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Aplastic anemia is a hematologic disorder characterized by a markedly decreased quantity of cellular elements in the peripheral blood, which ultimately results from failure of the bone marrow to produce/yield these peripheral blood elements. Specifically, the most defining characteristics of aplastic anemia are pancytopenia (a combination of anemia, leukopenia, neutropenia, and thrombocytopenia) and hypocellular/fatty bone marrow (1). The pathophysiology of aplastic anemia is believed to be immune-mediated, with active destruction of blood-forming cells by T lymphocytes. The aberrant immune response may be the result of a predisposed genetic abnormality or may be triggered by environmental exposures to chemicals, drugs, viral infections, or endogenous antigens generated by genetically altered bone marrow cells (5). This condition is fairly rare, with approximately 2000 cases presenting in the United States each year. This condition has a long history in which it was first described by Paul Erlich near the close of the nineteenth century, and the relative simplicity of its pathology has made aplastic anemia well known among all hematopoietic failure syndromes (5).
In addition. Some viral infections. hepatitis A. dyskeratosis congenita. glue. rheumatic disease. an epidemic of aplastic anemia appeared to follow the introduction of chloramphenicol. anti-neoplastic cytotoxic agents. B or C. and human parvovirus B19 have also been linked to development of aplastic . Of the chemicals known to be associated with secondary aplastic anemia. as well as insecticides. and pregnancy (1). phenylbutazone and even the commonly used nonsteroidal anti-inflammatory drugs (5). such as anticonvulsant medications (carbamazepine and dilantin). D-penicillamide. such as mononucleosis caused by Epstein-Barr virus. In the late 1940¶s and early 1950¶s. Inherited forms of the disorder are rare and consist of Fanconi¶s anemia. The following factors have been implicated as causes of secondary aplastic anemia: chemicals. idiopathic aplastic anemia. and the disease has also been linked to many classes of pharmaceuticals widely used in medical practice. in which no cause is apparent. and Schwachman syndrome. aplastic anemia can be acquired secondary to exposure to various environmental factors and in certain disorders. benzene has repeatedly been shown to be associated with the disease. Bone marrow failure in workers exposed to benzene led to heroic industrial hygiene crusades organized by Alice Hamilton and Harrison Martland in the United States in the 1920¶s and 1930¶s. accounts for nearly 65% (1). radiation. Among cases that are acquired. infectious agents. Historically. and various gold salts (1). drugs.Aplastic anemia can present as an inherited/congenital disorder or may be acquired (most common). aplastic anemia cases have been determined to be significantly correlated/associated with exposure to various chemicals and drugs in the environment.
and tumor necrosis factor. Repeated exposure to low doses of ionizing radiation associated with cancer treatments. In addition. The clinical presentation of aplastic anemia usually involves patients suffering from symptoms of bleeding and bruising due to the associated thrombocytopenia. with no abnormal (size/shape) cells in the peripheral blood.8 (1). a complete blood count with added reticulocyte count abnormally low levels of formed elements in the blood. chemicals. radiographs and CT scan are also linked to aplastic anemia (1). in which the pathophysiology of most cases is described as a Tlymphocyte mediated immune attack on the bone marrow¶s hematopoietic stem cells that give rise to the various formed elements of the blood. Most cases of acquired aplastic anemia thus can be characterized pathophysiologically as T-cellmediated. such as direct toxicity for stem cells or a deficiency of stromal-cell or hematopoietic growth factor function. To confirm a diagnosis of aplastic anemia one must also aspirate . or radiation. or recurrent infections caused by the associated neutropenia (2).anemia. Specifically. The pancytopenia in aplastic anemia reflects failure of the hematopoietic process. The alternative mechanism is the direct hematopoietic injury caused by drugs.. This aberrant immune response can sometimes be linked to a viral infection or to drug/chemical exposure as aforementioned (1). fatigue and pallor due to the reduction in red blood cells/hemoglobin. It is important to note that there is little evidence for other mechanisms. cytotoxic T cells are thought to mediate the suppressive effect on hematopoietic cells through the production of hematopoietic-inhibiting cytokines such as interferon. organ-specific destruction of bone marrow hematopoietic cells.
