Aplastic Anemia Definition Aplastic anemia is a physiologic and anatomic failure of the bone marrow characterized by a marked decrease

or absence of blood-forming elements in the marrow and pancytopenia (decreased red cells, white blood cells and platelets). (Lanzkowsky, 2011) The International Agranulocytosis and Aplastic Anemia Study has defined aplastic anemia as hemoglobin 10 g/dL, platelet count 50 109/L, granulocytes 1.5 109/L, and a bone marrow biopsy demonstrating a decrease in cellularity and the absence of significant fibrosis or neoplastic infiltration. Severe aplastic anemia (SAA) is diagnosed when there is less than 25% of normal bone marrow cellularity, determined by bone marrow biopsy, and at least two of the following peripheral blood findings: granulocytes < 0.5 109/L, platelets < 20 109/L, or absolute reticulocytes 40 109/L (<1% when corrected for hematocrit). Very severe AA is defined when the above criteria for SAA are met and the granulocyte count is < 0.2 109/L. Moderate AA is defined when there is an evidence of decreasing bone marrow cellularity and peripheral blood cytopenia do not fulfill the criteria for severe or very severe aplastic anemia. (Arceci, 2006)

Epidemiology The annual incidence of aplastic anemia is 2 cases per million population. The incidence of aplastic anemia peaks in people aged 15-25 years and after age 60 years. The male-to-female ratio for aplastic anemia is approximately 1:1. Geographic distribution shows that anemia aplastic is more common in Asia than in the West. (Bakhshi, 2011)

Etiology Aplastic anemia can be classified into acquired aplastic anemia and inherited aplastic anemia. But later the explanation just concentrate on acquired aplastic anemia. Table 2.1: Etiology of Aplastic Anemia

1. Acquired Aplastic Anemia a. Secondary aplastic anemia Irradiation Drugs and chemicals Regular effects Cytotoxic agents Benzene Idiosyncratic reactions Chloramphenicol Nonsteroidal anti-inflammatory drugs Antiepileptics Gold Other drugs and chemicals Viruses Epstein-Barr virus (infectious mononucleosis) Hepatitis virus (non-A, non-B, non-C, non-G hepatitis) Parvovirus (transient aplastic crisis, some pure red cell aplasia) Human immunodeficiency virus (acquired immunodeficiency syndrome) Immune diseases Eosinophilic fasciitis Hypoimmunoglobulinemia Thymoma and thymic carcinoma Graft-versus-host disease in immunodeficiency Paroxysmal nocturnal hemoglobinuria Pregnancy b. Idiopathic aplastic anemia 2. Inherited Aplastic Anemia a. Fanconi's anemia b. Dyskeratosis congenital c. Shwachman-Diamond syndrome d. Reticular dysgenesis e. Amegakaryocytic thrombocytopenia f. Familial aplastic anemias g. Preleukemia (e.g., monosomy 7) h. Nonhematologic syndromes (e.g., Down, Dubowitz, Seckel) (Source: Hoffman, 2005)

Pathophysiology Direct hematopoietic injury Certain chemical, drugs or physical agents can directly injure proliferating and quiescent hematopoietic cells by their toxic effects and complex immune reactions.

Immune-mediated T-cell destruction of marrow

(Source: Young, 2006) Antigens are presented to T lymphocytes by antigen presenting cells (APCs), which trigger T cells to activate and proliferate. T-bet, a transcription factor, binds to the interferon- (INF- ) promoter region and induces geneexpression. SAP binds to Fyn and modulates SLAM activity on IFN- expression, diminishing gene transcription. Patients with aplastic anemia show constitutive T-bet expression and low SAP levels. IFN- and TNF- 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- are mediated through interferon regulatory factor 1 (IRF-1), which inhibits the transcription of cellular genes and entry into the cell cycle. IFN- 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. (Young, 2006) Radiation

Marrow aplasia is a major acute toxic effect of radiation. Radiation can directly damage both stem and progenitor cells. The histologic picture of radiationmediated aplasia include necrosis, nuclear pyknosis and kayohexis, nuclear lysis and ultimately cytolysis. Bone marrow hypoplasia occurs wuth radiation doses higher than 1.5 to 2 Gy to the whole body. Drug and chemicals The mechanisms that lead to the development of AA after drug exposure include direct chemical toxicity and immune-mediated destruction. Drug and chemicals can cause aplastic anemia by regular effects or idiosyncratic reactions. Regular effects means that certain drugs and chemicals almost cause aplastic anemia. The severity of aplastic anemia is dose-dependent relation. Drugs that cause aplastic anemia by regular effects are cytotoxic agents and benzene. Benzene can cause aplastic anemia by its water-soluble products such as phenols, hydroquinones, and catechols. Benzene and its intermediate metabolites covalently and irreversibly bind to bone marrow DNA, inhibit DNA synthesis, and introduce DNA strand breaks. Benzene acts as a "mitotic poison" and as a mutagen. Acutely, the more mature, actively cycling marrow precursor cells are preferentially damaged over the more primitive progenitors. Intermittent exposure may be more damaging to the stem cell compartment than continuous exposure. Idiosyncratic reactions means that its occurrence are unexpectedly rare. Drugs that cause aplastic anemia by idiosyncratic reactions are aromatic hydrocarbons, chloramphenicol, NSAID, neuroleptics and psychotropic drugs, gold, antithyroid drugs such as thiouracil, antibiotics such as trimethoprim-sulfamethoxazole. Viruses Viruses can damage bone marrow directly by infection and cytolysis of hematopoietic cells or indirectly through induction of secondary immune pathways.

