Aplastic anaemia

The term aplastic anemia indicates

pancytopenia in the presence
of a hypocellular (aplastic) bone marrow
Aplastic anemia
can be either inherited or acquired. Causes of
acquired aplastic anemia
include chemical toxins, drugs and medications,
ionizing radiation, and
Infections
In at least half of acquired cases, no cause can be
determined (idiopathic aplastic anemia). Most
cases of idiopathic aplastic
anemia appear to be caused by immune
suppression or destruction of
hematopoietic precursor cells.
Aplastic anemia is caused by a failure of
hematopoietic stem cells. Failure
may be due to an abnormality of the
hematopoietic stem cells themselves
or to some factor that suppresses or destroys
them.
It is important to distinguish aplastic anemia from
other causes of pancytopenia
such as myelodysplasia, megaloblastic anemia,
and acute leukemia,
Causes of Aplastic anaemia
Familial
Fanconi’s anemia
Dyskeratosis congenita
Schwachman-Diamond syndrome (aplastic
anemia with pancreatic insufficiency
Acquired
Chemicals and toxins: benzene, insecticides (DDT,
parathion, chlordane), arsenic
Medications: chemotherapy drugs,
chloramphenicol, phenylbutazone,
anticonvulsants,
carbamazepine, Clonazipril, gold compounds, oral
hypoglycemic agents
Ionizing radiation
Viral infections: hepatitis, Epstein-Barr virus, HIV,
dengue
Miscellaneous: pregnancy, autoimmune disorders
(diffuse eosinophilic fasciitis)
Idiopathic
INHERITED (CONSTITUTIONAL) VARIANTS
OF
APLASTIC ANAEMIA
Inherited variants of aplastic anemia are rare.
The most common (approximately
two-thirds of cases) is Fanconi’s anemia,
which is associated with
increased chromosomal instability. Less common
variants include
Schwachman-Diamond syndrome
(pancreatic insufficiency with
pancytopenia)
and dyskeratosis congenita.
Fanconi’s Anemia
Fanconi’s anemia is inherited as an autosomal
recessive trait.Abnormalities
in at least eight separate genes may be involved.
The mechanisms by which
defects in these genes cause Fanconi’s anemia are
unclear
Clinical Manifestations

