Biomedical subjects

Wendell F Rosse

Publications and source records attributed to Wendell F Rosse.

4 recordsLinked to original sources

PubMed2004

Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan.

: To determine and directly compare the clinical course of white and Asian patients with paroxysmal nocturnal hemoglobinuria (PNH), data were collected for epidemiologic analysis on 176 patients from Duke University and 209 patients from Japan. White patients were younger with significantly more classical symptoms of PNH including thrombosis, hemoglobinuria, and infection, while Asian patients were older with more marrow aplasia. The mean fraction of CD59-negative polymorphonuclear cells (PMN) at initial analysis was higher among Duke patients than Japanese patients. In both cohorts, however, a larger PNH clone was associated with classical PNH symptoms, while a smaller PNH clone was associated with marrow aplasia. Thrombosis was significantly more prevalent in white patients than Asian patients, and was associated with a significantly higher proportion of CD59-negative PMN. For individual patients, CD59-negative populations varied considerably over time, but a decreasing PNH clone portended hematopoietic failure. Survival analysis revealed a similar death rate in each group, although causes of death were different and significantly more Duke patients died from thrombosis. Japanese patients had a longer mean survival time (32.1 yr vs. 19.4 yr), although Kaplan-Meier survival curves were not significantly different. Poor survival in both groups was associated with age over 50 years, severe leukopenia/neutropenia at diagnosis, and severe infection as a complication; additionally, thrombosis at diagnosis or follow-up for Duke patients and renal failure for Japanese patients were poor prognostic factors. These data identify important differences between white and Asian patients with PNH. Identification of prognostic factors will help the design of prospective clinical trials for PNH.

Adolescent↗

PubMed2004

Immune-mediated hemolytic anemia.

Hemolytic anemia due to immune function is one of the major causes of acquired hemolytic anemia. In recent years, as more is known about the immune system, these entities have become better understood and their treatment improved. In this section, we will discuss three areas in which this progress has been apparent. In Section I, Dr. Peter Hillmen outlines the recent findings in the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH), relating the biochemical defect (the lack of glycosylphosphatidylinositol [GPI]-linked proteins on the cell surface) to the clinical manifestations, particularly hemolysis (and its effects) and thrombosis. He discusses the pathogenesis of the disorder in the face of marrow dysfunction insofar as it is known. His major emphasis is on innovative therapies that are designed to decrease the effectiveness of complement activation, since the lack of cellular modulation of this system is the primary cause of the pathology of the disease. He recounts his considerable experience with a humanized monoclonal antibody against C5, which has a remarkable effect in controlling the manifestations of the disease. Other means of controlling the action of complement include replacing the missing modulatory proteins on the cell surface; these studies are not as developed as the former agent. In Section II, Dr. Alan Schreiber describes the biochemistry, genetics, and function of the Fc gamma receptors and their role in the pathobiology of autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura due to IgG antibodies. He outlines the complex varieties of these molecules, showing how they vary in genetic origin and in function. These variations can be related to three-dimensional topography, which is known in some detail. Liganding IgG results in the transduction of a signal through the tyrosine-based activation motif and Syk signaling. The role of these receptors in the pathogenesis of hematological diseases due to IgG antibodies is outlined and the potential of therapy of these diseases by regulation of these receptors is discussed. In Section III, Dr. Wendell Rosse discusses the forms of autoimmune hemolytic anemia characterized by antibodies that react preferentially in the cold-cold agglutinin disease and paroxysmal cold hemoglobinuria (PCH). The former is due to IgM antibodies with a common but particular structure that reacts primarily with carbohydrate or carbohydrate-containing antigens, an interaction that is diminished at body temperature. PCH is a less common but probably underdiagnosed illness due to an IgG antibody reacting with a carbohydrate antigen; improved techniques for the diagnosis of PCH are described. Therapy for the two disorders differs somewhat because of the differences in isotype of the antibody. Since the hemolysis in both is primarily due to complement activation, the potential role of its control, as by the monoclonal antibody described by Dr. Hillmen, is discussed.

Anemia, Hemolytic, Autoimmune↗

PubMed2003

Clinical manifestations of paroxysmal nocturnal hemoglobinuria: present state and future problems.

The clinical pathology of paroxysmal nocturnal hemoglobinuria (PNH) involves 3 complications: hemolytic anemia, thrombosis, and hematopoietic deficiency. The first 2 are clearly the result of the cellular defect in PNH, the lack of proteins anchored to the membrane by the glycosylphosphatidylinositol anchor. The hemolytic anemia results in syndromes primarily related to the fact that the hemolysis is extracellular. Thrombosis is most significant in veins within the abdomen, although a number of other thrombotic syndromes have been described. The hematopoietic deficiency may be the same as that in aplastic anemia, a closely related disorder, and may not be due to the primary biochemical defect. The relationship to aplastic anemia suggests a nomenclature that emphasizes the predominant clinical manifestations in a patient. This relationship does not explain cases that appear to be related to myelodysplastic syndromes or the transition of some cases of PNH to leukemia. Treatment, except for bone marrow transplantation, remains noncurative and in need of improvement.

Anemia, Aplastic↗

PubMedDate not supplied

The hematopoietic defect in PNH is not due to defective stroma, but is due to defective progenitor cells.

Although paroxysmal nocturnal hemoglobinuria (PNH) is often associated with aplastic anemia (AA), the nature of the pathogenetic link between PNH and AA remains unclear. Moreover, the PIG-A mutation appears to be necessary but not sufficient for the development of PNH, suggesting other factors are involved. The ability of PNH marrow cells to form in vitro hematopoietic colonies and the ability of PNH marrow to generate stroma that could support hematopoiesis of normal or PNH marrow in cross culture were investigated. PNH marrow from both post-Ficoll and post-lineage depleted hematopoietic progenitor cells grew similarly significantly fewer colonies than normal marrow. Sorting of CD59(+) and CD59(-) CD34(+) CD38(-) cells from patients with PNH showed similarly impaired clonogenic efficiency, indicating that the hematopoietic defect in PNH does not directly relate to GPI-anchored protein expression. PNH marrow readily grew stroma similar to marrow from normal donors. Cross culture experiments revealed that PNH stroma appears to function normally in vitro; it can support growth of normal marrow cells as well as normal stroma does, but neither PNH nor normal stroma could support the growth of PNH marrow cells. The hematopoietic defect in PNH is not due to defective stroma, but is due to defective progenitor cell growth related to additional unknown factors.

Adult↗