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Aplastic Anemia

?What is Aplastic Anemia


.Aplastic Anemia is a bone marrow failure disease

Bone marrow is
a Factory of
Blood Cells

Red Blood Cell

Platelets
White Blood Cell

Aplastic Anemia patients


Aplastic Anemia patients have
decreased amounts of:
- Red Blood Cells
White Blood CellsPlatelets-

Functions of Blood Cells


Red Blood Cells
Carry oxygen to all body organs
White Blood Cells
Fight infection and keep you
healthy
Platelets
Help control bleeding

Symptoms
Low Red Blood Cell
Fatigue, Headache, Inability to
Concentrate
Low White Blood Cell
Viral Infections, Bacterial Infections
Low Platelets
Easy Bruising, Nosebleeds, Petichiae

DEFINITION

A disorder of the hemtopoietic system


:characterized by
Bone marrow - marked reduction of all 3 cell
lines
Peripheral blood - pancytopenia

PATHOGENESIS
:Stem cell failure resulting from
An acquired intrinsic stem cell defect-1
An environmental cause-2
Immune mechanisms
Growth factor deficiency
Defects in the microenvironment

Epidemiology
Incidence: 5-10:106 per year
Age: 15 30 years
years 60
<
Sex: M = F

Etiology
Hereditary
Schwacman Diamond-1
Fanconis anemia syndrome-2
Dyskeratosis congenita-3

Acquired

Idiopathic-1
Drugs: dose related- 2
idiosyncratic
Radiation-3
Chemicals-4
Viruses-5
Pregnancy-6
PNH-7
Disorders of immune system-8

Clinical manifestations
Insidious onset
Manifestations caused by pancytopenia
Anemia - weakness, fatigue
Thrombocytopenia bleeding
Neutropenia - infections

Diagnosis
Peripheral blood

Bone marrow biopsy

Pancytopenia*
Empty fatty spaces*
Normocytic-normochromic anemia* Few hematopoietic cells*
Low reticulocyte index*
Lymphocytes and plasma cells*

Bone Marrow Failure


Congenital/ Syndromic
Acquired

Acquired Aplastic
Anemia

Acquired Aplastic Anemia


Secondary**
Idiopathic**

Secondary AA
Meds/ toxins. 1

Chemo, Chloramphenicol, benzene,


cimetidine,carbamazapine, indomethacin,
sulfas, acetazolamide, lithium

Radiation. 2
Viruses - EBV, HIV, parvo, hepatitis.3
Malnutrition. 4
Myelodysplastic syndromes. 5
Thymoma. 6

PATHOPHYSIOLOGY
Direct toxic injury to hematopoietic stem
cells can be induced by exposure to
ionizing radiation, cytotoxic chemotherapy,
or benzene. These agents can crosslink
DNA and induce DNA strand breaks leading
.to inhibition of DNA and RNA synthesis

Immune-mediated destruction of-2


hematopoietic stem cells
Direct killing of the stem cells has been -hypothesized to occur via interations
between Fas ligand expressed on the T
cells and Fas (CD95) present on the
stem
cells, which triggers programmed cell death
. (apoptosis)
T-lymphocytes also may suppress stem cell-proliferation by elaborating soluble factors
.including interferon-

Suppressproliferation

withligand,
signals
apoptosis

YoungNEJM1997

Idiopathic AA
or more of cases 70%*
Higher in SE Asia
M=F

AA - Clinical
:Symptoms are due to pancytopenia**
pallor, mucosal bleeding, ecchymoses, or
..petechiae and bacterial or fungal infections
Hepatosplenomegaly and lymphadenopathy do**
not occur; their presence suggests
.an underlying leukemia
Hyperplastic gingivitis is also a symptom of**
.aplastic anemia

AA - Labs
No RBC = pale, tachycardic
No platelet = bruising, bleeding
No WBC = infection
Retic < 1%
Plt < 20,000
ANC < 500

