mL per platelet apheresis. In 2000, Atoyebi et al, 5~ based on quality control monitoring, suggested that apheresis platelets contained 0.005 to 0.007 mL of RBC. Finally, Molnar et aP 1 in 2002 reported an RBC contamination in apheresis PCs obtained by Gambro-Spectra equipped with LRS devices, as low as 0.00017 mL. RBC Quantity Necessary to Induce Anti-D Alloimmunization When a relatively large amount of Rh(D)-positive RBCs (200 mL or more) is transfused to D-negative subjects, within 2 to 5 months anti-D can be detected in the plasma of some 85% of the recipients. 52-54 The remaining 15% of D-negative subjects fail to make anti-D within the following months. About half of these fail to make anti-D even after further injections of D + RBCs and have been termed nonresponders. Although small doses of D-positive RBCs, such as the quantity that is present in PCs, can provoke primary immunization, the number of individuals who respond is fewer, and the titers of anti-D produced are lower

than is observed after exposure to larger doses of D-positive RBCs. 55-59 There is some evidence that the minimum dose of RBCs necessary for primary immunization is only 0.03 mL. 6~ This arises from a few observations with doses less than 0.05 mL. In 1 series, 0.05 mL of RBCs of unstated Rh phenotype were given at 6 weekly intervals to 15 D-negative subjects and 4 of them formed anti-D. In another series, 1 man formed anti-D after 6 injections of 0.005 mL of D-positive RBCs of phenotype R2r after a total of about 0.03 mL of RBC. Finally, another man formed anti-D after ten injections of about 0.05 mL of D-positive RBC. These findings suggest that a cumulative RBC dose of about 0.03 mL is capable of inducing primary D alloimmunization, but these data do not define the frequency with which such a dose causes alloimmunization. 59,6~ From these data, one can conclude that wholeblood-derived PCs contain sufficient RBCs to produce an antibody response. Platelets obtained by modern apheresis methods, however, contain only small amounts of RBCs, quantities probably insufficient to provoke an alloimmune response, particularly in immunosuppressed patients. Anti-D AlIoimmunization: Time Course In Pollack et al's report, 52 22 Rh(D)-negative subjects were transfused with a unit of D-positive blood and 18 of them became alloimmunized; 9 had detectable anti-D in their serum 2 months after the transfusion, 7 after 3 months, 1 after 4, and the reminder after 5 months of the Rh(D)-incompatible transfusion. 52 In another series, 6 subjects received

PLATELET TRANSFUSION AND ABO/Rh(D)

5 mL of DcE/DcE RBCs, and one of them had detectable anti-D at 37 days. The 4 other responding subjects' antibody was first detected between 63 to 119 days. 61 Contreras and Mollinson 58 reported the results of a study in which 12 volunteers received 1 mL of DcE/DcE RBC and were tested at 2-week intervals. The earliest time at which anti-D was detected was 4 weeks. 58 In previously unimmunized D-negative subjects, anti-D cannot be produced more rapidly by giving a series of injections of D-positive RBCs rather than a single injection. For example, among 121 subjects given an initial injection of 5 mL of D-positive RBCs, followed by 2 mL every 5 weeks, 8 formed anti-D within 10 weeks, and 27 within 15 weeks. 62 Production of anti-D within a few weeks of a first stimulus has been observed after the injection of specially treated D-positive RBCs. The cells were incubated in low-ionic-strength medium at 37deg; C and at the time of injection reacted strongly with anti-C4, -C3, and -C5. One out of 7 subjects developed anti-D at 15 days, and 5 others developed anti-D between 41 and 71 days after injection. It was considered that the time before the appearance of antibody was not significantly shorter than that observed after the injection of untreated RBC. 63 In conclusion, the earliest time at which anti-D can be detected in primary immunization in immunocompetents individuals ranges from 4 to 10 weeks, with the production of anti-D within 2 weeks of a first stimulus observed only after the injection of specially treated D-positive RBCs. To interpret data in patients, it is important to exclude those who develop anti-D alloimmunization as a result of a secondary immune response, which generally appears within 4 weeks after the new stimulus. If we exclude such patients, the percentage of D alloimmunization varies as shown in table 2. We can exclude 1 patient in the series reported by Goldfinger and McGinnis 46 who was alloimmunized within 2 weeks. Baldwin et a164 reported 9 patients who formed anti-D, but 5 of them developed anti-D within 28 days after the first D-incompatible platelet transfusion. Finally, McLeod et a165 reported 3 patients who formed anti-D at 13, 24, and 83 days from the first Dincompatible platelet transfusion. Of note, 2 women who developed anti-D within 4 weeks had an obstetrical history. Thus, it is not possible to rule out a secondary immunization in those patients, and the frequency of D alloimmunization