Moreover. and megakaryocytic colonies in tissue culture are greatly reduced. absent in patients suffering from aplastic anemia. CD34 containing cells are nearly. which detects the CD34 cell antigen. The ability to distinguish between acquired and secondary forms of aplastic anemia has been greatly improved by specific assays for the chromosomal susceptibility to certain chemical cross-linking agents that characterize Fanconi anemia. an adhesion protein present on less than 1% of normal bone marrow (5). it is the failure of blood cell production associated with aplastic anemia that is responsible for the empty bone marrow. and assays of very primitive hematopoietic cells that are closely related/identical to stem cells show a similar consistent and severe defect (5). Magnetic resonance imaging of the vertebrae shows uniform replacement of marrow with fat as well (5). progenitor cells capable of forming erythroid. however. which usually presents in childhood but can be diagnosed well into . ³yellow fat´ accumulated in bone marrow spaces. Observing fatty bone marrow on biopsy is indicative of aplasia. and the absence of the morphologically diverse precursors of mature blood elements in bone marrow smears. Confirming a diagnosis and definitive cause of aplastic anemia is difficult due simply to the fact that differential diagnosis of bone marrow failure is quite difficult and complex. Immature hematopoietic cells can also be quantized by a technique known as fluorescent-activated flow cytometry. marrow hypocellularity can occur in various other hematologic diseases (5). myeloid.and inspect the bone marrow to check for characteristic hypocellularity and increased presence of fat tissue seen with aplastic anemia (3). if not completely. Thus.
such as hypocellular myelodysplasia (5). Treatments for aplastic anemia may include observation for mild cases. blood transfusions. and platelets. medications and. is life threatening and requires immediate hospitalization for treatment (2).adulthood. myelodyplasia is easily distinguished from aplastic anemia (3). However. all of which lack an entire class of distinctive cell-surface proteins (5). Aplastic anemia can be mild. in severe . In PNH an abnormal hematopoietic stem cell gives rise to an expanded population of mature red blood cells. moderate or severe. and that PNH may be observed as a ³late clonal event´ years after an initial diagnosis of aplastic anemia. When the marrow is normal or hypercellular and hematopoietic cells are obviously dysmorphic. granulocytes. It is well known that some patients afflicted with PNH will develop bone marrow failure that leads to aplastic anemia. In addition. The genetic basis of PNH is an acquired mutation in the PIG-A gene located on the X-chromosome that aborts synthesis of a glycosylphosphatidylinositol anchor structure. the presence of aneuploidy or structural abnormalities is relatively common in the myelodysplastic syndromes. recent advances in flow cytometry have made distinguishing between PNH and typical aplastic anemia much more efficient (5). which results in associated intravascular hemolysis (5). there exists a strong clinical relationship between aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH). Severe aplastic anemia. Mild or moderate aplastic anemia is still serious but usually doesn't require hospitalization to treat. However. in which your blood cell counts are extremely low. Chromosomes are normal in typical aplastic anemia upon cytogenetic testing of marrow cells.
The severity of aplastic anemia and the age of the afflicted patient are the two major variables that guide and direct the treatment of the condition.cases. It is of great importance that patients. The initial treatment strategy for aplastic anemia should include discontinuation of all unnecessary medications that could potentially be suppressing bone marrow function (2. but do relieve the various symptoms (4). which include transfusions of red blood cells. These platelets are then transfused into aplastic anemia patients in an effort to control internal blood loss. however. Many patients with aplastic anemia have decreased production of cytokines required in hematopoiesis.5). These transfusions are by no means a cure for the disorder. Platelets are collected from donors through a process called hemapheresis. The majority of patients suffering from aplastic anemia require multiple blood transfusions. particularly potential candidates for bone marrow transplantation. bone marrow transplantation (4). such as granulocyte colony stimulating factor and granulocyte-monocyte colony stimulating factor. and thus help alleviate anemia and fatigue. Administration of hematopoietic growth factors. Patients with aplastic anemia that is considered mild to moderate are then treated with androgens. as the sole treatment for aplastic anemia. receive as few blood . which act by stimulating erythropoiesis (5). or both. has not been overwhelming successful (5). platelets. in which blood is drawn from the median cubital vein superficial to the cubital fossa and is then circulated through a filter to remove platelets before returning blood to the body (4).3). Transfusions of red blood cells raise red blood cell counts. Growth factor administration as an adjunct to immunosuppressive treatment or following bone marrow transplantation has been useful and successful in decreasing periods of absolute neutropenia (2.
