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Dr. Mohammad A. Audeh

First semester
Nov 21st 2016

Aplastic anemia: Definitions

• Aplasia ≈ Impaired/defective ability of organ/tissue to develop normally

 Bone marrow aplasia implies impaired/defective capability to undergo

hematopoiesis .

 Pancytopenia: reduced in the number ALL blood cellular elements

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Aplastic anemia: Etiology

• A substantial reduction in the number of functional HSC

- Damaged HSC (unable to proliferate and differentiate)

- Physical destruction of HSC (immune-mediated)

- Impaired BM Microenvironment

BM stroma is required to provide the

suitable environment for HSC survival,

growth and development.

>> SC are unable to develop, proliferate

and differentiate effectively

Aplastic anemia: Classification

• Primary:
- Congenital :

- Fanconi’s anemia

- Dyskeratosis congenita

- Idiopathic acquired

• Secondary

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Fanconi’s anemia

• Autosomal recessive mutation of FANC proteins: complementation proteins

which are involved in the cellular DNA-repair mechanisms.

 high frequency of spontaneous chromosomal breakage

• FANC proteins: ~ A, C, D1, D2, E, F, G and L

• FANCA mutation is the most common

• The exact biochemical function(s) of the FA proteins is poorly understood.

Fanconi’s anemia

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Dyskeratosis congenita
• 80% are X-linked, 10% are autosomal dominant and 10% are autosomal
recessive.

• The X-linked form of the disease is caused by mutations in the DKC1 gene

that encodes the 58kD nucleolar protein (dyskerin).

• The autosomal form is known to be associated with mutations in the

telomerase reverse transcriptase RNA (TERC ) gene

• Both TERC and Dyskrine are involved in the maintenance of telomere length
• Associated with a triad of symptoms: abnormal skin pigmentation, nail
dystrophy and leukoplakia.

Dyskeratosis congenita

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Dyskeratosis congenita

Idipathic acquired
• Immune-mediated destruction of structurally and/or functionally abnormal
HSC (Cytotoxic T cells)

• Mutation of telomeres complementation (repair) system is evident with no

clear relevance.

• Evidances of immune etiology:

- Favorable response to various immunosuppressive drugs
(e.g.,antithymocyte globulin (AGM)or cyclosporin)
- Co-culture of hematopoietic colony forming units with patient lymph
results in inhibition of colony formation.
- Increased amounts of activated T cell cytokines such as IFN-α, TNF-α
and IL2

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Secondary BM aplasia
• Usually caused by damage to the stem cell compartment – either to the stem

cells themselves and/or to their microenvironment.

• Etiology: exposure to a variety of agents:

- Irradiation (ionizing radiation)
- Benzene containing chemicals
- Chemotherapeutic agents
- Some drugs such as chloramphenicol or anti convulsants
- Insecticides and weed killers
- Viral infection: Cytomegalovirus, EBV and hepatitis

Aplastic anemia: clinical features

•General signs and symptomes: associated with anemia, leukopenia and
thrombocytopenia:
- Anemia: e.g. Progressive fatigue, dyspnea (breathing difficulty) and palpitations
- Thrombocytopenia: Bleeding
- Leukopenia: Infections

•Congenital forms (Fanconi’s anemia):

- growth retardation
- Short stature
- cogenital defect of the skeleton
low birth-weight, microcephaly and hypolastic or aplastic thumb

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Aplastic anemia: Diagnosis

• Anemia is normochromic and normocytic (or macrocytic: MCV=95 – 110 fl)

• N or RBCs morphological abnormalities

• Severe AA fulfills 2 out the three following criteria:

- Platelet count of less than 20,000/uL
- Reticulocyte count less than 60,000/uL
- Absolute neutrophils count of less than 500/uL.
• BM
- Loss of hematopoietic tissues and its replacement with fatty tissues
(Fatty tissues represent > 75% of marrow)