aplastic anemia lapkas

7/31/2019 Aplastic Anemia Lapkas

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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 10

9/L (


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1. Acquired Aplastic Anemiaa. 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

VirusesEpstein-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 diseasesEosinophilic fasciitis

Hypoimmunoglobulinemia

Thymoma and thymic carcinoma

Graft-versus-host disease in immunodeficiency Paroxysmal nocturnal hemoglobinuria Pregnancy

b. Idiopathic aplastic anemia2. Inherited Aplastic Anemia

a. Fanconi's anemiab. Dyskeratosis congenitalc. Shwachman-Diamond syndromed. Reticular dysgenesise. Amegakaryocytic thrombocytopeniaf. Familial aplastic anemiasg. 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.


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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


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Marrow aplasia is a major acute toxic effect of radiation. Radiation can directly

damage both stem and progenitor cells. The histologic picture of radiation-

mediated 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:


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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. Anemia: normocytic, normochromic or macrocytic.

2. Reticulocytopenia: absolute count more reliable.

3. Leukopenia: granulocytopenia often less than 1,500/mm3.

4. Thrombocytopenia: platelets often less than 30,000/mm3.

5. Fetal hemoglobin: may be slightly to moderately elevated.

6. 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)


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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


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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.


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