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Bone marrow failure

 It implies that peripheral blood

cytopenia has arisend primarily as a
result of a specific failure happened
in the bone marrow precursor cells to
produce mature cells
 It composes the aplastic anemia and
the single-cell cytopenias

 Aplastic anemia defined as the

presence of the pancytopenia in the
perapheral blood and a hypocellular
marrow in which the normal
haemotapoietic marrow is replaced
by the fat cells .
 No abnormal cell can be found .

 Paul Ehrlich, MD, 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
Incidence and Prevalence
 A. Frequency
In China
 B. Race
No racial predisposition exists
 C. Sex
The male-to-female ratio in acquired
aplastic anemia is approximately 1:1
 D. Age
Aplastic anemia occurs in all age groups.
Etiology and Classification

(1)  Inherited aplastic anemia

fanconi anemia , estren-
dameshek anemia ,
(2)  Acquired aplastic anemia(50%
Idiopathic) ※
 Radiation
 X-ray
 Drugs and chemistry
 benzene, antineoplastic
 Idiosyncratic reaction
 sulfa drug(nimesulide),
 (non-steroid anti –inflammatory
drug) et.
 Viruses
 Epstein-Barr virus
 (infectious mononucleosis)
 Parvovirus B19※
 Hepatitis virus※
 Human immunodeficiency
 Immune diseases
 Eosinophilic fasciitis
 Hypoimmunoglobinemia
 Thyoma and thymic
 Graft-versus-host disease in
 Paroxysmal nocturnal
 Pregnancy
1.Seed theory
Defect in hemopoietic stem cells
1.Soil theory
Defect in the stromal microenvironment
3. Insect theory
Immune Impairment CD8 、 CD25 ,
Abnormal Cytokines
Etiology and pathogenesis
Cholormycetin division quantity and/or
1.Drugs Sedative (-) synthesis of protein (-) quality abnormality of
anti-cancer mRNA stem cells
(seed theory; defective
stem cell)
2.Chemical toxic Beyene
Substance inorganic arsenic (-)
3.Virus infection (+) antibodies resisting stem cells
(EB;hepatitis) self-immunition (+) IFN↑ (-)
(insect theory; disorder immunine function)
4.Physical factors copy of DNA (-) regeneration of hematopoietic
(X-ray,r-ray) (-) cells
damage microenviroment (-)hypoproliferation or failure of BM
(soil theory; defect of hemopoietic microenviroment)
Clinical Manifestations
A. Symptoms
1.  Bleeding-----The most common early symptom
2. Anemia-----Lassitude, weakness, shortness of
breath, and a pounding sensation in the ears.
3.  Infection
A striking feature of aplastic anemia is the
restriction of symptoms to the hematologic
system-----Patients often feel and look remarkably
well despite drastically reduced blood counts.
B. Physical examination
1.Petechiae and ecchymoses
2.Pallor of the skin and mucous membranes
3.Fever and signs of systemic or local infection
4.Lymphadenopathy and splenomegaly-----
Laboratory feature
1.   Blood finding
(1)   Pancytopenia
①The total leukocyte count is
②Neutrophil% decreased
③lymphocyte% increased
④Platelet decreased
(2)   Low reticulocyte index
2.   Marrow findings
(1)The marrow aspirate typically contains
numerous spicules with empty fatty spaces and
relatively few hemopoietic cells.
(2) Lymphocytes, plasma cells, macrophges, and
mast cells may be prominent, but this probably
reflects a lack of other cells rather than an increase
in these element.
(3)On ocassion, some spicules are celluar or even
hypercellular, but magakaryocytes are usually
(4)Marrow biopsy is essential to confirm the overall
Diagnosis and Differential
 The ultimate diagnosis of aplastic
anemia rests on the interpretation of an
adequate bone marrow biopsy

 According to the laboratory data,

classify aplastic anemia into two kinds
of type: Severe AA and Moderate AA.
The diagnostic criteria of
Aplastic anemia
Severe AA
Bone marrow cellularity <30%
Two of three peripheral blood criteria
Reticulocytes<15,000/ mm3
No other hematologic disease
Moderate AA
Patients with pancytopenia who do not fufill
the criteria of severe disease
Before make a diagnosis ,we should exclude
other causes of pancytopenia, as the

Table2 Differential Diagnosis of

Pancytopenia with hypocellular bone
Acquired aplastic anemia
Inherited aplastic anemia
Some myelodysplasia syndromes
Some acutue myelogenous leukemia
Some acute lymphoblastic leukemia in
Some lymphomas of bone marrow
Pancytopenia with cellular bone marrow
 Paroxysmal nocturnal hemoglobinuria
 Myelofibrosis
 Some acute myelogenous leukemia
 Bone marrow lymphoma
 Hairy cell leukemia
 Systemic lupus erythematouus
 hypersplenism
 VitaminB12, folate deficiency
 Overwhelming infection
 Alcoholism
 Brucellosis
 Sarcoidosis
 Tuberculosis
(1)Myelodysplastic syndromes:
Approximately 10% of patients with
myelodysplastic syndromes present with
hypoplasia rather than a hyper cellular marrow .
But in myelodysplasia marrow erythroid precusors
have both megablastoid and dysplastic features
with dumbell nuclei, Howell-Jolly bodies and
increased siderotic granules. Granulocyte
precusors have reduced granulation, with
abnormal blue cytoplasma in the promyelocytes
and megaloblastoid features. Cytogenetic
abnormalities are often found.
(2) Acute lymphocytic leukemia
This disease may have initially have a hypoplastic
phase, but we may found many clumps of
lymphocytic cells. Sometimes hairy-cell leukemia
maybe preceded by a hypoplastic phase. Both
conditions can be differentiated from severe aplastic
anemia by using of special stains.
1.   Marrow transplantation
 Stem cell transplantation offers the best
therapy for a young patient with a fully
histocompatible dibbling donor.
 Survival of patients younger than 20 years old
following stem cell transplantion is about
 Early consideration of the transplantation
option in a child or adolescent can avoid
unnecessary transfusions.
 Transfusion increased the risk of graft
rejection, already peculiarly high in
patients with aplastic anemia.
 Graft rejection is the major determinant
of a successful clinical outcome.
 It is usually not recommended for
patients with AA who are more than 45
years old. Because after 45, the
complications of transplantation are
 Management of patients in the
intermediate range, 20~45 years old,
depends on their transfusion history, on
their general clinical condition
2.   Immune suppressive therapy
(1)   The evidence for verifying the
 Improvement occurred in benzene-induced
AA in rabbits after ALG(Antilymphocyte
globulin) treatment.
 Many investigations found evidence of T-
cell mediated suppressor mechanisms by
in vitro marrow culture studies.
(2)      ATG (anti-thymocyte globulin )
 It is reported ATG not only act by reducing
cytotoxic T cells but also releasing
hemopoietic growth factors from certain T
 ATG therapy leads to recovery of autologous
BM function in about 50% of patients, usually
with independence from transfusion and a
leukocyte count adequate to prevent
 ATG can be given intravenously in a regimen
3-5mg/kg weigh for 5 days.
(3)      Cyclosporine A
 CsA can inhibit IL-2 production by T
cells and prevents expansions of
cytotoixc T cells in response to IL-2.
 The recommended dosage is
administered orally at an initial dose of
3~5 mg/kg weigh in adults with
subsequent adjustment.
 The most serious side-effects are
nephrotoxicity, hypertension, seizures
nd opportunistic infections.
(4)      ATG+CsA
The combination of ATG and CsA is
superior to ATG alone as initial therapy
for severe aplastic anemia, prodcing
hematologic responses in about 70% of
cases. Improvement in granulocytes
number is generally apparent within 2
months of treatment.
(5)Other combinations of
immunosuppressive agents:
3.   Androgen therapy
4.   Hemopoietic growth factors
5.   Other therapy
6.   Supportive principles
(1) Control the infection
(2) Platelet transfusion and stop bleeding
a. Platelet levels can be maintained by
b. Inhibitors of fibrinolysis
(3) Red blood cells transfusion
Course and prognosis
 The median survival of untreated patients
with AA is 3 to 6 months, with only 20%
percent surviving beyond a year. Very severe
AA has an extremely poor prognosis.
 The estimated 5-year survival rate for the
typical patient receiving immunosuppression
is 75% and for matched sibling donor BMT is
greater than 90%.
Key points

 The definition of aplastic anemia

 The clinical manifestation of
aplastic anemia
 The diagnostic criteria of severe
aplastic anemia