Volume 4, Number 11; July 20, 2005
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Volume 4, Number 11; July 20, 2005 |
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59-year-old female presenting with 1-2 days of lightheadedness and rash.
Recommended reading:
The relationship of aplastic anemia and PNH. [Review]
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Patient: 59 year old female presenting with lightheadedness and rash of 1-2 days duration. She had traveled to Mexico recently, had headache and 'bad vision' in the right eye, and exhibited postural changes. On physical examination, patient had icteric sclera, pallor, petichiae on the soft palate, and flame hemorrhage bilaterally. CBC showed severe leukopenia, anemia, and pancytopenia. Patient was ultimately HIV- and Hepatitis - negative. |
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Session Handout:
APLASTIC ANEMIA
Interesting facts:
Causes:
· External radiation (whole body radiation of >7 Gy causes irreversible marrow damage) · Drugs: Chloramphenicol, gold, sulfonamides, nifedipine, phenylbutazone (NSAID), Felbamate · Solvents/degreasing agents, pesticides, insecticides, prolonged exposure to benzene, glue vapor · Viruses: most commonly parvovirus B19, hepatitis viruses (non-A & non-B), EBV, HIV · Autoimmune: SLE, eosinophilic fasciitis, GVHD · Misc: PNH, thymoma, thymic cancer, pregnancy
Presentation:
DDx: Acute leukemias, myelodysplastic syndromes, fibrotic marrow, malignant infiltration of BM, severe megaloblastic anemia, PNH, HIV, or viral hemophagocytic syndrome
Diagnosis:
· Residual hematopoietic cells are morphologically normal · Hypocellular with < 25% cellularity · No malignant cells or fibrosis · Fat cells, stromal elements, and blood vessels · Flow Cytometry of BM Bx (helps distinguish PNH from AA)
Stages:
Treatment should be based on pancytopenia and symptoms NOT BM cellularity:
<1> Link Directly to Fulltext Article at Science Direct Unique Identifier [PMID]: 15885298 Authors: Brodsky RA. Jones RJ. Institution: Johns Hopkins University School of Medicine, Division of Hematology, and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA. brodsro@jhmi.edu Title: Aplastic anaemia. [Review] [105 refs]
Source: Lancet. 365(9471):1647-56, 2005 May. Abstract: Aplastic anaemia is a rare haemopoietic stem-cell disorder that results in pancytopenia and hypocellular bone marrow. Although most cases are acquired, there are unusual inherited forms. The pathophysiology of acquired aplastic anaemia is immune mediated in most cases; autoreactive lymphocytes mediate the destruction of haemopoietic stem cells. Environmental exposures, such as to drugs, viruses, and toxins, are thought to trigger the aberrant immune response in some patients, but most cases are classified as idiopathic. Similarly to other autoimmune diseases, aplastic anaemia has a varied clinical course; some patients have mild symptoms that necessitate little or no therapy, whereas others present with life-threatening pancytopenia representing a medical emergency. Paroxysmal nocturnal haemoglobinuria and myelodysplastic syndrome commonly arise in patients with aplastic anaemia, showing a pathophysiological link between these disorders. Acquired aplastic anaemia can be effectively treated by allogeneic bone-marrow transplantation, immunosuppression (generally antithymocyte globulin and ciclosporin), and high-dose cyclophosphamide. [References: 105] Publication Type: Journal Article. Review. Review, Tutorial.
