Clearance and Resistance of Red Blood Cells during Incompatible Transfusions

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 RBCss 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.