Fanconi Anemia can be characterized by physical

abnormalities, bone marrow failure, and increased
risk of malignancy. Physical abnormalities of
affected individuals include short stature;
abnormalities of the thumbs, forearms, skeletal
system, eyes, kidneys and urinary tract, ear, heart,
gastrointestinal system, oral cavity, and central
nervous system; hearing loss; hypogonadism; and
developmental delay. Progressive bone marrow
failure with pancytopenia typically presents in the
first decade, often initially with thrombocytopenia
or leukopenia.
Clinical Manifestations
The clinical picture of Fanconi’s anemia is variable
and can include pancytopenia,
skeletal abnormalities, neurologic abnormalities,
and others
Physical Abnormalities in Fanconi’s Anemia*
Skin hyperpigmentation: trunk, neck, intertriginous
areas
Short stature
Upper limb abnormalities: thumbs, hands, radii,
ulnae
Hypogonadism and genital abnormalities (males)
Other skeletal abnormalities: head, face, neck,
spine, lower extremities
Anomalies of eyes, eyelids, or epicanthal folds
Renal abnormalities
Treatment
The treatment of choice for patients with
Fanconi’s anemia and pancytopenia
is allogeneic bone marrow transplant, preferably
from a human
leukocyte antigen HLA-identical sibling. This cures
the hematologic disease
but, unfortunately, does not decrease the risk of
malignancy. Androgens
may improve the cytopenias if a compatible bone
marrow donor is not
available.
Treatment
The treatment of choice for patients with
Fanconi’s anemia and pancytopenia
is allogeneic bone marrow transplant, preferably
from a human
leukocyte antigen HLA-identical sibling. This
cures the hematologic disease
but, unfortunately, does not decrease the risk of
malignancy. Androgens
may improve the cytopenias if a compatible bone
marrow donor is not
available.
Other Constitutional Aplastic Anemias
Schwachman-Diamond Syndrome
The Schwachman-Diamond syndrome is an
inherited disorder characterized
by exocrine pancreatic deficiency, pancytopenia,
skeletal changes, and
others. Inheritance is autosomal recessive. The
cause is unknown, but chromosomal
fragility is not increased. Patients with
Schwachman-Diamond
syndrome also are predisposed to developing
myelodysplasia and acute
leukemia.
Dyskeratosis Congenita
Dyskeratosis congenita consists of
mucocutaneous abnormalities with variable
hematologic disorders. The mucocutaneous
changes include reticulated
pigmentation of skin in the upper body, mucosal
leukoplakia, and
dystrophic changes in the nails.
The inheritance pattern appears to be variable;
the majority are X-linked. Chromosomal fragility
is not increased. The
mucocutaneous changes appear in all patients,
usually before the age of 10
years. Aplastic anemia occurs in approximately
half of patients, usually in
their teens. Patients with dyskeratosis congenita
also have an increased risk
of malignancy
ACQUIRED APLASTIC ANEMIA
Acquired aplastic anemia can be due to a variety
of causes. Important examples
include chemicals, drugs or medications,
infections, and pregnancy.
However, at least half of cases are idiopathic, in
which no underlying cause
can be found.
Causes of Acquired Aplastic Anemia
Ionizing Radiation
Bone marrow injury is an inevitable consequence
of ionizing radiation, and
bone marrow failure is a common cause of death
in people exposed to lethal
Aplastic Anemia, Pure Red Cell Aplasia,
Congenital Dyserthropietic Anemia 141
doses of radiation.
Chemicals
Benzene is the chemical that has been most
closely tied to aplastic anemia.
Benzene and its metabolites bind to DNA, inhibit
DNA synthesis, and
induce strand breaks.
Benzene has also been linked to the development
of acute myelogenous leukemia
Other chemicals that have been linked to aplastic
anemia include other
hydrocarbons and organic solvents, pesticides, and
inorganic arsenic
Drugs and Medications
Drugs are the second most common cause of
aplastic anemia, responsible for
approximately 15 to 25% of cases. Drugs can
cause aplastic anemia .
Cancer chemotherapy drugs are the most common
causes of expected
dose-related aplastic anemia
chloramphenicol
and phenylbutazone. Other medications that
have been
implicated include gold compounds,
sulfonamides (trimethoprimsulfamethoxazole)
and other antibiotics, nonsteroidal anti-
inflammatory
drugs, antithyroid and anticonvulsant
medications,
Viral Infections
Viral infections are a well-documented cause of aplastic
anemia. The
strongest association is with hepatitis.
Approximately 5 to 10% of aplastic
anemia cases in the United States and Europe appear
to be related to hepatitis.
The hepatitis virus associated with aplastic anemia has
not been iden-tified; aplastic anemia does not appear
to be related to any of the known
hepatitis viruses (A, B, C, D [delta], E, or G). The signs
of aplastic anemia
usually appear approximately 1 to 2 months after the
onset of hepatitis,
occurring most often in young men.
Aplastic anemia can also rarely occur
with Epstein-Barr virus (EBV), HIV, parvovirus B19,
dengue virus, and flavivirus.
Miscellaneous
Aplastic anemia has been reported in pregnancy.
Completion or termination
of the pregnancy is usually followed by
hematologic recovery. Aplastic
anemia has occasionally been reported in
tuberculosis.Other causes include
autoimmune diseases (rheumatoid arthritis,
systemic lupus erythematosus,
diffuse eosinophilic fasciitis),
Idiopathic
Despite extensive evaluation, no underlying
cause can be found in at least
half of the cases (idiopathic aplastic anemia). It
is now clear that immunemediated
suppression of hematopoiesis is responsible for
most cases of
idiopathic aplastic anemia
Clinical Manifestations
Aplastic anemia is primarily a disease of younger
people, with a peak incidence
at 15 to 25 years. Some series show a second
peak after about 60 years.
The most common complaints are fatigue,
weakness or dyspnea on exertion,
and easy bruising and mucocutaneous bleeding.
Evaluation
History
A complete past medical history and family
history (with particular regard
to anemia or other hematologic diseases) are
required. A complete and
detailed medication history is mandatory,
including past as well as current
medications.
Physical Examination
The physical examination in aplastic anemia is
generally unremarkable except
for pallor and mucocutaneous petechiae or
purpura. There may be mild
splenomegaly. The presence of lymphadenopathy
or marked splenomegaly
indicates a disease process other than aplastic
anemia.
Laboratory Diagnosis
Complete Blood Count
The complete blood count shows a decrease in at
least two cell lines and
often all three. The blood smear may reveal mild
macrocytosis of red blood
cells, but other morphologic abnormalities, blasts
and other immature cells
must be absent. The reticulocyte count is
decreased.
Bone Marrow
Both a bone marrow aspirate and biopsy are
required. It is important that
the biopsy be adequate in size for evaluation (at
least 1 cm in length), without
extensive aspiration or crush artifact. The marrow
must be hypocellular.
aspirate usually has a predominance of
lymphocytes and plasma
cells; normal hematopoietic precursors of all types
are reduced
Treatment
With supportive care alone, the prognosis for
severe aplastic anemia is grim,
with less than 10% surviving at 1 year. Patients
with less severe disease survive
longer. The treatment of aplastic anemia can be
divided into two
phases: supportive care and definitive therapy.
Supportive Care
Supportive care includes red cell transfusions for
symptomatic anemia and
platelet transfusions for bleeding due to
thrombocytopenia. Prophylactic
platelet transfusions should be considered for
patients with severe thrombocytopenia
(5,000–10,000/L) even in the absence of bleeding.
Antibiotics should also be given for fevers or
infection in the presence of
neutropenia (absolute neutrophil count ≤500–
1,000/L). Initially, broadspectrum
antibiotics should be used for fever, with specific
antibiotics chosen
based on results of the cultures.
Definitive Therapy
Options for definitive therapy for aplastic anemia
include bone marrow
Transplantation