Clearance and Resistance of Red Blood Cells during Incompatible Transfusions Open Access
Liepkalns, Justine Suzanne (2012)
Abstract
Transfusion therapy is widely used to treat acute and chronic
anemia. Although compatibility testing has been used to avoid
pathophysiologies such as hemolytic transfusion reactions (HTRs),
incompatible transfusions still occur. Some incompatible
transfusions do not lead to pathophysiology and the survival of
incompatible RBCs is normal. This dissertation sought to study RBC
survival in the context of a novel murine model of incompatible
transfusions.
Studies herein were done using monoclonal antibodies against the
human blood group glycophorin A (hGPA) and Duffy (as part of a
fusion protein called HOD) antigens. Anti-Duffy antibodies were
found to clear HOD expressing RBCs via Fc-receptors. In contrast,
anti-hGPA antibodies were found to clear RBCs via a third novel
biphasic mechanism. In the first phase, anti-hGPA antibodies
agglutinate RBCs, sequestering them from circulation. During the
second phase, phagocytic cells are required for removal of the
sequestered RBCs independent of Fc-receptors and of complement. A
coinciding cytokine burst was found to require Fc-receptors, which
suggests a decoupling of phagocytosis and cytokine secretion during
the clearance of incompatible hGPA RBCs.
With the knowledge of the clearance pathways of RBCs bearing these
2 antigens, we investigated the RBC's ability to survive in vivo.
Not all hGPA and HOD RBCs cleared when faced with a bolus of
anti-hGPA and anti-Duffy antibodies, respectively. During hGPA or
HOD incompatible transfusions, a population of RBCs was found to be
resistant. Resistance of hGPA or HOD RBCs was found to not require
C3, contradicting previous findings. A titration of anti-hGPA
antibody-mediated clearance suggests a spectrum of RBC susceptibly
among hGPA RBCs. Incompatible transfusion studies with HOD RBCs
suggest that the resulting resistant RBCs did not acquire the
ability to resist but rather resistance is an innate quality of
that population of RBCs. Overall, incompatible RBC clearance
pathways seem to vary among blood group antigens and/or binding
antibody. The resulting RBC resistance may be relative to the blood
group in question. This thesis elucidates a novel RBC clearance
pathway and confirms incompatible RBC resistance as a phenomenon.
In this particular system, resistance was not found to require
Complement as previously suggested in other systems.
Table of Contents
Table of contents
Chapter 1 -
Introduction.......................................................................
1
Historical
background..............................................................................
2
Blood group
discoveries...........................................................................
4
Clinical significance of recipient
antibodies................................................. 4
The ABO blood group
system...................................................................
6
The MNS blood group
system...................................................................
7
The Duffy blood group
system..................................................................
9
Blood transfusion
therapy.......................................................................
10
Transfusion therapy and
anemia..............................................................
10
Chronic transfusion
...............................................................................
13
Conditions causing chronic
anemia...........................................................
16
Risks of transfusion
therapy....................................................................
21
Hemolytic disease of the fetus and
newborn............................................. 25
Age-dependent RBC clearance
mechanisms.............................................. 27
Antibody-dependent RBC clearance
mechanisms....................................... 29
Red blood cell survival in the presence of
antibody..................................... 36
Models of transfusion
research................................................................
39
References...........................................................................................
40
Chapter 2 - Biphasic clearance of incompatible RBCs through a
novel mechanism
requiring neither complement nor Fc gamma receptors in a
murine
model..................................................................................................
61
Abstract...............................................................................................
63
Introduction..........................................................................................
64
Methods................................................................................................
67
Results..................................................................................................
70
Discussion.............................................................................................
78
References.............................................................................................
85
Chapter 3 - Resistance of a Subset of RBCs to Clearance by
Antibodies in a
Mouse Model of Incompatible
Transfusion...........................................
102
Abstract................................................................................................
104
Introduction..........................................................................................
105
Methods................................................................................................
107
Results..................................................................................................
110
Discussion.............................................................................................
115
References............................................................................................
119
Chapter 4 - Resistance of Duffy expressing RBCs does not require
complement C3
but is instead innate to the persistent
population................................ 129
Abstract................................................................................................
131
Introduction..........................................................................................
132
Methods...............................................................................................
133
Results.................................................................................................
136
Discussion............................................................................................
142
References...........................................................................................
146
Chapter 5 -
Discussion........................................................................
160
Summary.............................................................................................
161
Discussion...........................................................................................
163
Clearance of incompatible
RBCs.............................................................
163
Resistance of incompatible
RBCs.............................................................
166
Future
directions...................................................................................
170
General
conclusions...............................................................................
172
References...........................................................................................
174
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