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Chapter 111 Principles of Red Blood Cell Transfusion 1709

RED CELL ALLOIMMUNIZATION with SCD patients lacking HLA-B35. GWAS studies currently being
pursued may clarify the role of genetic factors. Interestingly, the rate
Overview of alloimmunization was not proportionally observed in patients
receiving massive transfusion with uncrossmatched RBCs. This
RBCs have over 300 blood group antigens that are capable of mount- observation may be due to transient immunosuppression in the setting
ing humoral responses in antigen-naive transfused recipients. Direct of severe physiologic stress or by immune modulation due to the
exposure to nonself red cells from allogeneic blood transfusion, cir- overwhelming amount of foreign RBCs transfused. This phenomenon
culating fetal red cells in pregnant females, or even occasionally stem was also shown in pediatric SCD patients receiving RBC exchange.
cell/organ transplantation can cause red cell alloimmunization. In On rare occasions, solid organ transplant can also be a source of red
addition, recent studies have shown that indirect immune modula- cell alloimmunization as it may expose the recipient to residual donor
tion mediated via proinflammatory factors in stored RBCs, a proin- red cells with foreign antigens, despite immediate saline perfusion to
flammatory state in the host (e.g., endothelial damage or higher rinse the organ of blood. Clinical hemolysis may be observed, but
turnover rate of red cells in patients with chronic transfusion), and severe hemolytic complications are more likely a result of passenger
passive transfer of WBC antibodies (anti-HLA and anti-HNA) are lymphocytes that are capable of mounting an anamnestic response to
associated with a higher risk of RBC alloimmunization. Matzinger’s antigen-positive recipient red cells (Passenger Lymphocyte Syndrome).
Danger Theory/Model further proposes that nonself antigen exposure From knowledge gained through observational studies, the risk of red
with local danger signals from injured cells can synergize immune cell alloimmunization seems to be associated with both red cell expo-
responses. Therefore, red cell alloimmunization represents an intricate sure and host immune responses. However, the complete pathophysi-
yet complex interplay between transfused allogeneic RBCs and host ology still remains to be determined.
immunity.
The humoral response can be categorized into two phases. The
primary response occurs immediately when foreign antigen activates Molecular Pathophysiology
B lymphocytes leading to the high-affinity mutation selection process.
This process allows the activated B cells to proliferate and differentiate The exact cause of human RBC alloimmunization under myriad
into memory/plasma B cells that produce a specific antibody against clinical circumstances is multifactorial and difficult to accurately
the antigen. Although, the initially generated antibody may not lead identify. Thus, reductionist animal model based studies will be needed
to significant hemolysis of sensitized red cells. Upon reexposure to the to investigate the mechanisms and identify the specific etiologies of
same antigen (e.g., transfusing an individual who had preformed this clinical entity. Given the well-defined genetic background, ready
antibody but at an undetectable level), the second phase of the availability of a large number of participants, ability to adapt to many
immune response (anamnestic response) can lead to rapid and robust genetic manipulations, and largely conserved lineage-specific genes in
antibody production from the pregenerated antigen-specific memory/ the mouse immune system, mouse models are ideal to investigate this
plasma B cells. This response often causes clinically significant hemo- complex clinical entity. For example, transgenic human Rh, Kell, and
lysis that may even lead to a fatality in these transfused individuals. Duffy antigen-expressing mice have been generated to study the
In the blood bank, a process is in place to prevent clinically significant interaction with their cognate alloantibodies. In addition, human
hemolysis in transfused patients with preformed red cell alloantibody. hemolytic disease of the fetus and newborn (HDFN) associated with
There are two isotypes of red cell antibodies that are routinely evalu- alloantibody against the Kell antigen has been closely recapitulated
ated in the blood bank. Immunoglobulin M (IgM) is a pentavalent in pregnant transgenic Kell mice. Unlike the HDFN associated
antibody that appears during the early phase of antibody generation. with alloantibody against the RhD antigen that can be prevented with
It is primarily restricted to the intravascular compartment, can fix administration of Rh immune globulin, HDFN associated with
complement on the transfused red cells with cognate antigens, and alloantibody against the Kell antigen still lacks effective prevention.
could result in intravascular hemolysis. On the contrary, IgG antibody Therefore, this anti-Kell mouse model will be useful in revealing the
is produced mostly by memory/plasma B cells that can migrate to the mechanism of alloimmunization against the Kell antigen.
extravascular compartment (e.g., amniotic fluid, tissues, etc.). Due to There is a high red cell alloimmunization rate in SCD patients.
its capacity to move between compartments, it is commonly associ- The transgenic murine model of SCD revealed that the sickle cell
ated with extravascular hemolysis and fetal hemolysis. genetic mutation alone was not sufficient to independently cause
RBC alloimmunization. This study further suggests the critical roles
of environmental factors involved in this immune response. Indeed,
Individuals at Risk other mouse model studies have found that viral analog-induced
inflammation (e.g., polyinosinic polycytidylic acid, or poly:IC) can
Both the immunogenicity and quantity of foreign red cell antigens are independently enhance RBC alloimmunization. Furthermore,
critical determinants of alloimmunization. Therefore, frequent trans- experimental mice transfused in the absence of inflammation devel-
fusion exposure and transfusion across different ethnic groups are the oped immune tolerance against the transfused foreign red cell antigens
most common factors associated with alloimmunization. This issue is as compared with control mice in the presence of poly:IC. This
of great concern in patients with transfusion dependent hemoglobin- observation is supported by the fact that most transfused individuals
opathies [e.g., sickle cell disease (SCD) and thalassemia] and PRCA without infections do not make alloantibodies to nonself red cell
(e.g., Diamond-Blackfan anemia). In particular, SCD is associated antigens. Also, exogenous inflammatory factors accumulated during
with rapid sequestration of defective red cells and endothelial damage. RBC storage (storage lesion) were found to enhance sensitization to
The discrepancy in the prevalence of certain red cell antigens, such as foreign RBCs leading to a more than 10-fold increase in alloantibody
in the Rh system (DCcEe) and Kell (K1), between blood donors production. This concept has not yet been tested in prospective
(mostly Whites) and SCD patients (mostly African descent) signifi- controlled clinical trials.
cantly contributes to the increase in red cell alloimmunization rate While animal models are able to provide the reductionist view of
compared with the general population. Interestingly, by molecular red cell alloimmunization and can serve as a platform to study the
genotyping, it was found that SCD patients have a high frequency of mechanism of red cell alloimmunization, the study conclusions may
polymorphisms that can result in red cell alloimmunization even have limited general applicability. For example, the transgenic SCD
when serologically matched red cells are transfused. In addition, the mouse model has inherent differences in disease manifestations (e.g.,
endothelial damage and chronic inflammatory state associated with massive splenomegaly, large vessel vasculopathy, etc.) that are not
SCD have been hypothesized to cause synergy in red cell alloimmuni- observed in human SCD patients. In addition to the interspecies
zation. Genetic factors predisposing SCD patients to red cell alloim- genetic variation, the homogeneous nature of the experimental
munization have been studied, and patients with HLA-B35 have a mouse’s genetic background may not fully capture the true patho-
sixfold higher likelihood of making red cell alloantibodies compared physiology of red cell alloimmunization in the human population.