AA - Labs
Marrow : < 25% cellularity

AA - Evaluation

CBC w/ diff and retic*


Bone marrow*

Send DEB (Fanconis test)*


Send Hep A, B, C, D titers HIV *
Test for PNH (CD55, CD59)*
HLA typing*
Fetal hemoglobin*
Liver and renal function chemistries *

Quantitative immunoglobulins, C3, C4,*


.and complement
Autoimmune disease evaluation:*
Antinuclear antibody (ANA), total
hemolytic complement (CH50),
.Coombs test
HLA typing: Patient and family done*
at the time of diagnosis of severe
aplastic anemia to ensure a timely
.transplant

CLASSIFICATION
Designation

Criteria

Peripheral blood

Severe aplastic
anemia

-values 3 / 2Neutrophils < 500/L


-Platelets < 20,000/ ulReticulocyte index <1%

Very severe aplastic


anemia

As above but neutrophils <


200/L
Infection present

BM biopsy

Marked hypocellular <25% cellularity


Moderate hypocellular<25-50%
normal cellularity with<30% of remaining cell
hematopoietic

Treatment Options
Growth
Hormones

Bone Marrow
Transplant

Immune Suppressive
Therapy

Supportive Care

Help to save a Life

www.aaaoi.org

Fanconi Anemia

History: Guido Fanconi


Fanconi Anemia (Fanconi
pancytopenia syndrome):
1927 - 3 brothers with
pancytopenia and physical
abnormalities,
perniziosiforme
Fanconi Syndrome (renal
Fanconi syndrome): 1936
Ricketts, growth
retardation, proteinuria,
glucosuria, and proximal
renal tubular acidosis
Alter, FA101 (2006)

Fanconi Anemia (FA)


Rare (< 1/ 100,000 births)
Autosomal recessive
Many physical features
But up to 20-25% will have no physical
findings

Mean age at dx 7.8 yrs

Autosomal Recessive
Inheritance

FA- Clinical
Abnormality
Skin
Short Stature
Upper Limb Abnl
Head/ Microcephaly
Renal
Dev. Delay
None Reported
Short Stature Only
Skin Only

of FA Patients%
60%
57%
48%
27%
23%
13%
20%
1%
3%

Clinical Features
Progressive bone marrow failure

Most common etiology of inherited bone


marrow failure
Others include dykeratosis congenita,
amegakaryocytic thrombocytopenia,
Schwachman-Diamond syndrome

Increased risk of MDS and AML


(15,000x)

Many have monosomy 7, or duplication of 1q


(Auerbach et al., Cancer Genet Cytogenet 1991)

Clinical Features
Increased risk of solid tumor
formation (hepatic, esophageal,
oropharyngeal, vulvar)

*Average age at diagnosis is 23


**Cumulative incidence ~30% by age 45

*Shimamura et al., Gene Reviews 2002 (genetests.org)


**Alter et al. Blood 2003

FA - genetics
Identification of subtypes (compliment
groups)
A, B, C, D1, D2, E, F, G
Identical clinically
Sub-units of a common protein/ common pathway

Protein modifies FANCD2


FANCD2 interacts with BRCA1 and 2
BRCA1 and 2 needed for DNA repair

PATHOPHYSIOLOGY
DNA damage activates a complex
consisting of Fanconi proteins A, C,
G, and F. This in turn leads to the
modification of the FANCD2 protein.
This protein interacts, for example,
with the breast cancer susceptibility
.gene BRCA1

Fanconi anemia cells are characterized*


by hypersensitivity to chromosomal
breakage as well as hypersensitivity
to G2/M cell cycle arrest induced by
.DNA cross-linking agents
In addition there is sensitivity to *
oxygen-free radicals and to ionizing
.radiation

Diagnosis
Pts. with congenital abnormalities are -*
often diagnosed as neonates/infants
Others may be diagnosed when*
hematological problems occur
Median age of onset of pancytopenia is 7 *
Usually normal CBC at birth
First develop macrocytosis, then *
thrombocytopenia, and eventually
neutropenia

Diagnosis
Based on chromosomal hypersensitivity to
cross-linking agents
Chromosome fragility test: Mitomycin C (MMC)
or diepoxybutane (DEB) added to lymphoctyes
increases the number of chromosome breaks
and radial structures
Very specific for FA, regardless of severity
of disease
Can do chromosome breakage analysis on
amniotic cells, chorionic villus cells or fetal
blood

FA cells were treated with mitomycin C and harvested in metaphase. Typical


abnormalities include radial formation (green circle) and chromosome breaks (red
arrows).

