Aplastic Anemia

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Dr. Kalpana MallaMD Pediatrics

Manipal Teaching Hospital

PANCYTOPENIA:

• Simultaneous presence of anaemia, leukopenia, thrombocytopenia

• Causes: aplastic anemia Subleukemic leukemia cytotoxic drugs radiotherapy bone marrow infiltration hypersplenism megaloblastosis SLE

APLASTIC ANEMIA:

• Failure of two or more cell lines• Anaemia, leukopenia,

thrombocytopenia + Hypoplasia or aplasia of the marrow

Pathology:• Reduction in the amount of haemopoietic

tissue- inability to produce mature cells for discharge into the bloodstream

• Patchy areas of normo/hypercellularity betn areas of hypocellularity

CLASSIFICATION:

• Idiopathic• Secondary: idiosyncratic drug reaction chemical exposure infectious hepatitis paroxysmal nocturnal haemoglobinuria• Constitutional

CLASSIFICATION

CONSTITUTIONAL/CONGENITAL• Diamond-Blackfan syndrome• Shwachmann-Diamond syndrome• Fanconi anemia• Dyskeratosis Congenita• TAR (thrombocytopenia with absent radii)• Amegakaryocytic thrombocytopenia

FANCONI ANEMIA

• Familial • AR• M:F=1.3:1• Onset in 1st decade of life• Diminished capacity for DNA repair and

increased random chromosome breakage during mitosis

C/F:

• Facies – microphthalmia,depressed nasal bridge,epicanthic fold,micrognathia

• Hyperpigmentation, café-au-lait spots• Absent / hypoplastic thumb• Skeletal and renal lesions• Short stature, • Microcephaly , subnormal intelligence• Hypogonadism,ano malies of urinary tract• Predisposition to leukemias• Poor prognosis

DYSKERATOSIS CONGENITA

• X-linked, AR, AD• M:F= 4.3:1• Hyperpigmentation• Nail dystrophy, early loss of teeth• Leukoplakia• Ocular abnormalities: cataract etc• Short stature but No skeletal/renal lesions (diff

from FA)

DIAMOND BLACKFAN SYNDROME

• Congenital pure red cell aplasia• AD, AR, Sporadic• Familial in 15 %• 90 % diagnosed in 1st year of life• Intrinsic defect in RBC, early apoptosis• Macrocytic anemia, reticulocytopenia,

absence of RBC precursors in an otherwise normocellular bone marrow

DIAMOND BLACKFAN SYNDROME

• Eye - Wide set eyes, blue sclera,glaucoma,epicanthic fold,cataract,strabismus

• Thick upper,cleft lip palate in some cases• lip,intelligent expression• Upperlimb anomalies – flattening of thenar

eminence, Triphalangeal thumb

C/F:

• Profound anemia at 2-6 months of age• Short stature• Renal anomalies and hypogonadism maybe

present

ACQUIRED APLASTIC ANEMIA - CAUSES

• Radiation• Drugs and chemicals - chemotherapy - benzene - chloramphenicol - antiepileptics• Viruses: - CMV - EBV - Hep B, C,D - HIV

• Immune diseases: - eosinophilic fascitis - thymoma • Pregnancy• PNH• Marrow replacement: - leukemia - myelofibrosis - myelodysplasia

PATHOPHYSIOLOGY

• Direct destruction of haemopoietic progenitors

• Disruption of marrow micro-environment• Immune –mediated suppression of marrow

elements Cytotoxic T cells in blood and marrow

release gamma IFN and TNF -> inhibit early and late progenitor cells

Pathology:

• Hallmark: peripheral pancytopenia with hypoplastic/ aplastic bone marrow

CLINICAL FEATURESRBC (anemia)• Progressive and persistent pallor• Anemia related symptoms WBC (Leucopenia/neutropenia)• Prone to infections - Pyodermas, OM,

pneumonia, UTI, GI infections, sepsisPlatelets (Thrombocytopenia)• Petechiae, purpura, ecchymoses• Hematemesis, hematuria, epistaxis, gingival bleed• IC bleed- headache, irritability, drowsiness, coma

NO HEPATOMEGALY

NO SPLENOMEGALY

NO LYMPHADENOPATHY

Failure of entire RES. No extramedullary hematopoesis

Blood picture:

• Anemia-normocytic, normochromic • Leukopenia (neutropenia)• Relative lymphocytosis• Thrombocytopenia• Absolute reticulocyte count low• Mild to moderate anisopoikilocytosis

Other investigations

• BM : dry aspirate, hypocellular with fat (>70% yellow marrow)

SEVERITYSEVERE APLASTIC ANEMIA• Granulocyte count <500/cu.mm• Platelet count <20,000/cu.mm• Reticulocytes <1%• BM < 25% of hematopoeitic cells

VERY SEVERE/ EXTREME APLASTIC ANEMIA• Above + Granulocyte count <200/cu.mm

DIFFERENTIAL DIAGNOSIS• ITP• LEUKEMIA• MYELOID METAPLASIA

Management:

• Identification and elimination of underlying cause

• Supportive therapy:1. Red cell transfusion for anemia2. Prevention and treatment of haemorrhage3. Prevention and treatment of infection

SUPPORTIVE CARE

• Prophylactic antibiotics• If infection: cephalosporins + aminoglycosides

+ metronidazole• Antifungals: amphotericin B, fluconazole (if

fever >10 days despite antibiotics)

THERAPY

DEFINITIVE

• BONE MARROW TRANSPLANTATION• IMMUNOSUPPRESSION

BONE MARROW TRANSPLANTATION

• Treatment of choice• HLA matched donor. Usually siblings• Long term survival rates: 60-70%• Donor stem cells > 4 X 108 cells/kg

IMMUNOSUPPRESSION

• Antithymocyte globulin (ATG)• Antilymphocyte glubulin (ALG)• Cyclosporin• Intensive immunosupression :

cyclophosphamide• Corticosteroids

ATG administration:

• IV administration of Ig preparations containing antibody to human thymocytes

• Improvement in haematological indices in one-half of subjects

• Anaphylaxis

ATG AND ALG

• Dose : 40 mg/kg/day X 4 days• Hematologic response rate 45%• Survival rate 60%• Side effects: serum sickness

ANDROGENS

• No longer have primary role• Increase erythopoietin producion• Stimulate erythroid stem cells• Increase Hb levels in normal males methyl testosterone, testesterone enanthate,

oxymetholone, danazolOral dose : 2-5mg/kg/day, IM dose: 1-2mg/kg/wkSide effects: cholestatic jaundice, masculinization

Corticosteroids:

• High dose steroids combined with anabolic agents

• Uncertain benefits• Side-effects

HAEMATOPOIETIC GROWTH FACTORS

• GM-CSF• G-CSF• IL-3• IL-1• IL-6

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