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I. Background:
Aplastic anemia is a bone marrow failure syndrome characterized by peripheral pancytopenia
and marrow hypoplasia. Paul Ehrlich, introduced the concept of aplastic anemia in 1888
when he studied the case of a pregnant woman who died of bone marrow failure. However, it
was not until 1904 that this disorder was termed aplastic anemia by Chauffard.
Bone marrow failure is a term with a larger meaning, referring to disorders of the
hematopoietic stem cell which involves either one cell line or all of the myeloid cell lines (ie,
erythroid for red cells, myeloid for white blood cells, megakaryocytic for platelets). The
lymphoid cells, which primarily are involved in lymphoproliferative disorders, usually are
spared.
II. Pathophysiology:
The theoretical basis for marrow failure includes primary defects in or damage to the stem
cell or the marrow microenvironment. The distinction between acquired and inherited disease
may present a clinical challenge, but more than 80% of cases are acquired. In acquired
aplastic anemia, clinical and laboratory observations suggest that this is an autoimmune
disease.
Bone marrow failure can be inherited or acquired. It can involve just 1 cell line or all
3 cell lines. The pathophysiology of these defects includes the following mechanisms of
action:
1. decrease in or damage to the hematopoietic stem cells and their microenvironment,
resulting in hypoplastic or aplastic bone marrow;
2. maturation defects - vitamin B-12 or folate deficiency;
3. differentiation defects - myelodysplasia.
Generally, hematopoietic stem cells are damaged by a congenital defect or exposure
to a noxious substance or factor. Pathophysiologic mechanisms are
a. an acquired stem cell injury from viruses, toxins, and chemicals that leads to a
quantitative or qualitative abnormality;
b. abnormal humoral or cellular control of hematopoiesis;
c. an abnormal or hostile marrow microenvironment;
d. immunologic suppression of hematopoiesis (ie, mediated by antibodies, T cells, or
lymphokines);
e. mutations in genes, causing inherited bone marrow failure syndromes.
The principal mechanism is implying the hematopoietic stem cell, because little
evidence points to a defective microenvironment as a cause of aplastic anemia. In patients
with severe aplastic anemia, the stromal cell function is normal, including growth factor
production.
The role of an immune dysfunction was suggested in 1970. Subsequently, numerous
studies have shown that, in approximately 70% of patients with acquired aplastic anemia,
immunosuppressive therapy improves marrow function. Suppression of hematopoiesis likely
is mediated by an expanded population of the following cytotoxic T lymphocytes (CTLs):
CD8 and HLA-DR+, which are detectable in both the blood and bone marrow of patients
with aplastic anemia. These cells produce inhibitory cytokines, such as gamma interferon and
tumor necrosis factor, which are capable of suppressing progenitor cell growth.
III. Epidemiology
The annual incidence of aplastic anemia in Europe is similar to that indicated by US
data, at 2 cases per million population.
Aplastic anemia is thought to be more common in Asia than in the West. The incidence
determined was at 4 to 6 cases per million population Thailand and as high 14 cases per
million population in Japan.
The male-to-female ratio in acquired aplastic anemia is approximately 1:1, although
some data suggest that a male preponderance may exist in the Far East.
Aplastic anemia occurs in all age groups.
A small peak in incidence in childhood is observed due to the inclusion of
inherited marrow failure syndromes.
The peak incidence of aplastic anemia is observed in people aged 20-25 years,
and a subsequent peak in incidence is observed in people older than 60 years.
IV. Causes:
Congenital/inherited (20%)
o Patients usually have dysmorphic features or physical stigmata. Occasionally,
marrow failure may be the initial presenting feature.
o Fanconi anemia
o Dyskeratosis congenita
o Shwachman-Diamond syndrome
o Familial aplastic anemia
Acquired (80%)
o Idiopathic 75%
o Infectious causes such as hepatitis viruses, Ebstein-Barr virus (EBV), HIV,
parvovirus, and mycobacterial infections
o Toxic exposure to radiation and chemicals such as benzene
o Drugs, such as chloramphenicol, phenylbutazone, and gold, may cause aplasia
of the marrow.
o Paroxysmal Noctural Hemoglobinuria is caused by an acquired genetic defect
limited to the stem cell compartment affecting the PIGA gene. The PIGA gene
mutations render cells of hematopoietic origin sensitive to increased
complement lysis. Approximately 20% of patients with aplastic anemia have
evidence of PNH at presentation as detected by flow cytometry.
o Transfusional graft versus host disease
o Orthotopic liver transplantation for fulminant hepatitis
o Pregnancy
o Eosinophilic fascitis
V. History
The clinical presentation of aplastic anemia includes symptoms related to the decrease in
bone marrow production of hematopoietic cells. The onset is insidious, with the initial
symptom relating to anemia or bleeding, but fever or infections often are noted at
presentation.
Anemia may manifest as pallor, headache, palpitations, dyspnea, fatigue, or foot swelling.
Thrombocytopenia may present as mucosal and gingival bleeding or petechial rashes.
VIII. Differential
lupus
All pancytopenias
o Failure of production of blood cells
a) bone marrow infiltration
- acute leukemias
- hairy cell leukemia
- multiple myeloma
- lymphoma
- myelofibrosis
- metastatic carcinoma
b) aplastic anemia
o Ineffective hematopoesis
- myelodysplastic syndrome
- vit.B12 and folate deficiency
o Increased destruction of blood cells
- hipersplenism
- autoimmune disorders
- paroxysmal nocturnal hemoglobinuria
o Myelosuppression after irradiation or antiproliferative drugs
IX. Staging
Based on International Aplastic Anemia Study Group (Camitta, 1983)
Blood
o Neutrophils - Less than 0.5 X 109/L
o Platelets - Less than 20 X 109/L
o Reticulocytes - Less than 1% corrected (percentage of actual hematocrit [Hct]
to normal Hct)
Marrow
o Severe hypocellularity
o Moderate hypocellularity with hematopoietic cells representing less than 30%
of residual cells
Severe aplasia is defined by any 2 or 3 peripheral blood criteria and either marrow
criterion.