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Clinical Question: 1) W
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Readings:
<2> Unique Identifier [PMID]: 12430920 Authors: Young NS. Maciejewski JP. Sloand E. Chen G. Zeng W. Risitano A. Miyazato A. Institution: Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA. Title: The relationship of aplastic anemia and PNH. [Review] [40 refs]
Source: International Journal of Hematology. 76 Suppl 2:168-72, 2002 Aug. Abstract: Bone marrow failure has been regarded as one of the triad of clinical manifestations of paroxysmal noctumal hemoglobinuria (PNH), and PNH in turn has been described as a late clonal disease evolving in patients recovering from aplastic anemia. Better understanding of the pathophysiology of both diseases and improved tests for cell surface glycosylphosphatidylinositol (GPI)-linked proteins has radically altered this view. Flow cytometry of granulocytes shows evidence of an expanded PNH clone in a large proportion of marrow failure patients at the time of presentation: in our large NIH series, about 1/3 of over 200 aplastic anemia cases and almost 20% of more than 100 myelodysplasia cases. Clonal PNH expansion (rather than bone marrow failure) is strongly linked to the histocompatability antigen HLA.-DR2 in all clinical varieties of the disease, suggesting an immune component to its pathophysiology. An extrinsic mechanism of clonal expansion is also more consistent with knock-out mouse models and culture experiments with primary cells and cell lines, which have failed to demonstrate an intrinsic proliferative advantage for PNH cells. DNA chip analysis of multiple paired normal and PIG-A mutant cell lines and lymphoblastoid cells do not show any consistent differences in levels of gene expression. In aplastic anemia/PNH there is surprisingly limited utilization of the V-beta chain of the T cell receptor, and patients' dominant T cell clones, which are functionally inhibitory of autologous hematopoiesis, use identical CDR3 regions for antigen binding. Phenotypically normal cells from PNH patients proliferate more poorly in culture than do the same patient's PNH cells, and the normal cells are damaged as a result of apoptosis and overexpress Fas. Differences in protein degradation might play a dual role in pathophysiology, as GPI-linked proteins lacking an anchor would be predicted to be processed by the proteasome machinery and displayed in a class I H.A. context, in contrast to the normal pathway of cell surface membrane recycling, lysosomal degradation, and presentation by class II HLA. The strong relationship between a chronic, organ-specific immune destructive process and the expansion of a single mutant stem cell clone remains frustratingly enigmatic but likely to be the result of interesting biologic processes, with mechanisms that potentially can be extended to the role of inflammation in producing premalignant syndromes. [References: 40] Publication Type: Journal Article. Review. Review, Tutorial.
<3> Link Directly to Fulltext article in Ovid Unique Identifier [PMID]: 11926789 Authors: Young NS. Institution: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1652, USA. Title: Acquired aplastic anemia. [Review] [62 refs]
Source: Annals of Internal Medicine. 136(7):534-46, 2002 Apr 2. Abstract: In aplastic anemia, hematopoiesis fails: Blood cell counts are extremely low, and the bone marrow appears empty. The pathophysiology of aplastic anemia is now believed to be immune-mediated, with active destruction of blood-forming cells by lymphocytes. The aberrant immune response may be triggered by environmental exposures, such as to chemicals and drugs or viral infections and, perhaps, endogenous antigens generated by genetically altered bone marrow cells. In patients with post-hepatitis aplastic anemia, antibodies to the known hepatitis viruses are absent; the unknown infectious agent may be more common in developing countries, where aplastic anemia occurs more frequently than it does in the West. The syndrome paroxysmal nocturnal hemoglobinuria (PNH) is intimately related to aplastic anemia because many patients with bone marrow failure have an increased population of abnormal cells. In PNH, an entire class of proteins is not displayed on the cell surface because of an acquired X-chromosome gene mutation. The PNH cells may have a selective advantage in resisting immune attack. In contrast, the disease myelodysplasia can be confused with aplasia and can also evolve from aplastic anemia. The occurrence of cytogenetic abnormalities in patients years after presentation implies that genomic instability is a feature of this immune-mediated disease. Aplastic anemia can be effectively treated by stem-cell transplantation or immunosuppressive therapy. Transplantation is curative but is best used for younger patients who have histocompatible sibling donors. Antithymocyte globulin and cyclosporine restore hematopoiesis in approximately two thirds of patients. However, recovery of blood cell count is often incomplete, recurrent pancytopenia requires retreatment, and some patients develop late complications (especially myelodysplasia). [References: 62] Publication Type: Journal Article. Review.
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Resident Report / Department of Medicine & Grady Branch Library Emory University School of Medicine 2005 Edition Participating Faculty: Carlos Del Rio MD / Joyce Doyle MD / Lorenzo Difrancesco MD / Erich Folch MD / Alicia Hidron MD
Contact:
Karl Woodworth
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