63

after D-incompatible platelet transfusions in immunosuppressed patients could be lower than that cited. The observation interval after transfusion may have played a role in producing the variation in the reported frequencies of anti-D development after transfusion of a D-positive PC. The response times range from approximately 1 to 5 months in immunocompetent individuals, with the majority of responding recipients producing anti-D within 3 months. 52,58,61 The reported follow-up in immunosuppressed patients is quite variable. There are 2 articles whose authors reported no anti-D alloimmunization after D-positive platelet transfusions to a Rh(D)-negative recipient with a median follow up to 3 months, an interval perhaps insufficient for detectable alloantibody formation in immunosuppressed patients. Atoyebi et aP ~ found no anti-D alloimmunization in a group of 24 patients with hematological diseases after a median follow-up of 8 weeks (range, 2-76). These authors reported frequencies of 13.5% anti-D alloimmunization in a group of 59 patients with nonhematological diseases, after a median follow-up of 38 weeks (range, 2-133). Cid et a147 reported no anti-D formation in 22 D-negative patients with hematological diseases after a median follow-up of 8 weeks (range, 1-37). Of note, 41% of these patients did not survive 7 weeks. Moreover, the article by McLeod et a165 reported the highest frequencies of anti-D alloimmunization after Rh(D)-incompatible platelet transfusions in immunosuppressed patients. These authors reported 2 patients who formed anti-D very quickly and the median follow-up for the series was only 3 weeks (range, 2-12). 65 Apart from anti-D, other alloantibodies have been reported after platelet transfusions. McLeod et a165 reported 2 patients who formed anti-C. One patient reported by Heim et a149 developed anti-E and anti-Co(b) even though no E-positive RBC units had been transfused. The antigen status of the Colton antigen in the transfused blood products is unknown. 49 Schonewille et a166 detected anti-E after 2 platelet transfusions in a D-positive male patient with myelodysplastic syndrome who had screened negative for alloantibodies on 2 previous occasions and had not received RBC transfusions.

64

Effect of ABO Incompatibility on Primary Rh(D) Immunization A possible protective effect of ABO incompatibility against D alloimmunization was first reported after analyzing groups of parents of infants with Rh(D) hemolytic disease. This effect was first shown experimentally by Stern et al, 67 who injected a group of male voluntaries with D-incompatible RBCs matched and unmatched for the ABO. Ten out 17 subjects injected with ABOcompatible developed anti-D; titer was 16 to 128 in 5 and 256 to 512 in the remaining 5. By contrast, among the 22 subjects who received Rh(D)- and ABO-incompatible RBCs, anti-D developed in only 2; the titer ranged between 2 and 8. 67 The same author extended this study, and the figures for the production of anti-D were as follows. Seventeen out of 24 subjects developed anti-D after ABO-compatible RBC with a titer >-16. Only 5 out of 32 subjects formed anti-D after ABO-incompatible RBC infusions with a titer --<8. Moreover, 10 subjects who failed to form anti-D after receiving ABO-incompatible RBCs were subsequently injected with ABO-compatible RBCs, and 4 of them produced anti-D. 68 For some of the reports on Rh(D) alloimmunization after platelet transfusions, the percentage of ABO incompatible transfusions is provided (table 2). Lichtiger et a148 reported that 88.6% of Dincompatible platelet transfusions were ABO-compatible. Baldwin et a164 showed that nearly of 90% of D-incompatible platelet transfusions were ABO compatible. This figure was 79% in the report by Molnar et a151 and 89% in the report by Cid et al. 47 Thus, the protective effect associated with the transfusion of ABO- mad D-mismatched RBC's is unlikely, given the high incidence of ABO-matched transfusions given in the studies reported. 69

