| MECHANISMS OF TRANSFUSION ALLOIMMUNIZATION |

Understanding red blood cell alloimmunization triggers

Jeanne E. Hendrickson1,2 and Christopher A. Tormey1,3

1
Department of Laboratory Medicine and 2Department of Pediatrics, Yale University School of Medicine,
New Haven, CT; 3Pathology & Laboratory Medicine Service, VA Connecticut Healthcare System,
West Haven, CT

Blood group alloimmunization is “triggered” when a person lacking a particular antigen is exposed to this antigen during
transfusion or pregnancy. Although exposure to an antigen is necessary for alloimmunization to occur, it is not alone
sufficient. Blood group antigens are diverse in structure, function, and immunogenicity. In addition to red blood cells

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(RBCs), a recipient of an RBC transfusion is exposed to donor plasma, white blood cells, and platelets; the potential
contribution of these elements to RBC alloimmunization remains unclear. Much attention in recent years has been
placed on recipient factors that influence RBC alloantibody responses. Danger signals, identified in murine and human
studies alike as being risk factors for alloimmunization, may be quite diverse in nature. In addition to exogenous or
condition-associated inflammation, autoimmunity is also a risk factor for alloantibody formation. Triggers for alloim-
munization in pregnancy are not well-understood beyond the presence of a fetal/maternal bleed. Studies using animal
models of pregnancy-induced RBC alloimmunization may provide insight in this regard. A better understanding of
alloimmunization triggers and signatures of “responders” and “nonresponders” is needed for prevention strategies to be
optimized. A common goal of such strategies is increased transfusion safety and improved pregnancy outcomes.

Although antigen avoidance strategies exist to minimize RBC

Learning Objectives alloimmunization in patients at highest risk for this complication, the
• To consider the role of RBC antigen characteristics and blood genetic or immunologic signature that differentiates a “responder” from
processing in RBC alloimmunization a “nonresponder” to RBC antigens remains poorly understood. Despite
• To understand the role of recipient genetics and environmental this lack of understanding, it is hoped that this manuscript will provide
influences in RBC alloimmunization insight to readers into some triggers of RBC alloimmunization.

Antigen considerations
One factor that makes human studies of RBC alloimmunization so
Introduction difficult is the large number and structural diversity of blood group
Red blood cell (RBC) alloimmunization, or the formation of antibodies antigens. Hundreds of blood group antigens have been described to
against non–self-antigens on RBCs, may occur after exposure through date, such that a 1 “unit” of an RBC transfusion may contain many
transfusion or pregnancy. These antibodies may be clinically significant in antigens that are foreign to the transfusion recipient. Some of these an-
both settings, leading to delayed hemolytic or serologic transfusion re- tigens differ by a single amino acid polymorphism from the antithetic
actions or hemolytic disease of the fetus and newborn (HDFN). As shown antigen expressed on the recipient’s own RBCs (eg, K vs k), and others
in Table 1, the number of alloimmunized transfused patients1 is likely are entirely foreign to the transfusion recipient (eg, rhesus D [RhD]).
higher than the 1% to 3% commonly quoted, taking into consideration Some blood group antigens are proteins and others are carbohydrates;
the frequent occurrence of RBC antibody evanescence. Complications some antigens are expressed solely on RBCs, whereas others are also
from RBC alloantibodies are a leading cause of transfusion-associated expressed on organs or tissues. In rare instances, patients may express
death,2 although the true morbidity/mortality burden from RBC an antigen elsewhere in their body but not on their RBCs, as is observed
alloimmunization is likely higher than that appreciated from the Food with the Fy antigen in patients with a GATA-box silencing mutation.
and Drug Administration–reported statistics alone.3,4 Given blood group antigen expression on some organs, RBC alloan-
tibodies may be clinically relevant not only in transfusion or pregnancy
Donor and recipient factors play a role in RBC alloimmunization settings, but also in transplant settings. For example, recipient allo-
(Figure 1) and range from characteristics of particular blood group antibodies against Jk antigens have been described to impact the
antigens to the recipient’s ability to present the antigens to their outcomes of transplanted kidneys from Jk-positive donors.5,6
immune system. In addition to genetic factors, emerging data em-
phasize the importance of environmental factors in the formation of RBC phenotyping, or the evaluation of antigen expression on RBCs
RBC alloantibodies. Findings from descriptive human studies have using serologic methodology, has historically been used to char-
led to the testing of hypotheses using reductionist animal models, and acterize a particular donor or recipient’s blood group antigen status.
outcomes observed in animal models have been studied in humans. However, recent advances in molecular medicine have led to

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Off-label drug use: None disclosed.