Other Congenital Marrow


Failures
Dystkeratosis Congenital
Rare
Different modes of inheritance
Ectodermal dysplasia
develop aplastic anemia in midteens 50%

Schwachman-Diamond
Cartilage-Hair Hypoplasia
Familial Marrow Dysfunction

Marrow Failure
Pearsons syndrome
Seckels syndrome
Amegakaryocytic Thrombocytopenia
Noonans syndrome

Marrow Failure
Single Cytopenias
Pure Red Cell Aplasia (Diamond-Backfan)Congenital Neutropenia (Kostmanns)
-Thrombocytopenia with Absent Radii

Definition
A syndrome characterized by
Normocytic normochromic anemia
Reticulocytopenia <1%
BM erythroblasts < 0.5%
Aplasia selective to erythroid cell line
!only

Epidemiology
Relatively uncommon
May affect any age group but predominantly of
infancy and childhood
M=F
No ethnic predisposition
Of autosomal dominant inheritance

Etiology & Pathogenesis


Congenital
hypoplastic
anemia
Diamond-Blackfan(
)syndrome

Acquired PRCA
Primary

Secondary

Acquired PRCA

Primary

Autoimmune
Preleukemic
Idiopathic

Secondary

Thymoma
Hematologic malignancies
Solid tumors
Infections
Chronic hemolytic anemias
Collagen vascular diseases
Pregnancy
Severe renal failure
Severe nutritional deficiencies
Drugs & chemicals
Miscellaneous

Mechanisms of Immunologic
Inhibition
Antibodies directed against
Erythropoietin
?Erythroblasts

Cellular inhibition
Inhibitory T cells
NK cells

Pure red cell aplasia

IgG inhibitors

T cell inhibition

Erythropoietin

Epo Responsive cells

Parvovirus

Clinical Manifestations

Symptoms of anemia
The median age at presentation of anemia is 2*
months and the median age at diagnosis of
.DBA is 3 months
Physical anomalies, excluding short stature*
.No hepatosplenomegaly*
Malignant potential*
In patients with long-standing PRCA
transfusional hemosiderosis

Laboratory Evaluation
:Diagnostic criteria
Normochromic, usually macrocytic anemia, relative to -patients age and occasionally
normocytic anemia developing in early childhood
Reticulocytopenia-Normal or only slightly decreased granulocyte count -Normal or slightly increased platelet count -:Supportive criteria
Typical physical abnormalitiesIncreased fetal hemoglobinIncreased erythrocyte adenosine deaminase (eADA) activity -

BM
Absence of erythroblasts <1% on BM*
absence of normoblasts, in some cases with(
relative increase in proerythroblasts or
normal number of proerythroblasts with a
). maturation arrest
.normal myeloid and megakaryocytic series*
Usually normal karyotype, except for *
preleukemic cases

Treatment

Congenital Hypoplastic Anemia


Corticosteroids
AlloBMT
IL-3 experimental
Patients refractory to all treatments
regular transfusions & desferioxamine

Treatment

Acquired PRCA
Discontinuation of all drugsR/O infectionsIf parvovirus suspected high dose IgGIn the presence of thymoma thymectomy-

In 30-40% erythropoiesis remits within4-8 weeks


Non-responding pts. should be treatedas primary acquired PRCA
Thymectomy in the absence of thymomais not recommended
If an underlying disease treat the disease-

Treatment

Acquired PRCA

For primary or secondary PRCA not responding


:to treatment of underlying disease
Prednisone
Cyclophosphamide / azathioprine
Cyclosporine
ATG
High dose IgG
Plasmapheresis
Splenectomy
Rituximab