Rh(D) Alloimmunization and the Level of Imunosuppression Obviously, the level of immunosuppression affects the response to D-positive RBCs in D-negative patients ranging the reported incidence of D alloimmunization after D-incompatible platelet transfusions of between 0% and 19%. 46-51,64,65,70 Ramsey et al va reported on 19 D-negative patients who were transfused with several units of D-positive RBCs during liver or heart transplant surgery. Those patients received immunosuppressive ther-

LOZANO AND CID

apy with cyclosporine and corticosteroids. Only 3 of them developed anti-D, but the antibody appeared at l l to 15 days. As described earlier, it is not possible to rule out a secondary Rh(D) immunization in those patients. Cummins et a172reported that in 51 D recipients of heart, lung, or heart-lung D-positive allografts under immunosuppressive therapy including cyclosporine, only 1 developed anti-D, and this was a multiparous woman in whom the response was presumed to be secondary. Of 6 Rh(D)-negative patients transfused with Rh(D)-positive RBCs, only 2 developed anti-D and then only transiently. 72 Finally, Casanueva et a172 reported 17 D-negative recipients of liver transplants. The patients received a median of 19 units of Rh(D)+ RBCs (range, 5-41 U). No patient was shown to develop anti-D even after a median follow-up of 15 (2-70) months. 73

Rh(D Alloimmunization: Prevention Stern et a167 first reported that if Rh(D)-positive RBCs were coated in vitro with anti-D before being injected into D-negative subjects, there might be no alloantibody response. Later Pollack et a174 defined the dose of anti-D required for suppressing Rh(D) alloimmunization. A fixed amount of IgG anti-D (RhIG), namely 267 ~g, was given intramuscularly to groups of D-negative subjects who received doses of D-positive RBCs varying from 11.6 to 37.5 mL. Control subjects received the same dose of RBCs without anti-D. All the subjects were given a challenge dose of 0.2 mL of whole blood at 6 months and tested 1 week later. Of the controls, 49 (57%) out of 86 formed anti-D. In the treated group, only 15 (16%) of 92 formed anti-D. From these results, the authors concluded that 267 p~g of anti-D was completely effective against about 13 mL of RBC and was partially effective against larger amounts. 52 From this and other studies, 52,54,58,61,74 it was concluded that about 20 ~g anti-D per mL of D-positive RBCs is sufficient to suppress D alloimnmnization. The availability of intravenous RhIG provides a more convenient and less painful approach to Rh immunoprophylaxis for those uncommon events when a D-negative person has been inadvertently transfused with D + RBC. Anderson et a175 published the first report using Food and Drug Administration-approved intravenous RhIG for this indication. The manufacturer's recommended dose for intravenous RhIG is 18 /xg/mL of D + RBCs, ad-

PLATELET TRANSFUSION AND ABO]Rh/D)

ministered as 600/xg (3000 IU) every 8 hours until the total dose is reached. 76 According to this protocol, an injection of a 220 /xg (600 IU) vial of intravenous RhlG should be adequate for preventing Rh(D) alloimmunization with a wide margin of safety after transfusion of a pool of random donor platelets or apheresis platelets. There are 2 reports that support this view. Helm et a149 reported successful prevention of D alloimmunization in 36 D-negative patients who received 200 /xg (1,000 IU) of anti-D just before transfusion of platelets from D positive donors. Only 1 patient developed detectable anti-D 5 weeks after transfusion of 1 D-incompatible platelet transfusion because administration of anti-D was omitted. 49 In the other report, Zeiler et al 7~ used only 20 ~g (100 IU) to prevent D alloimmunization. Anti-D was added directly to the concentrate or given intravenously in advance of the transfusion. None of the 20 patients developed anti-D within a median follow-up of 5.5 months (range, 3-13 months), v~ Unfortunately, the use of RhlG is not free of adverse effects. It is a plasma-derived product so the risk of transmission of viral diseases is not 0. 77-79 The current preparation of intravenous RhIG in use in the North America has been solvent/ detergent treated to inactivate the lipid enveloped viruses such as hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. The product has also undergone filtration to remove some of the nonlipid-enveloped viruses. 8~ First reports about the intravenous route of administration of RhIG showed pyrexia and hemoglobinuria as the only untoward effect. 59,81 A wide range of side effects has been described more recently. Tarantino et a182 reported the use of intravenous RhIG in D + children for the treatment of immune thrombocytopenic purpura. The side effects varied from headache, nausea, chills, fever, and dizziness to more severe reactions such as excessive hemolysis of RBCs with a subsequent decline in the patient's hemoglobin concentration. 82 Other authors have reported similar findings. 83 Thus, guidelines have developed for deciding which patients with ITP should receive treatment with intravenous RhlG. 84 The use of intravenous RhIG for preventing D alloimmunization in D-negative recipients who receive platelet transfusions from D-positive donors has not been associated to adverse e f f e c t s 49,7~ However, serologic problems have appeared after the infusion of RhIG. Rushin et a185 performed

65

serologic testing of different production lots of intravenous RhlG and reported the presence of multiple blood group alloantibodies, including anti-C, -E, -G, -Fya, -V, as well as high titers of anti-DY These caused crossmatch difficulties after the prophylactic use of RhlG 86 and obscured the detection of an alloanti-K, s7 Transfusion-related acute lung injury has been reported after the infusion of intravenous Rhlg 88 as well as allergic reactions. 89 Intravenous RhlG contains trace amounts of IgA, and persons who are deficient in IgA have the potential of developing IgA antibodies and are therefore at risk for anaphylactic reactions, so Moreover, published reports exist about the failure of IV anti-D to prevent D alloimmunization.90.9 CONCLUSIONS There are still areas in platelet transfusion practice that are not clearly defined. In the case of an ABO-mismatched platelet transfusion, only in the case of a pediatric patient and a minor ABO mismatch, does consensus exist on the necessity of reducing the volume of ABO-incompatible plasma to be transfuse with the platelets. Nevertheless, there is compelling evidence that the platelet recovery after a transfusion of a major ABO incompatibility PC will be diminished, although the decrease most of the time is deemed to be of little or no clinical significance. Moreover, in adults, there are increasing reports of acute hemolytic episodes after a minor ABO mismatched (most of them, A group recipient of 1 O group donation) platelet transfusion, in some cases leading to the death of the recipient. However, some of the data suggest that to proceed systematically to reduce the volume of the incompatible plasma in case of a minor ABO-mismatched platelet transfusion probably would not totally prevent such hemolytic episodes. Some investigators have suggested that the measurement of ABO isohemagglutinin titer would allow the identification of donors with high titers and avoid transfusing such platelet concentrates to ABO incompatible recipients. Nevertheless, no established consensus exists in defining the ABO isohemagglutinin titers that make such donors dangerous. Reports also exist on other detrimental effects of minor ABO-mismatched platelet transfusions on the recipient. Some have found a negative impact on leukemic patients' and bone marrow transplan-

66

LOZANO AND ClD

tation recipients' survival. Contradictory findings h a v e b e e n published in other clinical settings such as cardiovascular surgery patients. A n o t h e r important issue to take into account before a platelet transfusion can be issued is the risk of anti-D a l l o i m m u n i z a t i o n in case o f the R h ( D ) - n e g a t i v e recipient o f D - p o s i t i v e d o n o r platelet products. The risk o f a l l o i m m u n i z a t i o n seems to be l o w e r in i m m u n o s u p p r e s s e d patients than in i m m u n o c o m p e t e n t individuals. M o r e o v e r , this risk could be lower, at the present time, than p r e v i o u s l y cited because the intensity of i m m u n o suppressive treatments h a v e increased and also because of the R B C content in apheresis-derived platelet concentrates tends to be lower. H o w e v e r , at present there are no clear r e c o m m e n d a t i o n s in case of D - n e g a t i v e patients r e c e i v i n g platelets products f r o m D - p o s i t i v e donors. The A m e r i c a n A s s o c i a t i o n o f B l o o d Banks Standards state that the "Transfusion service shall h a v e a policy for Rh I m m u n e G l o b u l i n prophylaxis for R h - n e g a t i v e patients w h o r e c e i v e c o m p o n e n t s containing Rh-pos-

itive red cells. ''21 The C o u n c i l of E u r o p e G u i d e for the Preparation, U s e and Quality A s s u r a n c e of B l o o d C o m p o n e n t s establish that " D negative f e m a l e recipients o f child bearing age or y o u n g e r . . . . (in case of r e c e i v i n g platelets f r o m R h ( D ) positive donors) . . . . the p r e v e n t i o n o f Rh D i m m u n i z a t i o n by the use o f R h - i m m u n e globulin should be considered. ''92 O n l y r a n d o m i z e d , welldefined and w e l l - c o n d u c t e d studies will p r o v i d e the necessary data to clearly define guidelines for these still u n r e s o l v e d aspects of platelet transfusion.