Diagnosis Clinical presentation The symptoms are related to pancytopenia:

Anemia results in pallor, easy fatigability, weakness and loss of appetite but some individuals can tolerate low hemoglobin levels without complain. Pallor is common and is best appreciated on the mucosal membrane and palmar surface.

Thrombocytopenia leads to petechiae, easy bruising, severe nosebleeds and bleeding into the gastrointestinal and renal tracts. Heavy menstrual flow or irregular vaginal bleeding can occur in younger women. Aplastic anemia patient may have also retinal hemorrhages, ginggival oozing or epistaxis. Extensive hemorrhage from any organ may occur late of the disease. Petechiae are often present over the pretibial surface of the lower leg and the dorsal aspect of the forearm and wrist. Ecchymoses may be seen typically on area exposed to minor trauma.

Leukopenia leads to increased susceptibility to infections and oral ulcerations and gingivitis that respond poorly to antibiotic therapy

Hepatosplenomegaly and lymphadenopathy do not occur; their presence suggests an underlying leukemia.

Laboratory Evaluation 1. 2. 3. 4. 5. 6. Anemia: normocytic, normochromic or macrocytic. Reticulocytopenia: absolute count more reliable. Leukopenia: granulocytopenia often less than 1,500/mm3. Thrombocytopenia: platelets often less than 30,000/mm3. Fetal hemoglobin: may be slightly to moderately elevated. Bone marrow: Marked depression or absence of hematopoietic cells and replacement by fatty-tissue-containing reticulum cells, lymphocytes, plasma cells and usually tissue mast cells. (Lanzkowsky, 2011)

Differential Diagnosis Fanconis anemia This congenital form of aplastic anemia is an autosomal recessive inherited condition in which 10% of patients present beyond childhood. Typical physical stigmata include short stature, skin hyperpigmentation, microcephaly, thumb or radius hypoplasia, urogenital abnormalities, and mental retardation. Fanconis anemia is confirmed by cytogenetic analysis of peripheral blood lymphocytes, which show chromosome breaks after culture with substances that promote chromosome stress (eg, diepoxybutane or mitomycin C). Paroxysmal nocturnal hemoglobinuria PNH is an acquired disorder that is characterized by anemia caused by intravascular hemolysis and manifested by transient episodes of hemoglobinuria and life-threatening venous thromboses. A deficiency of CD59, an erythrocyte surface antigen that inhibits reactive lysis, is largely responsible for the hemolysis.13 Approximately 10% to 30% of patients with aplastic anemia develop PNH later in the clinical course.14 It is possible that the majority of patients with PNH have an underlying aplastic process. The diagnosis of PNH is currently made by demonstrating decreased expression of the cell surface antigen CD59 by flow cytometry, replacing previously used screening tests such as the sucrose hemolysis test and examination of the urine for hemosiderin. Myelodysplastic syndromes The MDSs are a group of clonal hematopoietic stem cell disorders that are characterized by abnormal bone marrow differentiation and maturation, which leads to bone marrow failure with peripheral cytopenias, dysfunctional blood elements, and probability of leukemic conversion. The bone marrow in MDS is typically hypercellular or normocellular, although hypocellularity may also be detected. It is important to distinguish hypocellular MDS from aplastic anemia because the diagnosis dictates clinical management and prognosis. A critical feature that identifies hypocellular MDS is an associated clonal cytogenetic abnormality (such as deletions in chromosome arms 5q and 7q). Idiopathic myelofibrosis

The two major features of idiopathic myelofibrosis are extramedullary hematopoiesis (in spleen, liver, and other organs) and bone marrow fibrosis. The extramedullary hematopoiesis causes hepatosplenomegaly in the majority of patients. Bone marrow biopsy specimens show varying degrees of reticulin or collagen fibrosis, with prominent megakaryocytes. Aleukemic leukemia Aleukemic leukemia, a rare condition characterized by the absence of blast cells in the peripheral blood of patients with leukemia, occurs in fewer than 10% of all leukemic patients and is generally seen in very young children or in elderly patients. Bone marrow aspirate and biopsy demonstrate the blast cells. Pure red cell aplasia This rare disorder that involves only erythrocyte production is characterized by severe anemia, a reticulocyte count of less than 1%, and a normocellular bone marrow containing less than 0.5 % mature erythroblasts. Agranulocytosis Agranulocytosis is an immune disorder that affects the production of blood granulocytes but not that of platelets or erythrocytes. (Alkhouri and Ericson, 1999) Idiopathic trombositopenic purpura Peripheral smears only shows trombositopenia without granulositopenia or leukopenia. Bone marrow analysis shows normal cellularity or elevation of megakaryocytes.

Management Supportive management Supportive treatment is given to prevent and cure infection and bleeding. Infection Patient should be isolated in isolated room to prevent infection.