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APLASTIC ANEMIA And Pancytopea
Aplastic anemia is a bone marrow failure syndrome characterized by
peripheral pancytopenia and marrow hypoplasia.
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
epidemiology
annual incidence in Europe and US - 2 cases per million population, but 4
cases in Bangkok 6 in Thailand and 14 in Japan.
no racial predisposition exists in the United States; however, prevalence
is increased in the Far East.
The male-to-female ratio is approximately 1:1.
Aplastic anemia occurs in all age groups.
a small peak in incidence in childhood.
a peak incidence in people aged 20-25 years, and a peak in people older
than 60 years
Etiology
Congenital/inherited (20%)
Patients usually have dysmorphic features or physical stigmata.
Occasionally, marrow failure may be the initial presenting feature.
Fanconi anemia
Dyskeratosis congenita
Shwachman-Diamond syndrome
Familial aplastic anemia
Acquired:
Drugs
- Cytotoxic drugs
- Antibiotics - Chloramphenicol
-
Anti-inflammatory - Anti-convulsant
- Sulphonamides
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- 2-3 months usually between exposure and the development of aplastic
anemia
Radiations
Chemicals e.g., Benzene and pesticides, chloramphenicol,
phenylbutazone, and gold,
Viruses:
Hepatitis A, Non-A and Non-B
Herpes simplex
E-B virus
Parvovirus: Transient
Important clinically in patients with hemolytic anemias
5-10% of cases of AA in the West and 10-20% in the Far East.
2-3 months between exposure to the virus and the development of AA.
Immune: SLE, RA (rheumatoid arthritis)
Pregnancy
Idiopathic: 75%
PNH
Pathogenesis
Potential mechanisms:
Absent or defective stem cells (stem cell failure).
Abnormal marrow micro-environment.
Inhibition by an abnormal clone of hemopoietic cells.
Abnormal regulatory cells or factors.
Immune mediated suppression of hematopoiesis.
It is believed that genetic factors play a role.
There is a higher incidence with HLA (11) histo comp.
Antigen. Immune mechanism is involved
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The latest theory is:
there is an intrinsic derangement of hemopoietic proliferative capacity,
which is consistent with life.
the immune mechanism attempt to destroy the abnormal cells (self
cure) and the clinical course and complications depend on the balance.
If the immune mechanism is strong, there will be severe pancytopenia.
If not, there will be myelodysplasia.
Forms of disease:
Inevitable:
dose related e.g. cytotoxic drugs, ionizing radiation. The timing, duration
of aplasia and recovery depend on the dose. Recovery is usual except
with whole body irradiation.
Idiosyncratic:
unpredictable to drugs e.g., anti-inflammatory antibiotics, anti-epileptic,
these agents usually do not produce marrow failure in the majority of
persons exposed to these agents.
Common Traits To All Various Causes
Aplasia due to any cause may recover after immunosuppressive therapy
indicating that immune mechanisms are involved.
Transition to a clonal disorder of hemopoiesis can occur in any patient
who has recovered bone marrow function, suggesting that fragility of
the hemopoietic system is common to all forms of aplasia
Clinical Features
anemia pallor and/or signs of congestive heart failure, such as
shortness of breath.
thrombocytopenia bruising (eg, ecchymoses, petechiae) on the skin,
gum bleeding, or nosebleeds.
neutropenia fever, cellulitis, pneumonia, or sepsis
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jaundice and evidence of clinical hepatitis in subset of patients
adenopathy or organomegaly should suggest an alternative diagnosis.
In any case of aplastic anemia, look for physical stigmata of inherited
marrow failure syndromes such as
skin pigmentation,
short stature,
microcephaly,
hypogonadism,
mental retardation,
skeletal anomalies.
investigations
CBC
Reticulocyte count
Blood film.
B12/folate.
Liver function tests
Virology
Bone marrow aspirate & trephine
PNH screen.
CBC : Anemia is common, and red cells appear morphologically normal.
The reticulocyte count usually is less than 1%. Thrombocytopenia, with
a paucity of platelets in the blood smear. Agranulocytosis (ie, decrease
in all granular white blood cells, including neutrophils, eosinophils, and
basophils) and a decrease in monocytes are observed. A relative
lymphocytosis occurs. The degree of cytopenia is useful in assessing the
severity of aplastic anemia
Bone marrow exam : A bone marrow biopsy is performed in addition to
the aspiration. In aplastic anemia, these specimens are hypocellular.
Aspirations alone may appear hypocellular because of technical reasons
(eg, dilution with peripheral blood), or they may appear hypercellular
because of areas of focal residual hematopoiesis.
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A core biopsy provides a better idea of cellularity; the specimen is
considered hypocellular if it is less than 30% cellular in individuals
younger than 60 years or less than 20% in those older than 60 years.
other investigations
Hemoglobin electrophoresis - may show elevated fetal
hemoglobin.
Biochemical profile, including evaluation of transaminases,
bilirubin, lactic dehydrogenase, Coombs test, and kidney function,
is useful in evaluating etiology and differential diagnosis.
Serologic testing for hepatitis EBV, CMV, and HIV
Autoimmune disease evaluation for evidence of collagen-vascular
disease
The Ham test or sucrose hemolysis test frequently is performed
for excluding PNH.
Histocompatibility testing should be conducted early to establish
potential related donors, especially in younger patients
Criteria for diagnosis
1. pancytopenia -
Hb
<10g/dL
-
ANC
<1,5 G/L
-
PL
<100 G/L
2. Bone marrow histology and cytology
- decreased marrow cellularity (< 25%)
- increased fat cells component
- no extensive fibrosis
- no malignancy or storage disease
APLASTIC ANEMIA – differential
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Immune pancytopenias in connective tissue disorders (eg,
systemic lupus erythematosus, refractory anemia)
Causes of pancytopenia
1.Failure of production of blood cells
a) bone marrow infiltration
- acute leukemias
- hairy cell leukemia
- multiple myeloma
- lymphoma
- myelofibrosis
- metastatic carcinoma
b) aplastic anemia
2. Ineffective hematopoesis
- myelodysplastic syndrome
- vit.B12 and folate deficiency
3. Increased destruction of blood cells
- hipersplenism
- autoimmune disorders
- paroxysmal nocturnal hemoglobinuria
4. Myelosuppression after irradiation or antiproliferative drugs
Classification of aplastic anemia
1. Severe aplastic anemia is defined if at last two of the following
criteria are present:
ANC < 0.5 G/l
PLT < 20 G/l
RTC < 1% (20 G/l)
Hypoplastic bone marrow (less than 25%) on biopsy
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2. Very severe aplastic anemia
- criteria as above but ANC < 0.2 G/l
3. Non-severe aplastic anemia
Aplastic Anemia - Treatment
Withdrawal of etiological agents.
Supportive.
Restoration of marrow activity:
Bone marrow transplant
Immunosuppressive treatment
- Prednisolone
- Antilymphocyte glob.
- Cyclosporin
- Anti T cells abs.
- Splenectomy
Androgens
Growth factors
Supportiv care
Transfusion
Treatment of anemia
Treatment of bleeding
Prevention and treatment of infection
APLASTIC ANEMIA – complications
Infections
Bleeding
Iron overload
Complications of BMT
Graft versus host disease
Graft failure