ACKNOWLEDGMENTS

The authors thank Drs A n t o n i o Ordinas and R o b e r t o M a z z a r a (Hospital Clfnico B a r c e l o n a ) and D r C a r m e n Martin V e g a (Blood Transfusion Center and Tissue B a n k Barcelona) for their support and e n c o u r a g e m e n t . T h e assistance of the editorial staff o f the International Journal of Artificial Organs is also gratefully a c k n o w l e d g e d .

REFERENCES

1. Klein E, Djerassi I, Farber S: Maintenance of normal platelet levels in recipients of multiple transfusions of platelets from incompatible blood. Proceedings of the VIIth Congress of the International Society of Hematology. Rome, Italy, September 7-13, 1958 (abstr 957) 2. Djerassi I, Farber S, Evans AE: Transfusion of fresh platelet concentrates to patients with secondary thrombocytopenia. N Engl J Med 268:221-226, 1963 3. Gurevitch J, Nelken D: ABO groups in blood platelets. Nature 173:356, 1954 (letter) 4. Dunstan RA, Simpson MB, Knowles RW, et al: The origin of ABH antigens on human platelets. Blood 65:615-619, 1985 5. Santoso S, Kiefel V, Mueller-Eckhardt C: Blood group A and B determinants are expressed on platelet glycoproteins IIa, IIIa, and Ib. Thromb Haemost 65:196-201, 1991 6. Skogen B, Rossebo HB, Husebekk A, et al: Minimal expression of blood group A antigen on thrombocytes from A 2 individuals. Transfusion 28:456-459, 1988 7. Ogasawara K, Ueki J, Takenaka M, et al: Study on the expression of ABH antigens on platelets. Blood 82:993-999, 1993 8. Dunstan RA, Mansbach CM: Biochemical characterisation of A blood group activity on human platelets. Vox Sang 49:149-153, 1985 9. Duquesnoy RJ, Filip DJ, Aster RH: Influence of HLA-A2 on the effectiveness of platelet transfusions in alloimmunized thrombocytopenic patients. Blood 50:407-412, 1977 10. Dunstan RA, Simpson MB: Heterogeneous distribution of antigens on human platelets demonstrated by fluorescence flow cytometry. Br J Haematol 61:603-609, 1985 11. Aster RH: Effect of anticoagulant and ABO incompati-

bility on recovery of transfused human platelets. Blood 26:732743, 1965 12. Pfisterer H, Thierfelder S, Stich W: ABO Rh blood groups and platelet transfusion. Blut 17:1-5, 1968 13. Kelton JG, Hamid C, Aker S, et al: The amount of blood group A substance on platelets is proportional to the amount in the plasma. Blood 59:980-985, 1982 14. Duquesnoy RJ, Anderson AJ, Tomasulo PA, et al: ABO compatibility and platelet transfusions of alloimmunized thrombocytopenic patients. Blood 54:595-599, 1979 15. Lee EJ, Schiffer CA: ABO compatibility can influence the results of platelet transfusion. Results of a randomized trial. Transfusion 29:384-389, 1989 16. Heal JM, Blumberg N, Masel D: An evaluation of crossmatching, HLA, and ABO matching for platelet transfusions to refractory patients. Blood 70:23-30, 1987 17. Heal JM, Rowe JM, Blumberg N: ABO and platelet transfusion revisited. Ann Hematol 66:309-314, 1993 18. Klumpp TR, Herman JH, Innis S, et al: Factors associated with response to platelet transfusion following hematopoieric stem cell transplantation. Bone Marrow Transplant 17: 1035-1041, 1996 19. Lin Y, Callum JL, Coovadia AS, et al: Transfusion of ABO-nonidentical platelets is not associated with adverse clinical outcomes in cardiovascular surgery patients. Transfusion 42:166-172, 2002 20. Heal JM, Masel D, Rowe JM, et al: Circulating immune complexes involving the ABO system after platelet transfusion. Br J Haematol 85:566-572, 1993 21. Gorlin JB, ed. Standards for Blood Banks and Transfusion Services (20th Edition). Bethesda, MD, American Association of Blood Banks, 2000

PLATELET TRANSFUSION AND ABO/Rh(D)