and use a stool softener (5). Sandimmune). wash hands frequently. Cyclosporine inhibits interleukin-2 .5). These patients should avoid fresh fruits and vegetables. cyclosporine (Gengraf.5). This immunosuppressive therapy. which usually consists of anti-thymocyte globulin (ATG). Aplastic anemia patients who do qualify for and receive BMT are also given immunosuppressive treatment in combination with BMT (1. patients aged greater than 60 years are not treated with BMT but rather are subjected to immunosuppressive treatment.5). Bone marrow transplantation (BMT) from an HLA-matched sibling is the treatment of choice for severe aplastic anemia in patients age 60 years or younger. Survival rates as high as 70-90% following BMT have been reported in numerous studies. with survival rates even higher reported for patients younger than 40 years of age who receive HLA-identical BMT (5). urine and any anatomic location in which infection is suspected (2. and corticosteroids. Because the risk of morbidity and mortality following BMT increases with age. With febrile neutropenia. and older patients or patients with a history of coronary artery disease may require hemoglobin levels to be maintained at more than 8 g/dL (3. focus on careful and diligent oral hygiene. Neoral. Also precautions for neutropenia should be followed in patients with aplastic anemia. minimize invasive procedures. a broad-spectrum antibiotic should be administered after cultures have been obtained from blood.products/transfusions as possible in order to decrease the risk of sensitization (5). Younger patients may tolerate hemoglobin levels of 7 to 8 g/dL. is aimed at suppressing T-cell subsets that might exert a suppressive effect on bone marrow function (1.3). Platelet transfusions should be given when the patient has an active bleeding episode or when the platelet count becomes severely depressed (< 10 x 10^9/L) (5).
With rapid and efficient diagnostic evaluation and the appropriate supportive care. aplastic anemia (especially more severe forms) is a rare disorder. with the advent of BMT and immunosuppressant drugs the cure rate for aplastic anemia has risen to 75-85% for untransfused patients and 55-65% for patients who received multiple transfusions prior to BMT (5). However. and about 15% suffer a relapse of aplastic anemia (5). Acquired aplastic anemia is usually immunemediated. recovery of blood cell count is often incomplete. and shares clinical and epidemiologic features and pathophysiological mechanisms with other human autoimmune diseases in which restricted numbers of Tcell clones effect severe. but must be included in the differential diagnosis of patients presenting with pancytopenia and/or hypocellularity of bone marrow. Prior to the availability of BMT and intense immunosuppressive therapy for patients afflicted by aplastic anemia the prognosis was rather grim. Patients receiving an immunosuppressive therapy that includes cyclosporine should be closely monitored because the drug may cause renal dysfunction or hypertension. and is known to interact with various other drugs. with more than 25% of patients dying within 4 months of diagnosis and 50% dying within the first year (5).(IL-2) production by T-cells and also inhibits proliferation of T-cells in response to IL-2 (5). In closing. However. recurrent pancytopenia requires retreatment. Approximately 20-30% of all aplastic anemia patients undergoing BMT eventually suffer from graft-versus-host disease (GVHD). and some patients develop late complications (especially myelodysplasia) (5). Treatment with both anti-thymocyte globulin and cyclosporine has been shown to restore hematopoiesis in approximately 67% of patients (1. tissue-specific destruction (5).5). the majority of aplastic anemia .
.patients respond to aggressive treatment with immunosuppressive agents or to bone marrow transplantation.
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