446 American Society of Hematology

Table 1. Alloimmunization rates reported in various patient Blood group antigens differ not only in structure and function, but
populations and disease states* also in antigen density. RhD is the best example of such differences
Reported in humans. RBCs from donors that express an RhD antigen or
alloimmunization a “partial” D antigen may sensitize an RhD-negative recipient to the
Population or disease state rate (%) RhD antigen. However, RBCs from donors that express the “weak”
D antigen (eg, the same antigen as that seen in RhD donors, but at
General adult patients a low antigen density, particularly those with weak D types 1, 2, or
Retrospective analysis 1-3
3) are unlikely to sensitize an RhD-negative recipient to the RhD
Prospective analysis 8-10
antigen. This latter fact has led the American Association of Blood
Hemoglobin disorders Banks, College of American Pathologists, American Congress of
Sickle cell disease 19-43 Obstetricians and Gynecologists, and several other agencies to
Thalassemia major 5-45 encourage RhD genotyping to categorize women of childbearing
age with RhD phenotyping suggestive of a possible weak D. If
Inflammatory disorders these women genotype as weak D types 1, 2, or 3, they are not
Autoimmune disorders, general 16 treated with Rh immune globulin (RhIg) during pregnancy and they
Inflammatory bowel diseases 8-9

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are able to safely be transfused with RBCs from RhD-positive
donors. In addition to RhD, variations in antigen density are ob-
Lymphoid disorders
served in donors homozygous or heterozygous for a particular
Acute lymphoid leukemia ,1
Hodgkin lymphoma ,1
blood group antigen.
Non-Hodgkin lymphoma 2-3
Serologists use screening RBCs with the highest antigen copy
Myeloid disorders numbers to identify the specificity of a particular recipient alloan-
Acute myeloid leukemia 3-16 tibody. However, few studies have directly investigated the role in
Myelodysplastic syndromes (includes 15-59 humans that antigen copy number plays in the immunogenicity of
myelodysplastic/myeloproliferative non-RhD antigens. Animal studies allow for single variables, such as
disorders) antigen copy number, to be investigated, with copy number recently
being hypothesized to play an important role in immune re-
Solid tumors, nonhematopoietic 1-10
sponses to transfused transgenic murine RBCs expressing the human
Transplantation
KEL glycoprotein. Recipients transfused with RBCs from donors
Hematopoietic progenitor cell 1-4 expressing a KEL at a very low copy number (“weak” KEL) fail
Liver transplant 4-23 to generate anti-KEL glycoprotein alloantibodies. In contrast, re-
Other sites or multiple organ 1-10 cipients transfused with RBCs expressing the KEL antigen at a more
transplantation moderate copy number have been shown to generate anti-KEL al-
loantibodies after a single transfusion.9
*As reviewed in Hendrickson and Tormey.1