22. Simon TL, Sierra ER: Concentration of platelet units into small volumes. Transfusion 24:173-175, 1984 23. Moroff G, Friedman A, Robkin-Kline L, et al: Reduction of the volume of stored platetet concentrates for use in neonatal patients. Transfusion 24:144-146, 1984 24. Schiffer CA, Anderson KC, Bennett CL, et al: Platelet transfusion for patients with cancer: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:1519-1538, 2001 25. Zoes C, Dube VE, Miller HJ, et al: Anti-A1 in the plasma of platelet concentrates causing a hemolytic reaction. Transfusion 17:29-32, 1977 26. McLeod BC, Sassetti RJ, Weens JH, et al: Haemolytic transfusion reaction due to ABO incompatible plasma in a platelet concentrate. Scand J Haematol 28:193-196, 1982 27. Conway LT, Scott EP: Acute hemolytic transfusion reaction due to ABO incompatible plasma in a plateletapheresis concentrate. Transfusion 24:413-414, 1984 28. Pierce RN, Reich LM, Mayer K: Hemolysis following platelet transfusions from ABO-incompatible donors. Transfusion 25:60-62, 1985 29. Ferguson DJ: Acute intravascular hemolysis after a platelet transfusion. Can Med Assoc J 138:523-524, 1988 30. Reis MD, Coovadia AS: Transfusion of ABO-incompatible platelets causing severe haemolytic reaction. Clin Lab Haematol 11:237-240, 1989 31. Murphy MF, Hook S, Waters AH, et al: Acute haemolysis after ABO-incompatible platelet transfusions. Lancet 335: 974-975, 1990 32. Mair B, Benson K: Evaluation of changes in hemoglobin levels associated with ABO-incompatible plasma in apheresis platelets. Transfusion 38:51-55, 1998 33. McManigai S, Sims KL: Intravascular hemolysis secondary to ABO incompatible platelet products. An underrecognized transfusion reaction. Am J Clin Pathol 111:202-206, 1999 34. Larsson LG, Welsh VJ, Ladd DJ: Acute intravascular hemolysis secondary to out-of-group platelet transfusion. Transfusion 40:902-906, 2000 35. Valbonesi M, De Luigi MC, Lercari G, et al: Acute intravascular hemolysis in two patients transfused with dryplatelet units obtained from the same ABO incompatible donor. Int J Artif Organs 23:642-646, 2000 36. Reducing supernatant plasma of pooled platelets before administration to ABO-incompatible adult recipients. CBBS, e-Network forum. Available at: http://www.cbbsweb.org/enetPltpoolPlasma.html. Accessed May 12, 2002 37. Wallace EL, Churchill WH, Surgenor DM, et al: Collection and transfusion of blood and blood components in the United States, 1994. Transfusion 38:625-636, 1998 38. Ervin DM, Young LE: Dangerous universal donors. 1. Observation on destruction of recipient's A cells after transfusion of group O blood containing high titer of A antibodies of immune type no easily neutralizable by soluble A substance. Blood 5:61-73, 1950 39. Benjamin RJ, Mcgurk S, Ralston MS, et al: ABO incompatibility as an adverse risk factor for survival after allogeneic bone marrow transplantation. Transfusion 39:179-187, 1999 40. Benjamin RJ, Antin JH: ABO-incompatible bone marrow transplantation: The transfusion of incompatible plasma may exacerbate regimen-related toxicity. Transfusion 39:12731274, 1999

