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Review
. 2006 Oct 15;108(8):2509-19.
doi: 10.1182/blood-2006-03-010777. Epub 2006 Jun 15.

Current concepts in the pathophysiology and treatment of aplastic anemia

Neal S Young  1 , Rodrigo T Calado, Phillip Scheinberg
Affiliations
Review

Current concepts in the pathophysiology and treatment of aplastic anemia

Neal S Young et al. Blood. .

Abstract

Aplastic anemia, an unusual hematologic disease, is the paradigm of the human bone marrow failure syndromes. Almost universally fatal just a few decades ago, aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. The molecular basis of the aberrant immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways. Immunosuppression with antithymocyte globulins and cyclosporine is effective at restoring blood-cell production in the majority of patients, but relapse and especially evolution of clonal hematologic diseases remain problematic. Allogeneic stem-cell transplant from histocompatible sibling donors is curative in the great majority of young patients with severe aplastic anemia; the major challenges are extending the benefits of transplantation to patients who are older or who lack family donors. Recent results with alternative sources of stem cells and a variety of conditioning regimens to achieve their engraftment have been promising, with survival in small pediatric case series rivaling conventional transplantation results.

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Figures

Figure 1.
Figure 1.
Pathophysiology of acquired aplastic anemia. The figure stresses the crucial and related roles of the hematopoietic stem-cell compartment as a target for the immune response. An inciting event, such as a virus or medical drug, provokes an aberrant immune response, triggering oligoclonal expansion of cytotoxic T cells that destroy hematopoietic stem cells (left panel, Onset). Bone marrow transplantation or immunosuppressive therapy leads to complete response (CR) or partial response (PR) by eradicating or suppressing pathogenic T-cell clones (middle panel, Recovery). Relapse occurs with recurrence of the immune response, and the immunologically stressed and depleted stem-cell compartment also allows selection of abnormal hematopoietic clones that manifest as paroxysmal nocturnal hemoglobinuria, myelodysplasia (MDS), and occasionally acute myelogenous leukemia (AML) (right panel, Late Disease).
Figure 2.
Figure 2.
Venn diagram of the clinical and pathophysiologic relationships among the bone marrow failure syndromes, leukemia, and autoimmune diseases. Overlapping circles indicate difficulties in diagnostic discrimination and shared underlying mechanisms.
Figure 3.
Figure 3.
Immune destruction of hematopoiesis. Antigens are presented to T lymphocytes by antigenpresenting cells (APCs), which trigger T cells to activate and proliferate. T-bet, a transcription factor, binds to the interferon-γ (INF-γ) promoter region and induces gene expression. SAP binds to Fyn and modulates SLAM activity on IFN-γ expression, diminishing gene transcription. Patients with aplastic anemia show constitutive T-bet expression and low SAP levels. IFN-γ and TNF-α up-regulate other T cells' cellular receptors and also the Fas receptor. Increased production of interleukin-2 leads to polyclonal expansion of T cells. Activation of Fas receptor by the Fas ligand leads to apoptosis of target cells. Some effects of IFN-γ are mediated through interferon regulatory factor 1 (IRF-1), which inhibits the transcription of cellular genes and entry into the cell cycle. IFN-γ is a potent inducer of many cellular genes, including inducible nitric oxide synthase (NOS), and production of the toxic gas nitric oxide (NO) may further diffuse toxic effects. These events ultimately lead to reduced cell cycling and cell death by apoptosis.
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References

    1. Young NS. Aplastic anemia. In: Young NS, ed. The Bone Marrow Failure Syndromes. Philadelphia, PA: W. B. Saunders; 2000: 1-46.
    1. Kojima S, Nakao S, Tomonaga M, et al. Consensus conference on the treatment of aplastic anemia. Int J Hematol. 2000;72: 118-123. - PubMed
    1. Marsh JCW. Management of acquired aplastic anaemia. Blood Rev. 2005;19: 143-151. - PubMed
    1. Nakao S, Feng X, Sugimori C. Immune pathophysiology of aplastic anemia. Intl J Hematol. 2005;82: 196-200. - PubMed
    1. Young NS. Acquired aplastic anemia. In: Young NS, Gerson SL, High K, eds. Clinical Hematology. Philadelphia, PA: Elsevier; 2006: 136-157.

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