Acquired Aplastic Anemia.docx

1、Acquired Aplastic AnemiaAcquired Aplastic AnemiaYoung, Neal S. MDAuthor InformationFrom the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.For author affiliation and current address, see end of text.Acknowledgments: The author thanks Drs. Jaroslaw Maciej

2、ewski, John Barrett, Elaine Sloand, and Cynthia Dunbar for their careful reading of the manuscript.Grant Support: Dr. Young is supported entirely by intramural funds from the National Heart, Lung, and Blood Institute.Requests for Single Reprints: Neal S. Young, MD, Building 10, Room 7C103, National

3、Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-1652.Back to TopAbstractIn 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

4、 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,

5、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

6、 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, th

7、e 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

8、 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 c

9、ount is often incomplete, recurrent pancytopenia requires retreatment, and some patients develop late complications (especially myelodysplasia).Aplastic anemias long history, from its early description by Ehrlich (1) at the end of the 19th century, and the simplicity of its pathology, an empty bone

10、marrow, have made it the paradigm of hematopoietic failure syndromes. Aplastic anemia is now increasingly recognized as being closely related to other hematologic diseases (Figure 1). Erythrocytes, granulocytes, and platelets, which are normally produced in the bone marrow, decrease to dangerously l

11、ow levels. Blood cell counts determine presentation and prognosis. Anemia leads to fatigue, dyspnea, and cardiac symptoms; thrombocytopenia to bruising and mucosal bleeding; and neutropenia to sharply increased susceptibility to infection. When patients are treated with transfusions and antibiotics

12、alone, survival rates are poor and related to the severity of the pancytopenia, as defined by the presence of two of three criteria: a neutrophil count less than 0.5 109 cells/L, a platelet count less than 20 109 cells/L, and a reticulocyte count less than 1%. When the neutrophil count is less than

13、0.2 109 cells/L, the disease is characterized as very severe. In the early 20th century, patients often died quickly of heart failure, profuse hemorrhage, or overwhelming infection. In the modern era of erythrocyte and platelet transfusions, the most common causes of death are recurrent bacterial se

14、psis or fungal invasion of critical organs secondary to refractory granulocytopenia.Figure 1 Historically, aplastic anemia has been strongly associated with exposure to chemicals and drugs in the environment, giving the disease a social impact disproportionate to its incidence (2). The recognition o

15、f bone marrow failure in workers exposed to benzene led to heroic industrial hygiene crusades by Alice Hamilton and Harrison Martland in the United States in the 1920s and 1930s. In the late 1940s and early 1950s, an epidemic of aplastic anemia appeared to follow the introduction of chloramphenicol,

16、 and the disease has been linked to many classes of pharmaceuticals widely used in medical practice (Table). Because aplastic anemia has become such a feared disorder as a result of its association with common drug use, even a few cases can have a profound effect on new drug development by the pharm

17、aceutical industry. Also, this believed association with numerous, diverse possible causes, from chemicals and drugs to hepatitis, infectious mononucleosis, pregnancy, and collagen vascular processes (for example, eosinophilic fasciitis), has led to the belief that there also are numerous and differ

18、ent mechanisms of disease.Table. Drugs Associa. However, we now have a plausible, unified model of the pathophysiology of aplastic anemia, drawn from both compelling clinical observations of therapeutic efficacy and systematic laboratory experimentation. The early, successful use of bone marrow tran

19、splantation to cure aplastic anemia implicated a stem-cell deficiency. Later, responses to immunosuppressive therapies pointed to an immune mechanism of hematopoietic failure. As aplastic anemia is progressively demystified, questions of some biological interest emerge. These are relevant to bone ma

20、rrow failure as well as to our conceptions of autoimmune diseases of other organ systems and to the relationship of immune mechanisms to malignant transformation.Back to TopImmune Pathophysiology of Aplastic AnemiaMost cases of acquired aplastic anemia can be pathophysiologically characterized as T-

21、cellmediated, organ-specific destruction of bone marrow hematopoietic cells (4). In an individual patient, the aberrant immune response can sometimes be linked to a viral infection or to drug or chemical exposure (Figure 2). There is much less evidence for other mechanisms, such as direct toxicity f

22、or stem cells or a deficiency of stromal-cell or hematopoietic growth factor function. Furthermore, the variability in clinical course and response to treatment can be explained by the quantitative degree of stem-cell destruction and qualitative variations in immune response.Figure 2 Back to TopHema

23、topoietic FailureThat failure of blood cell production was responsible for the empty bone marrow was a prescient conclusion of the earliest observers of the “yellow fat” of the bony spaces and the absence of the morphologically diverse precursors of mature blood elementsstill so striking on examinat

24、ion of bone marrow aspirate smears or core biopsy specimens (5). Magnetic resonance imaging of the vertebrae shows uniform replacement of marrow with fat. Immature hematopoietic cells can also be quantitated by fluorescent-activated flow cytometry, which can detect the CD34 cell antigen, an adhesion

25、 protein present on less than 1% of normal bone marrow. CD34 cells are almost absent in aplastic anemia. Progenitor cells capable of forming erythroid, myeloid, and megakaryocytic colonies in tissue culture are greatly reduced, and assays of very primitive, quiescent, hematopoietic cells that are cl

26、osely related if not identical to stem cells show a similar consistent and severe deficit. By extrapolation from such functional studies of aplastic bone marrow, it is likely that patients present with pancytopenia when stem-cell and progenitor-cell populations have decreased to approximately 1% or

27、less of normal. Such a profound deficiency has important qualitative consequences, as reflected in the shortened telomere length of granulocytes of patients with aplastic anemia (6).Back to TopImmune DestructionThe efficiency of immune system destruction of blood-forming cells is obvious in “runt di

28、sease” in animals and in transfusion-associated graft-versus-host disease (GVHD) in humans (7). In these syndromes, small numbers of alloreactive T cells produce fatal aplastic anemia, and in the mouse model, we know that stem-cell destruction is rapid and almost complete. Much laboratory data suppo

29、rt the hypothesis that, in most patients with acquired aplastic anemia, lymphocytes are responsible for the destruction of the hematopoietic cell compartment (4).Early experiments showed that the patients lymphocytes suppressed hematopoiesis. These cells produced a soluble, inhibitory factor that wa

30、s eventually identified as interferon-gamma. Activation of a TH1-type T-cell response has been inferred from immunophenotypic characterization of T cells and excessive production of interferon, tumor necrosis factor, and interleukin-2. Detection of intracellular interferon-gamma in patient samples b

31、y flow cytometry may correlate with responsiveness to immunosuppressive therapy and may predict relapse (8). Altered immunity results in destruction, specifically Fas-mediated CD34 cell death, and in activation of intracellular pathways leading to cell-cycle arrest. Immunity is local and has been mo

32、deled in tissue culture when low concentrations of interferon-gamma are secreted into the marrow microenvironment. In an animal model, bone marrow failure after injection of alloreactive lymphocytes can be prevented by treatment with a monoclonal antibody to interferon-gamma (9).The nature of the antigen or antigens driving the pathologic immune response is unknown. At the molecular level, lymphocytes in aplastic anemia show similarity to T cells in multiple sclerosis, diabetes, and other related illnesses. Characterizat