Clinical

therapeutics
A 15 yr old girl consulted to the ER with a petechial rash,
fatigue, and a history of recurrent sinus infection over the
past 3 months.

Her past medical history is significant for an idiopathic

autoimmune dysfunction of cytotoxic T cells.

Lab results reveal anemia, neutropenia, and

thrombocytopenia.

You decide to admit the patient to the hospital and

schedule a bone marrow biopsy.
• General data: 15 year-old girl

• Chief complaint: petechial rash, fatigue

• PMH: recurrent sinus infection (3months)
: significant for an idiopathic autoimmune
dysfunction of cytotoxic T cells

• Lab results: (+) anemia

(+) neutropenia
(+) thombocytopenia
Diagnosis
APLASTIC ANEMIA
 What is AA?    
Aplastic anemia may occur in all age groups
• and both genders.
Aplastic anemia is a condition where bone
The disease is characterized by peripheral
marrow does not pancytopenia
produce sufficient new cells
and accompanied by a
to replenish blood cellshypocellular bone marrow.
• Aplastic anemia is a severe, life threatening
syndrome in which production of anaemia
History of Aplastic
erythrocytes, WBCs, and(1854-1915)
Paul Ehrlich platelets described
has failed.
the first
case of aplastic anaemia in a pregnant
woman who died of marrow failure in1888.
The term “aplastic anaemia” first used by
Anatole Chauffard in 1904.
 Etiology
• INHERITED(20%)
• ACQUIRED(80%)
• Idiopathic
• Secondary cause
Major causes of aplastic anemia In most instances,
ACQUIRED
however, no initiating
1. IDIOPATHIC ACQUIRED STEM CELL DEFECTS
factor
IMMUNEcan be identified;
MEDIATED
2. CHEMICAL AGENTS about 65% of
DOSE RELATED cases fallAGENTS,
– ALKYLATING
into this category.
ANTIMETABOLITES
BENZENE
CHLORAMPHENICOL
INORGANIC ARSENICALS
3. IDIOSYNCRATIC CHLORAMPHENICOL, PHENYLBUTAZONE,
ORGANIC ARSENICALS,
METHYLPHENYLETHYLHYDANTOIN, CBZ,
PENICILLAMINE, GOLD SALTS
4. PHYSICAL AGENTS WHOLE-BODY IRRADIATION
5. VIRAL INFECTIONS HEPATITIS (UNKNOWN VIRUS), CMV,
EBV, HERPES ZOSTER (VARICELLA
ZOSTER)
INHERITED
FANCONI ANEMIA Robbinns
TELOMERASE DEFECTS (2011)
pathologic
basis of
disease
 Anatomy and Physiology
• Bone marrow - is a sponge-like tissue inside
the bones. It makes stem cells that develop:
– Red blood cells
– White blood cells
– Platelets
 PATHOPHYSIOLOGY
The pancytopenia in aplastic anemia reflects
failure of the hematopoietic process
manifested as a severe decrease in the
numbers of all hematopoietic progenitor cells.
Two mechanisms have been suggested for bone
marrow failure.

• First mechanism
– direct hematopoietic injury
• chemicals (eg, benzene)
• drugs
• radiation
Second mechanism
- immune-mediated suppression of marrow cell

Cytotoxic T cell
IFN-y
TNF-α
suppressive effect on hematopoietic cells
 Autoimmune
• Inverted CD4/CD8
• Oligoclonal expansion
of cytotoxic T cells
• Direct cell-mediated
killing of stem cells or
cytokine-transduced
inhibition/apoptosis
 Short Telomeres

Environmental precipitant + Host genetic background + Immune response = AA

Sekeres et al. (2007) Clinical Malignant Hematology

 Clinical presentation
• Fatigue, shortness of breath & weakness
(reduce RBCs)
• Gingival bleeding, petechiae, oral blood
blisters, hematuria, heavy menses (reduce
platelets)
• Recurrent bacterial infections (reduce WBCs)
– Sepsis, pneumonia, UTI
– Invasive fungal infections
• Reticulocytopenia
• Enlarged spleen or liver
 Staging
• Criteria of the International Aplastic Anemia Study
Group, as follows:

• Blood - Neutrophils less than 0.5 X 109/L; platelets

less than 20 X 109/L; reticulocytes less than 1%
corrected

• Marrow - Severe hypocellularity; Moderate

hypocellularity, with hematopoietic cells representing
less than 30% of residual cells
 Differential diagnosis
Aplastic anemia Acute Myelodysplastic
lymphoblastic Syndrome
leukemia
Anemia (+) (+) (+)
Leukopenia (+) (+) (+)
Thrombocytopenia (+) (+) (+)
Sex M/F F>M M>F
Age All age groups 1-10 years Between 60 and 75
years
Marrow hypocellular hypercellular Hypocellular or
hypercellular
 WORK-UP
• Bone marrow aspirate and biopsy
• Complete blood count
• Reticulocyte count
• History of iatrogenic exposure to cytotoxic chemotherapy
• X-rays, computed tomography (CT) scans, or ultrasound
imaging tests
• Liver tests
• Viral studies
• Vitamin B12 and folate levels
• Blood tests for paroxysmal nocturnal hemoglobinuria
• Test for antibodies
 Treatment
• Removal of cause
• Supportive care
Blood & platelet transfusion
Infection: Broad spectrum antibiotics
Asepsis
• Bone Marrow Transplant
• Immunosuppression:
Cyclosporine,
Glucocorticoids
Antilymphocyte or Antithymocyte globulin (ALG /
ATG)
Cyclophosphomide
Thank you!!!
THANK YOU!