67

41. Blumberg N, Heal JM, Hick GL, et al: Association of ABO-mismatched platelet transfusions with morbidity and mortality in cardiac surgery. Transfusion 41:790-793, 2001 42. Marini AM, Matassi G, Raynal V, et al: The human Rhesus-associated RhAG protein and a kidney homologue promote ammonium transport in yeast. Nat Genet 26:341-344, 2000 43. Dunstan RA, Simpson MB, Rosse WF: Erythrocyte antigens on human platelets. Absence of Rh, Duffy, Kell, Kidd, and Lutheran antigens. Transfusion 24:243-246, 1984 44. Fijnheer R, Pietersz RNI, de Korte D, et al: Platelet activation during preparation of platelet concentrates: A comparison of the platelet-rich plasma and the buffy coat methods. Transfusion 30:634-638, 1990 45. Lozano M, Estebanell E, Cid J, et al: Platelet concentrates prepared and stored under currently optimal conditions: Minor impact on platelet adhesive and cohesive functions after storage. Transfusion 39:951-959, 1999 46. Goldfinger D, McGinniss MH: Rh-incompatible platelet transfusions---Risks and consequences of sensitizing immunosuppressed patients. N Engl J Med 284:942-944, 1971 47. Cid J, Ortin X, Elies E, et al: Absence of anti-D alloimmunization in hematologic patients after D-incompatible platelet transfusions. Transfusion 42:173-176, 2002 48. Lichtiger B, Surgeon J, Rhorer S: Rh-incompatible platelet transfusion therapy in cancer patients. A study of 30 cases. Vox Sang 45:139-143, 1983 49. Heim MU, B6ck M, Kolb HJ, et al: Intravenous anti-D gammaglobulin for the prevention of Rhesus isoimmunization caused by platelet transfusion in patients with malignant diseases. Vox Sang 62:165-168, 1992 50. Atoyebi W, Mundy N, Croxton T, et al: Is it necessary to administer anti-D to prevent RhD immunization after the transfusion of RhD-positive platelet concentrates? Brit J Haematol 111:980-983, 2000 51. Molnar R, Johnson R, Sweat LT, et al: Absence of D alloimmunization in D- pediatric oncology patients receiving D-incompatible single-donor platelets. Transfusion 42:177-182, 2002 52. Pollack W, Ascari WQ, Crispen JF, et al: Studies on Rh prophylaxis. II. Rh immune prophylaxis after transfusion with Rh-positive blood. Transfusion 11:340-344, 1971 53. Urbaniak SJ, Robertson AE: A successful program of immunizing Rh-negative maie volunteers for anti- D production using frozen/thawed blood. Transfusion 21:64-69, 1981 54. Bowman HS: Effectiveness of prophylactic Rh immunosuppression after transfusion with D-positive blood. Am J Obstet Gynecol 124:80-84, 1976 55. Mollison PL, Hughes-Jones NC, Lindsay M, et al: Suppression of primary RH immunization by passively-administered antibody. Experiments in volunteers. Vox Sang 16:421439, 1969 56. Woodrow JC, Finn R, Krevans JR: Rapid clearance of Rh positive blood during experimental Rh immunisation. Vox Sang 17:349-361, 1969 57. Samson D, Mollison PL: Effect on primary Rh immunization of delayed administration of anti-Rh. Immunology 28: 349-357, 1975 58. Contreras M, Mollison PL: Failure to augment primary Rh immunization using a small dose of "passive" IgG anti-Rh. Br J Haematol 49:371-381, 1981

68

59. The Rh blood group system (and LW), in Mollison PL, Englefriet CP, Contreras M (eds): Blood Transfusion in Clinical Medicine (ed 10).London, Blackwell Science, 1997, pp 151185 60. Shirey RS, King KE: Alloimmunization to blood group antigens, in Anderson KC, Ness PM (eds): Scientific Basis of Transfusion Medicine. Implications for clinical practice. Philadelphia, PA, 2000, pp 393-400 61. Gunson HH, Stratton F, Cooper DG, et al: Primary immunization of Rh-negative volunteers. Br Med J 1:593-595, 1970 62 Archer GT, Cooke BR, Mitchell K, et al: Hyper-immunisation des donneurs de sang pour la production des gammaglobulines anti-Rh(D). Rev Franq Transfus 12:341-350, 1969 63. Gunson HH, Stratton F, Phillips PK: The use of modified cells to induce an anti-Rh response. Br J Haematol 21:683-694, 1971 64. Baldwin ML, Ness PM, Scott D, et al: Alloimmunization to D antigen and HLA in D-negative immunosuppressed oncology patients. Transfusion 28:330-333, 1988 65. McLeod BC, Piehl MR, Sassetti RJ: Alloimmunization to RhD by platelet transfusion in autologous bone marrow transplant recipients. Vox Sang 59:185-189, 1990 66. Schonewille H, Haak HL, vanZijl AM: Alloimmunization after blood transfusion in patients with hematologic and oncologic diseases. Transfusion 39:763-771, 1999 67. Stern HS, Goodman S, Berger M: Experimental isoimmunization to hemoantigens in man. J Immunol 87:189-198, 1961 68. Stern K, Davidsohn I, Masaitis L: Experimental studies on Rh immunization. Am J Clin Pathol 26:833-943, 1956 69. Menitove JE: immunoprophylaxis for D- patients receiving platelet transfusions from D+ donors. Transfusion 42:136138, 2002 70. Zeiler T, Wittmann G, Zingsem J, et al: A dose of 100 IU intravenous anti-D gammaglobulin is effective for the prevention of Rh(D) immunisation after Rh(D)-incompatible single donor platelet transfusion. Vox Sang 66:243, 1994 (letter) 71. Ramsey G, Hahn LF, Comell FW, et al: Low rate of Rhesus immunization from Rh-incompatible blood transfusions during liver and heart transplant surgery. Transplantation 47: 993-995, 1989 72. Cummins D, Contreras M, Amin S, et al: Red cell alloantibody development associated with heart and lung transplantation. Transplantation 59:1432-1435, 1995 73. Casanueva M, Valdes MD, Ribera MC: Lack of alloimmunization to D antigen in D-negative immunosuppressed liver transplant recipients. Transfusion 34:570-572, 1994 74. Pollack W, Gorman JG, Hager HJ, et al: Antibodymediated immune suppression to the Rh factor: Animal models suggesting mechanism of action. Transfusion 8:134-145, 1968 75. Anderson B, Shad AT, Gootenberg JE, et al: Successful prevention of post-transfusion Rh alloimmunization by intrave-

