Clearance and Resistance of Red Blood Cells during Incompatible Transfusions Pubblico

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

About this Dissertation

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Pathology Biology, Molecular Health Sciences, Immunology
Parola chiave	clearance glycophorin A red blood cell hemolytic transfusion
Committee Chair / Thesis Advisor	Zimring, James C, Emory University
Committee Members	Selvaraj, Periasamy, Emory University Iwakoshi, Neal N., Emory University Cooper, Max Dale, Emory University Lollar III, Pete, Emory University

Ultima modifica

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	Clearance and Resistance of Red Blood Cells during Incompatible Transfusions ()	2018-08-28 13:08:33 -0400	Press to Select an action Download

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions