APLASTIC ANEMIA

by
Dr. Kadek Mulyantari, Sp.PK
(Department of Clinical Pathology Medical Faculty Udayana
University/Sanglah General Hospital Denpasar)

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 HEMATOPOIESIS
 Hematopoiesis is The proses of making blood cells.
 The term comes from the Greek haima (blood) and
poiein (to make). For the average adult, the bone
marrow produces ~5x1011 cells per day.

 The cells of the blood can be divided into erythrocytes

(red blood cells), leukocytes (white blood cells) of various
types, and platelets.

 Erythrocytes : Erythropoiesis
 Leukocytes : Leukopoiesis
 Thrombocyte : Thrombopoiesis

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 THE LOCATION OF
HEMATOPOIESIS
 Hematopoiesis begins in the yolk sac during the first month
of embryogenesis but gradually shifts to the liver and, to a
lesser extent, the spleen.
 The liver is the primary site of hematopoiesis during the
second trimester.
 The bone marrow becomes the primary site of
hematopoiesis after the seventh month.
 After birth, the bone marrow is normally the sole site of
hematopoiesis (intramedullary hematopoiesis).
 Hematopoiesis may resume in the liver and spleen after
birth in conditions associated with fibrosis of the bone
marrow (extramedullary hematopoiesis).

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 NUTRITIONAL REQUIREMENT
OF ERYTHROPOIESIS
Vitamin B12
Folic acid
Vitamin B6
Trace Metals
Iron
Other Vitamins ( Vit C, Vit A, Vit E)

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Classification of anemias (simplified)

1. Deficiency anemias
2. Aplastic anemia
3. Hemolytic anemias
4. Secondary anemias

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 Morphologic classification of anemias
Type MCV MCHC Common cause
________________________________________________________
Macrocytic anemia increased normal Vitamin B12 deficiency
Folic acid deficiency
Microcytic anemia
- hypochromic decreased decreased Iron deficiency
Thalassemia
- normochromic decreased normal Spherocytosis
or normal
Normocytic anemia normal normal Aplastic anemia
- normochromic Chronic renal failure
Some hemolytic anemia

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 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
c) vit.B12 and folate deficiency
2. Ineffective hematopoesis
- myelodysplastic syndrome
3. Increased destruction of blood cells
- hipersplenism
- autoimmune disorders
- paroxysmal nocturnal hemoglobinuria
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4. Myelosuppression after irradiation or antiproliferative drugs
 DEFINITION OF APLASTIC
ANEMIA
Aplastic anemia (AA) is defined as peripheral
blood pancytopenia with bone marrow
hypocellularity (i.e., < 25% cellular).

Severe AA is defined by an absolute neutrophil

count less than 500/mL, a platelet count less
than 20,000/mL, and an absolute reticulocyte
count less than 50,000/mL

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 Severe AA (SAA)
Bad prognosis
Two of three peripheral blood criteria:

 Neutrophils < 500 / cmm,

 Platelets < 20,000/cmm,

 Reticulocyte < 0-0.5%

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 In Aplastic Anemia all of cells precursor decrease
Eryhtrocyte decrease
Leucocyte decrease
Thrombocyte decrease

Incidence (acquired)
2/1000000
rare < 1 year; plateaus 20-60 yrs; increase > 60 yrs

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 ETIOLOGY
 The causes of aplastic anemia can be classified as :
 Idiopathic
 Secondery
 inherited

 Approximately 50% of AA cases are idiopathic.

 Secondary causes of AA should be excluded by appropriate history and labo­
ratory investigation.
 Other physical anomalies may suggest an inherited cause of AA.
 For example, cafe au lait spots, short stature, thumb abnormalities, and renal
malformations are frequent findings in patients with Fanconi anemia.
 The diagnosis of Fanconi anemia is confirmed by demonstrating increased rates
of sister chro­matid exchange in peripheral blood lymphocytes in response to
agents such as diepoxybutane and bleomycin.

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 Etiology
Inherited
Fanconi’s Anemia

Acquired
Idiopathic (majority)-2/3rd of cases
Drug : Acetazolamide, Carbamazepine, Gold, Hydantoin,
Penicillin, Phenylbutazone,
Chemical
Radiation exposure
Viral illness

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 Other causes of Pancytopenia:
Drugs,
Megaloblastic anemia
Bone Marrow infiltration or Replacement: Lymphoma,
Myeloma,Acute Leukemia, Secondaries
Hyperspleenisn
SLE
Disseminated TB
PNH
Sepsis

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 PATOPHYSIOLOGY

There is evidence that the normal development of the

hematopoietic stem cell (HSC) may be suppressed by the
immune system in A A.
Spontaneous remission of idiopathic AA after failed bone
marrow transplantation led to the hypothesis that the
immunosuppressive conditioning regimen allowed return of
normal hematopoiesis

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 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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 Pathogenesis (Cont…)
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.
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 Pathophysiology of aplastic anemia

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 BM
FAILURE
ANEMIA

LEUCOPENIA

THROMBOCYTOPENIA

CARDIO VASKULER SYSTEM

FAILURE

ORGAN TARGET ISCHEMIA,

INSUFISIENSI

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Clinical Features
Signs & symptoms of :
Anemia:……….
Bleeding: Ecchymoses ,Bleeding gums,
Epistaxis
Infections: Fever,Mouth ulcers

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 CLINICAL PRESENTATION

Patients with AA usually present with symptoms and signs of bone

marrow failure.
 Anemia leads to pallor, weakness, fatigue, dyspnea on exertion,
palpitations, exertional chest pain, headache, and pounding tinnitus.
 Thrombocytopenic hemorrhage may take the form of easy bruising,
petechiae (especially in dependent areas or in tissues with increased
hydrostatic pres­sure), gingival bleeding, epistaxis, and menorrhagia.
 Neutropenic infections occur but typically are not the reason for
seeking medical attention.
 Constitutional symptoms, adenopathy, and splenomegaly should all
suggest alternative causes of pancytopenia.

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 Diagnosis of aplastic anemia

1. Personal medical history; family history

2. Physical examination
3. Clinical symptoms:
- infections
- bleeding
- symptoms of anemia
4. Laboratory findings:
- anemia, neutropenia, thrombocytopenia
- bone marrow: hypocellular with fatty changes

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 Criteria for diagnosis of AA (1)
1. Cytopenia - Hb <10g/dL
- WBC <1,5 x
109/L
- PLT <100 x109/L
2. Bone marrow histology and cytology
- decreased marrow cellularity (< 25%)
- increased fat cells component
- no extensive fibrosis
- no malignancy or storage disease
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 Criteria for diagnosis of AA (2)

3. No preceding treatment with X-ray or

antyproliferative drugs
4. No lymphadenopathy or hepatosplenomegaly
5. No deficiencies or metabolic diseases
6. No evidence of extramedullary hematopoiesis

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 Diagnosis
Blood peripheral smear :
Pancytopenia and reticulocytopenia

Bone marrow aspiration & biopsy : Hypocellular /

aplastic bone marrow with increased fat spaces

Tests for underlying cause ( viral titers)

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BM biopsy
hypocellular
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,increased fat spaces 10/5/2011
 HYPOCELLULAR BONE MARROW
IN APLASTIC ANEMIA

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 TREATMENT

Supportive care,
allogeneic HSC transplantation, and
immunosuppressive therapy all play a role in the treatment of AA.

 Supportive care
 Many practices have been advocated for the prevention of infection
 Antibiotics
 Granulocyte colony stimulating factor (G-CSF) and granulocyte macrophage
colony-stimulating factor (GM-CSF)
 The trigger for red blood cell (RBC) transfusion depends on the physiologic
status of the patient.
 Androgens can stimulate erythropoiesis
 The value of prophylactic platelet transfusion for prevention of life-threatening
hemorrhage or increased survival has never been proved
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 SUPPORTIVE CARE
 Many practices have been advocated for the prevention of
infection
 Antibiotics
 Granulocyte colony stimulating factor (G-CSF) and granulocyte
macrophage colony-stimulating factor (GM-CSF)
 The trigger for red blood cell (RBC) transfusion depends on the
physiologic status of the patient.
 Androgens can stimulate erythropoiesis
 The value of prophylactic platelet transfusion for prevention of
life-threatening hemorrhage or increased survival has never been
proved

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 Treatment
Treatment of underlying cause –if possible
Removal of cause
Supportive care
Blood & platelet transfusion
Infection: Broad spectrum antibiotics
Asepsis
Bone Marrow Transplant (SCT)
patient age <40yrs , availability of a HLA-identical
sibling marrow donor

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 Immunosuppression:
Cyclosporine,
Glucocorticoids : in cong Pure Red Cell
Aplasia
Antilymphocyte or Antithymocyte globulin
(ALG / ATG)
Cyclophosphomide
Androgens
Thymectomy : for Adult Pure Red Cell Aplasia

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 ALLOGENEIC HEMATOPOIETIC STEM
CELL TRANSPLANTATION

Normal hematopoiesis can be reconstituted in AA patients

by transplantation of HLA-matched HSCs
Patients receive an immunosuppressive conditioning
regimen, such as high-dose cyclophosphamide,
antithymocyte globulin (ATG), and total body irradiation,
before allogeneic HSC infusion to allow donor cell
engraftment
Most patients do not have an HLA-identical family member
donor available.
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 Thank You For Your
Attention!

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 Agranulocytosis
Leukopenia: Decrease in Total Leukocyte Count

Neutropenia: Decrease in Neutrophil count < 1500 /

micro L

Agranulocytosis: severe neutropenia < 500

neutrophils / micro L

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 Causes
Congenital
Drug induced:Chloramphenicol,CBZ, Carbimazole ,
Co-trimoxazole, Gold, Phenytoin, Sulfa drugs
Infections:
Viral-Hepatitis,Influenza,HIV
Bacterial-Typhoid,Miliary TB
Benign ( familial/racial)
Cyclical
Immune: AI, SLE,Felty’s,

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 Clinical Features

Mouth infection,Sore throat ( Mucositis)

Ulcers of : Mouth & throat , Skin, Anus

Features of Sepsis (Gm +ve &–ve):

Fever +/-
Hypotension,
MODS
In prolonged neutropenia Fungal infections are
likely to develop: Candida (Oral), Aspergillus(Pulm)

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Investigations and Treatment

The peripheral blood smear shows a marked

decrease or absence of neutrophils.

The bone marrow may show myeloid hypoplasia or

absence of myeloid precursors.

In many cases, the bone marrow is cellular with a

maturation arrest at the promyelocyte stage.

On occasion, the marrow may be hypercellular.

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 CASE
A 23 years old woman gives a 3 month history
of progressively increasing tiredness with
bruising, malaise and menorrhagia. On
examination she is anemic and has multiple
bruises. A full blood count shows HGB 6.9 g/dL,
WBC 1.1 x 109/l (ANC 0.3 x 109/l), platelets 17 x
109/l). Her chest X ray shows pneumonia.
What further investigations should be undertaken?
What are the possibility diagnostic for this patient?
What seems to be the cause of this case?

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 Clinical Features of Fanconi’s Anemia
Common Findings:
 Low birth weight
 Short stature
 Microcephaly
 Microphthalmia
 Microstomia
 Skeletal abnormalities, particularly of thumbs and radii
 Hypoplastic hypothenar eminences
 Generalized increased pigmentation of skin
 Patches of hypopigmentation
 Cryptorchism
 Abnormalities of renal anatomy
- Horseshoe kidneys - Pelvic kidney
 Strabismus
 Hyper-reflexia
Uncommon associations:
 Mental retardation
 Vascular malformations
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 Growth hormone deficiency