genotyping, or the evaluation of predicted RBC antigen expression using Blood collection, processing, modification, and
DNA extracted from white blood cells (WBCs), becoming more widely storage considerations
available. Used primarily by blood donor centers and immunohema- As with blood group antigen diversity, there are also a large number of
tology reference laboratories, genotyping allows for a more exact pre- variables involved in blood collection, processing, modification, and
diction of alloimmunization risks in certain circumstances. For example, storage that may, at least theoretically, impact the immunogenicity of
approximately 30% of patients with hemoglobinopathies that serologi- a particular unit. Screening questionnaires eliminate several potentially
cally phenotype as C positive actually have C variants as detected by infectious donors, but a donor that is not feeling well at the time of
genotyping. These C-variant patients are at risk for alloimmunization to donation may inadvertently donate not only RBCs, but also trans-
the C antigen if they are transfused with RBCs from donors whose RBCs missible inflammatory cytokines or other soluble factors. In addition,
express a normal C antigen. each bag of blood collected from a donor contains not only anticoagulant
preservative solution, but also plasma, platelets, and WBCs. Filter
The importance of wild-type or variant antigen status ultimately ties leukoreduction, which removes the vast majority of donor WBCs and
into the concept of immunogenicity (ie, how likely an antigen- is accepted to decrease febrile transfusion reactions, human leukocyte
negative individual is to mount an immune response to an antigen- antigen (HLA) alloimmunization, and the transmission of some viruses,
positive exposure). In the transfusion setting, immunogenicity can be has been shown in some but not all human10,11 and murine12 studies
empirically determined by exposing donors to antigens that they lack to decrease the rate or magnitude of RBC alloantibody responses.
and then measuring the percentage that develop an antibody response.7 However, hundreds of thousands of WBCs may still be present in
Because this is a laborious (and risky) undertaking, most antigen a leukoreduced RBC unit, and leukoreduction filters also have different
immunogenicity calculations are estimates based on the number of degrees of efficiency of platelet reduction. Thus, even in a leukoreduced
individuals in a population producing an alloimmune response to unit, residual WBCs, platelets, or their breakdown products including
a given antigen and their probability of exposure to that antigen based pro-inflammatory cytokines, microparticles,13 or damage-associated
on the frequency with which it is seen in the donor population. molecular patterns14 may have the potential to impact the recipient’s
Previous studies have shown marked variability in the “potency” of immune response to the transfused RBC antigens. Further, the timing of
clinically significant blood group antigens, with up to 30-fold dif- processing may impact the number of WBCs, cytokines, and micro-
ferences noted between some of the highest (K, E, Jka) and lowest (S) particles in the bag, with units processed after an overnight hold being
immunogenicity antigens.8 reported to have more potentially biologically active contaminants than

Hematology 2016 447

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Figure 1. A schematic model of the potential triggers for blood group alloimmunization including donor, recipient, unit, and RBC-specific factors that may
influence the development of alloantibodies.

those processed soon after collection.13,15 Reductionist studies of the HLA is thought capable of presenting a portion of the antigen,
impact of many of these elements on RBC alloimmunization in humans whereas other antigens such as Fya24 and K25 have been shown to
are logistically difficult, given the number of other involved variables. have more restricted HLA presentation. In addition to HLA re-
striction studies, a recent population based study has suggested that
Over the past decade, there has been much interest in the impact of RBC HLA-DRB1*15 may predispose transfused recipients to the for-
storage duration on patient outcomes. These studies, reviewed else- mation of multiple different RBC alloantibodies.26
where, have focused primarily on mortality and outcomes such as length
of intensive care unit stay; few prospective studies of RBC storage In addition to HLA differences, there are a multitude of genetic
duration have included RBC alloimmunization as an outcome measure. variants in recipient immunoregulatory genes that may, in theory,
The human studies that have investigated this issue have largely con- impact RBC alloimmune responses. Polymorphisms in TRIM
cluded that storage duration does not impact alloimmunization,16-18 21 (Ro52)27 and CD8128 have been implicated in recipient alloimmune
although at least 1 study has shown human RBCs of greater storage responses in humans. Few genome-wide association studies have
duration are more readily phagocytosed using an in vitro assay19; an- been completed in RBC alloantibody responders and nonresponders,
other study has shown a relationship between storage age and and no large effect responder loci have been described to date.29
alloimmunization in the setting of sickle cell disease.20 Reductionist
murine studies have also shown increased phagocytosis of stored
Other recipient considerations, including immune
compared with fresh RBCs,21 along with increased rates/magnitudes
status, disease state, and environment
of alloimmunization for some but not all RBC antigens.12 Differ-
Although genetic predisposition to alloimmunization is likely quite
ences are observed in storage characteristics from donor to donor,22
important, several emerging studies in animal models and humans
however, with storage duration being just one variable to consider.
alike have highlighted the relevance of a “danger signal” in the
formation of RBC alloantibodies. This danger signal may be in the
Recipient genetic status form of exogenous Toll-like receptor agonists such as polyinosinic-
Exposure to a nonself blood group antigen is, for all practical polycytidylic or 59-C-phosphate-G-39 administered to transfusion
purposes, a requirement for a recipient to generate an alloantibody. recipients in murine models,12 with these agonists turning non-
However, exposure alone is not sufficient to lead to alloimmuni- responders into responders in some models, or increasing the
zation, or else every transfusion recipient would be highly alloim- magnitude of the immune response in other models. Transfusion in
munized. The ability to present a particular RBC antigen on a the presence of a danger signal like polyinosinic-polycytidylic acid is
recipient HLA is a requirement for antigens that are dependent on known to increase consumption of RBCs by recipient dendritic cells
T-cell help. Studies in the area of neonatal alloimmune thrombo- and to increase costimulatory signals on antigen-presenting cells.30
cytopenia are an example of how the ability to present an antigen (in Further, depletion of dendritic cells in general, and an absence of
that case, human glycoprotein 1a) is required but not alone sufficient functional bridging channel dendritic cells in particular, abrogates
for an anti-human glycoprotein 1a alloantibody response.23 It is alloantibody responses to stored RBCs in at least 1 murine model.31
assumed that the majority of clinically significant human RBC
antigens are T-cell dependent, though few studies exist. Antigens Studies in humans have found that patients with sickle cell disease
such as RhD are large and diverse enough that virtually any recipient transfused during acute illness (such as acute chest syndrome or