A further subclassification followed the recognition that individuals with neutrophils
lower than 0.2 X 109/L constituted a very severe aplastic anemia (VSAA) group. This
group is less likely to respond to immunosuppressive therapy.
X. Treatment:
X.1. Diet
The diet for the patient with aplastic anemia who is neutropenic or on immunosuppressive
therapy should be tailored carefully to exclude raw meats, dairy products, or fruits and
vegetables that are likely to be colonized with bacteria, fungus, or molds. Further, a diet
limiting salt is recommended during therapy with steroids or CSA.
X.2. Activity:
The patient should avoid the following:
Any activity that increases the risk of trauma during periods of thrombocytopenia
Risk of community-acquired infections during periods of neutropenia
Infections - Infections are a major cause of mortality in these patients. The risk factors
include prolonged neutropenia and the indwelling catheters used for specific therapy. Fungal
infections, especially Aspergillus, pose a major risk.
After blood is drawn and other cultures are taken, broad-spectrum antibiotics should be
started empirically in the presence of febrile neutropenia. Coverage for the most
common gram-positive and gram-negative organisms should be considered. With the
new broad-spectrum antibiotics, a single antibiotic generally is sufficient. The choice
can be altered later, depending on the results of sensitivity tests from positive cultures.
Specially consider including antipseudomonal coverage at initiation of treatment for
patients with febrile neutropenia.
The addition of antifungal agents should be considered in the presence of persistent
fever despite adequate antibacterial coverage. Liposomal amphotericin B is indicated if
renal dysfunction is present because of toxicity resulting from the drug in another form.
Cytokine support with granulocyte colony stimulating factor (G-CSF) and granulocytemacrophage colony stimulating factor (GM-CSF) may be considered in refractory
infections, although weighted against cost and efficacy.
b. Bone marrow transplantation is the treatment of choice for young patients (under 50-55
years) with a good potential for cure. The procedure is limited by the existence of a potential
donor.
HLA-matched sibling donor BMT is the treatment of choice for a young patient with
severe aplastic anemia (controversial but generally accepted for age <60 y). The
conditioning regimen most often used includes a combination of antithymocyte
globulin (ATG), cyclosporine (CSA), and cyclophosphamide. The addition of ATG and
CSA to the conditioning regimen has resulted in reduction of graft rejection. When
radiation was used as part of the conditioning regimen, a higher incidence of chronic
graft versus host disease and malignant disease was found. With current BMT
regimens, most patients with severe aplastic anemia have a 60-70% long-term survival
rate.
Unrelated donor BMT probably only can be justified if the donor is a full match and the
patient has failed immunosuppressive therapy or as part of a clinical trial. Using
matched unrelated donors still is experimental (11-20% survival rates).
Early referral to a transplant center at diagnosis is recommended in all younger patients,
even if they lack a suitable related donor.
c. Immunosuppressive therapy
Immune suppression as a treatment for aplastic anemia is especially useful if a matched
sibling donor for BMT is not available or if the patient is older than 60 years.
The various options include combination therapy, including ATG, CSA, and
methylprednisolone, with or without cytokine support.
o Antithymocyte globulin, equine (Atgam) - inhibits cell-mediated immune
response either by altering T cell function or eliminating antigen-reactive cells.
The dose recommended : 10-20 mg/kg/day for 8-14 days. Attention to serum
sickness.
o Antithymocyte globulin, rabbit (Thymoglobulin) - may modify T-cell
function and possibly eliminate antigen-reactive T lymphocytes in peripheral
blood. The dose indicated : 0,75 mg/kg/day for 8 days.
d. Other treatments :
Androgens :
These agents push the resting hematopoietic stem cells into cycle, making them more
responsive to differentiation by hematopoietic growth factors.
They also stimulate endogenous secretion of erythropoietin.
Androgens were used in the past, but most are masculinizing and poorly tolerated by
females and children. Danazol is a nonmasculinizing androgen that may be useful.
The response rate is limited to approximately 45%, and results may require 6-10
months of therapy.
Hematopoietic growth factors - such as granulocyte colony-stimulating factor (G-CSF) and
granulocyte-macrophage colony-stimulating factor (GM-CSF), may be useful in patients with
neutropenia who have infections, without requiring a WBC transfusion.
XI. Complications:
Infections
Bleeding
Over time, the transfusion of packed red cells increases the total iron load to the
patient.
Measure iron stores in the form of ferritin.
Increased levels of iron are toxic to various organs, including the heart.
Iron toxicity can cause arrhythmia by blocking the bundle of His, diabetes by
damaging the islets of Langerhans in the pancreas, liver cirrhosis, and bronze
color in fair-skinned individuals.
Administering a chelating agent is an effective method of removing excess iron.
Chelating agents are composed of molecules that bind tightly with free iron and
remove the iron by carrying it as the agent is excreted from the body.
o Desferrioxamine is the iron chelator available in parenteral form.
o Desferasirox is the iron chelator available orally.
Complications of BMT
o Graft versus host disease
o Graft failure
XII. Prognosis:
The prognosis of bone marrow failure depends on the duration of the marrow function
abnormality.
Most inherited forms of bone marrow failure, such as Fanconi anemia, are associated
with transformation into leukemia several years later.
Viral causes, such as parvoviruses, usually are self-limiting.
Acquired idiopathic aplastic anemia usually is permanent and life threatening. Half the
patients die during the first 6 months.