Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / "August 2002." Typescript. Vita. Includes bibliographical references (leaves 95-109).

Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 95-109). Also available on the Internet.

Thrombotic microangiopathies (TMA) are disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microthrombi leading to organ dysfunction. Atypical hemolytic uremic syndrome (aHUS) is a rare subtype of TMA mediated by complement dysregulation. We present a case of a 59-year-old female who presented with acute kidney injury and mild thrombocytopenia but with normal hemoglobin. We highlight the importance of prompt diagnosis of aHUS and initiating appropriate treatment with eculizumab.

The clinical manifestations of hemolytic disease of the fetus and newborn mediated by anti-K, an antibody of the Kell blood group system, are distinguishable from the classical form of the disease. Affected fetuses have low numbers of circulating reticulocytes and antibody titers and bilirubin levels are not reliable predictors of anemia. These observations suggest that antibodies to Kell glycoprotein lead to anemia through suppression of erythropoiesis. This study established a liquid erythroid progenitor cell culture model in which to perform analyses on the mechanism of the suppressive growth effect of anti-Kell glycoprotein. Using this culture model, this study demonstrated the requirement for co-ligation of Kell glycoprotein by a bivalent antibody for growth suppression. The absence of markers of apoptosis in cell cultures treated with anti-Kell glycoprotein suggests that the mechanism of growth suppression is distinct from programmed cell death and necrosis. Furthermore, this growth suppression cannot be rescued by erythropoietin.

No description available.

The clinical manifestations of hemolytic disease of the fetus and newborn mediated by anti-K, an antibody of the Kell blood group system, are distinguishable from the classical form of the disease. Affected fetuses have low numbers of circulating reticulocytes and antibody titers and bilirubin levels are not reliable predictors of anemia. These observations suggest that antibodies to Kell glycoprotein lead to anemia through suppression of erythropoiesis. This study established a liquid erythroid progenitor cell culture model in which to perform analyses on the mechanism of the suppressive growth effect of anti-Kell glycoprotein. Using this culture model, this study demonstrated the requirement for co-ligation of Kell glycoprotein by a bivalent antibody for growth suppression. The absence of markers of apoptosis in cell cultures treated with anti-Kell glycoprotein suggests that the mechanism of growth suppression is distinct from programmed cell death and necrosis. Furthermore, this growth suppression cannot be rescued by erythropoietin.

Typical Hemolytic Uremic Syndrome (HUS) presents as a complication of infection with Shiga-toxin producing E. coli (STEC). While there are many animal models for infection, few show true signs of HUS. Additionally, these models differ greatly from the clinical presentation that affects small children and elderly populations. Immunohistochemical assays of tissues from a known HUS model may provide insight into molecular changes associated with the condition, particularly as it pertains to clotting factors. In this study, tissue factor (TF) was investigated in the kidneys of non-human primates previously injected with Shiga-Toxin 2 (STX2). The animals’ condition was indicative of HUS through three main clinical signs: thrombocytopenia, hemolytic anemia and decreased kidney function. Tissue factor antigen in the kidneys varies between animals that exhibited HUS when compared to those that had recovered or treated with anti-STX2 antibody. Overall, tissue factor is strongly detected in the renal tubules of those afflicted with HUS; tissue factor was not strongly expressed in the glomerular epithelial space, as it was in recovered, clinically healthy animals. This suggests a change throughout the time course of disease and recovery. Investigating tissue factor’s role, if any, in the pathology of the disease could lead to new therapeutics. Although many types of treatments have been suggested and tried, the primary clinical procedure is to administer fluids and allow symptoms to subside. With increasing knowledge about HUS through studies like these, we can hope to gain insight into potent therapeutics and therefore, save lives associated with typical HUS.

Background: Hemolytic disease of the fetus and newborn (HDFN) attributable to anti-M is rare, although case reports implicate anti-M in varying severities of HDFN, including fetal hydrops and intrauterine death. Case Description: We describe the case of a newborn with HDFN associated with an atypical immunoglobulin (Ig) G anti-M that reacted best at cold temperatures. The maternal antibody detected in pregnancy was not reactive at 37°C, and a direct antiglobulin test (DAT) on red blood cells (RBCs) from the newborn was negative, suggesting an anti-M that should not have been clinically relevant. However, the infant developed hyperbilirubinemia (bilirubin level, 17.6 mg/dL), hemolytic anemia (hemoglobin nadir, 5.5 g/dL), and reticulocytopenia. Laboratory testing demonstrated the presence of an IgG anti-M in maternal and neonatal samples reacting best at 4°C. This passively acquired IgG anti-M provoked hemolytic anemia in the infant and likely suppressed erythropoiesis, resulting in reticulocytopenia with prolonged anemia. He was treated for IgG anti-M HDFN with 10 intravenous Ig infusions and 10 days of oral prednisone followed by a taper. He required seven transfusions with M− RBCs. His hemoglobin level normalized at 3 months of age. Follow-up at 2 years revealed no hematologic or neuro-developmental concerns. Conclusion: To our knowledge, this is the second report of HDFN attributable to an IgG anti-M reacting preferentially at cold temperature with no 37°C reactivity. Clinically relevant IgG anti-M may elude standard testing. Early recognition and testing for cold-reacting IgG anti-M should be considered for newborns with hemolysis, a negative DAT, and prolonged anemia.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online as viewed 8/06/2009 through Digital Dissertations.