448 American Society of Hematology

Table 2. Unanswered questions and future research areas for RBC with diseases requiring a large lifetime transfusion burden is ap-
alloimmunization triggers pealing, though intermittent antigen exposure may be required to
Unanswered questions Future research areas maintain such nonresponsiveness.

What defines a “responder” • Identification of reproducible In addition to past RBC exposure, prior contact with non-RBC
to RBC antigens in genetic markers of responsiveness antigens that possess shared sequences with RBC antigens may
transfusion or pregnancy? • Assessment of unique aspects impact future responses to transfused RBCs. For example, a
(signatures) of the innate or adaptive
number of organisms have linear peptide sequences that overlap
immune systems of responders and
nonresponders
with blood group antigen sequences; Haemophilus influenza shares
• Evaluation of other donor/recipient orthology with KEL and Yersinia pestis shares orthology with Fy.
characteristics that may predispose This is not just a theoretical concern; it has been demonstrated that
to responsiveness peripheral blood mononuclear cells from humans never before
What steps can be taken to • Feasibility of extended genotyped exposed to RBCs have evidence of T-cell reactivity upon stimu-
limit or avoid antibody or phenotyped matched units on a lation with overlapping KEL peptides.25 Similarly, animal studies
development in confirmed large scale using a model antigen have shown that exposure to sequences
responders? • Modification of antigen presentation