LOZANO AND CID

nous Rho (D) immune globulin (WinRho SD). Amer J Hematol 60:245-247, 1999 76. Sandier SG: Treating immune thrombocytopenic purpura and preventing Rh alloimmunization using intravenous rho (D) immune globulin. Transfus Med Rev 15:67-76, 2001 77. Kenny-Walsh E: Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group. N Engl J Med 340:1228-1233, 1999 78. Lawlor E, Columb G: Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. N Engl J Med 341:762, 1999 (letter) 79. Bonis PA: Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. N Engl J Med 341:763, 1999 (letter) 80. Birch GA, Alving BM: Plasma derivatives and adverse reactions, in Popovsky MA (ed): Transfusion Reactions (ed 2). Bethesda, MD, AABB Press, pp 401-404 81. Bowman JM: The advantages of intravenous Rh-immune globulin. Clin Obstet Gynecol 25:341-347, 1982 82. Tarantino MD, Madden RM, Fennewald DL, et al: Treatment of childhood acute immune thrombocytopenic purpura with anti- D immune globulin or pooled immune globulin. J Pediatr 134:21-26, 1999 83. Gaines AR: Acute onset hemoglobinemia and/or hemoglobinuria and sequelae following Rh-o(D) immune globulin intravenous administration in immune thrombocytopenic purpura patients. Blood 95:2523-2529, 2000 84. Imbaeh P, Kuhne T: Sequelae of treatment of ITP with anti-D (Rho) immunoglobulin. Lancet 356:447-448, 2000 85. Rushin J, Rumsey DH, Ewing CA, et al: Detection of multiple passively acquired alloantibodies following infusions of 1VRh immune globulin. Transfusion 40:551-554, 2000 86. Wright J, Freedman J, Lim FC, et al: Crossmatch difficulties following the prophylactic use of Rh immune globulin. Can Med Assoc J 120:1235-1238, 1979 87. Stroncek DF, Procter JL, Moses L, et al: Intravenous Rh immune globulin prevents alloimmunization in D-granulocyte recipients but obscures the detection of an alloanti-K. Immunohematology 17:37-41, 2001 88. Rizk A, Gorson KC, Kenney L, et al: Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 41: 264-268, 2001 89. Rivat L, Rivat C, Parent M, et al: Accident survenu aprbs injection de gamma-globulines anti-Rh dfi h la prrsence d'anticorps anti-gamma A. Presse Med 78:2072, 1970 90. Branch DW, Guyman G, Scott JR: Failure to prevent rhesus immunisation with rhesus immune globulin after incompatible blood transfusion. Lancet 1:393-394, 1985 91. Bowman JM, Pollock JM: Failures of intravenous Rh immune globulin prophylaxis: An analysis of the reasons for such failures. Transfus Med Rev 1:101-112, 1987 92. Guide to the preparation, use and quality assurance of blood components. Strasbourg, France, Council of Europe Publishing, 2001