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contained in a virus are able to prime a recipient to robustly respond
or modulation of the immune system to a transfusion of RBCs containing the shared epitope.40 Of note,
before antigenic exposure
an RBC antibody screen completed in a clinical blood bank after
What other strategies may • Consideration of tolerance induction
prevent alloimmunization in strategies
virus exposure but before RBC exposure would never detect this
transfusion or pregnancy? • Exploration of antibody-mediated prior T-cell “priming.”
immune suppression
Exposure to RBC antigens during pregnancy or delivery
Although this manuscript is primarily focused on potential triggers
of RBC alloimmunization during transfusion, a brief discussion of
vasoocclusive crisis) are more likely to become alloimmunized than
triggers during pregnancy and delivery is warranted. All pregnant
patients transfused in their baseline state of health.32 In addition,
women are exposed to fetal RBCs during pregnancy and around the
patients with inflammatory bowel disease,33 other inflammatory
time of delivery. The vast majority of women do not become
disorders,34 or chronic autoimmune diseases35 have been described
alloimmunized after this exposure, although a subset do. The im-
to have higher rates of alloimmunization than control patients. On the
munogenicity of the RBC antigen appears to be one critical factor in
other hand, patients receiving immunosuppressive medications have
whether a woman will become alloimmunized, with the majority of
been described to have lower rates of alloimmunization than control
clinically significant HDFN cases being due to antibodies against
patients.36
antigens in the Rh, K, Fy, Jk, and MNS families. ABO incom-
patibility between mother and fetus plays a protective role against
Patients with sickle cell disease and thalassemia have among the
RBC alloimmunization, presumably because of maternal iso-
highest rates of RBC alloimmunization of all transfused patient
hemagglutinins rapidly clearing fetal RBCs from the maternal
populations. Antigenic variants in donors and recipients likely
circulation.
account for some degree of alloantibody formation,37 though other
variables may also be involved. However, vascular abnormalities,
In addition to fetal/maternal bleeds, 1 other trigger of RBC alloim-
inflammation, and immune dysregulation may also play a con-
munization in pregnancy is intrauterine transfusion.41 These trans-
tributing role. Further, in keeping with the theory that “responders”
fusions are typically given to women in the late second or third
are distinct in some way from “nonresponders,” RBC alloimmu-
trimesters of pregnancy if their fetus shows signs of anemia or hydrops.
nization has been associated with the formation of HLA alloan-
Given that HDFN is most often secondary to maternal alloimmuni-
tibodies in patients with sickle cell disease receiving solely
zation, the pregnant women being transfused have already proven
leukoreduced blood products.38 Antigen avoidance is the primary
themselves to be “responders” to RBC antigens. Thus, that at least 25%
strategy taken at the present time to minimize alloimmunization in
of these women form additional RBC antibodies in response to in-
these patient populations. However, alloantibody formation con-
trauterine transfusions is not entirely surprising. These women are not
tinues to occur in some patients despite phenotype-matched trans-
only at risk of forming additional RBC alloantibodies, but also of
fusions and may complicate future transfusion, transplantation, and
forming HLA alloantibodies.
pregnancy.
Reviewed in a past issue of the ASH Education Book,42 a better
Prior antigen exposure in the recipient understanding of the mechanism of action of RhIg may facilitate an
Past exposure to blood group antigens may, in theory, either prime understanding of the way in which fetal RBCs expressing the RhD
a transfusion recipient for a rapid anamnestic antibody response, antigen stimulate anti-RhD formation in women. Further, a better
result in ignorance, or lead to tolerance. Anamnestic responses as understanding of the mechanism of action of RhIg may facilitate
well as tolerance have been shown to occur in murine models, with the production of a standardized RhIg-like product that is not
donor antigen characteristics and recipient inflammatory status dependent on immunizing RhD-negative male volunteers with
playing a role in determining whether responsiveness or tolerance RhD-positive RBCs. In-depth mechanistic studies are logistically
results following RBC transfusion.9,39 Although tolerance per se has difficult to complete in humans; an RhD transgenic mouse has
not been shown in human studies, nonresponsiveness has been recently been generated and may provide the answers to some of
suggested in patients with thalassemia or sickle cell disease that were these questions. Studies of strategies to prevent alloantibody for-
initially exposed to RBCs at a relatively young age. The possibility of mation through pregnancy in other animal models may provide
inducing sustained nonresponsiveness or even tolerance in patients additional insight.

Hematology 2016 449

Conclusions 12. Ryder AB, Zimring JC, Hendrickson JE. Factors influencing RBC
There are many potential triggers of RBC alloimmunization in alloimmunization: lessons learned from murine models. Transfus Med
transfusion and pregnancy settings. Although much has been learned Hemother. 2014;41(6):406-419.
13. Radwanski K, Garraud O, Cognasse F, Hamzeh-Cognasse H, Payrat JM,
about “responders” and “nonresponders” to RBC antigens over the
Min K. The effects of red blood cell preparation method on in vitro
past few decades, many questions remain (Table 2). Future studies markers of red blood cell aging and inflammatory response. Transfusion.
investigating whether a “signature” of a responder exists will be 2013;53(12):3128-3138.
useful in generating strategies to decrease the likelihood of antibody 14. Land WG. Transfusion-related acute lung injury: the work of DAMPs.
formation; such studies may also allow for the conservation of highly Transfus Med Hemother. 2013;40(1):3-13.
phenotypically/genotypically matched RBC units for patients at 15. Thibault L, Beauséjour A, de Grandmont MJ, Lemieux R, Leblanc JF.
highest risk of alloimmunization. Future investigations identifying Characterization of blood components prepared from whole-blood do-
potential donor characteristics associated with recipient alloimmu- nations after a 24-hour hold with the platelet-rich plasma method.
nization will also be informative, although each RBC unit will re- Transfusion. 2006;46(8):1292-1299.
main biologically unique. Serving as an adjunct to human studies, 16. Dinardo CL, Fernandes FL, Sampaio LR, Sabino EC, Mendrone A Jr.
Transfusion of older red blood cell units, cytokine burst and alloim-
studies in animal models allow mechanistic questions not capable of
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37(5):320-323.

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