2. Aplastic Anemia Failure of the bone marrow percursors to produce mature cells. Characterized by hypocellular marrow and pancytopenia. Etiology: Acquired: More common Acquired: More common Inherited: Fanconi anemia Inherited: Fanconi anemiaAcquired: 1. Drugs - Cytotoxic drugs- Antibiotics - Chloramphenicol- Anti-inflammatory - Anti-convulsant- Sulphonamides - 2-3 months usually between exposure and the development of aplastic anemia.

3. Aplastic Anemia: (Cont.) Acquired: Radiations Radiations Chemicals e.g., Benzene and pesticides Chemicals e.g., Benzene and pesticides Viruses: Viruses: –Hepatitis A, Non-A and Non-B –Herpes simplex –E-B virus –Parvovirus: Transient  Important clinically in patients with hemolytic anemias  5-10% of cases of AA in the West and 10-20% in the Far East.  2-3 months between exposure to the virus and the development of AA. Immune: SLE, RA (rheumatoid arthritis) Immune: SLE, RA (rheumatoid arthritis) Pregnancy Pregnancy Idiopathic: 75% Idiopathic: 75% PNH PNH

4. 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.

5. 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. 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. 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.

6. Common Traits To All Various Causes Aplasia due to any cause may recover after immunosuppressive therapy indicating that immune mechanisms are involved. Aplasia due to any cause may recover after immunosuppressive therapy indicating that immune mechanisms are involved. Transition to a clonal disorder of hemopoiesis can occur in any patient who has recovered bone marrow function, suggesting that fragility of the hemopoietic system is common to all forms of aplasia. Transition to a clonal disorder of hemopoiesis can occur in any patient who has recovered bone marrow function, suggesting that fragility of the hemopoietic system is common to all forms of aplasia.

7. Clinical Features Non-specific: Non-specific: –Bruising, petechiae –Manifestations of anemia –Infections Hematological findings: Hematological findings: Peripheral blood: –Pancytopenia: initially only 1 or 2 parameters. WBC < 2.0, Hb < 10. Plat. < 100. No gross morphological abnormalities. –Anemia is usually NCNC. –Reticulocytopenia. –10% Ham’s test is + (complement mediated lysis)

8. Clinical Features Hematological findings: (Cont…) Hematological findings: (Cont…) Bone Marrow: –Hypocellular: <50% of normal cellularity Trephine biopsy is the most important for diagnosis. –Most of the cells present are lymphocytes, plasma cells and stromal cells. –Iron stores: increased

12. Treatment Withdrawal of etiological agents. Withdrawal of etiological agents. Supportive. Supportive. Restoration of marrow activity: Restoration of marrow activity: –Bone marrow transplant –Immunosuppressive treatment - Prednisolone- Antilymphocyte glob. - Cyclosporin- Anti T cells abs. - Splenectomy –Androgens –Growth factors

13. Clinical Course Usually fatal in constitutional type. Usually fatal in constitutional type. In the acquired type depends on severity: defined by retic count, months or years depending on the severity. Stable course: constant over a long period. Stable course: constant over a long period. Progressive, fluctuating. Progressive, fluctuating. Unstable: Associated with abnormal clones. Unstable: Associated with abnormal clones.

14. Inherited Anemia Fanconi’s Anemia: The most common type of inherited aplastic anemias. The most common type of inherited aplastic anemias. Associated with anomalies e.g., skeletal, skin. Associated with anomalies e.g., skeletal, skin. Autosomal recessive. Autosomal recessive. Marrow failure is at the level of CFU-GM. Marrow failure is at the level of CFU-GM.Genetics: Increased sensitivity of the cells to chromosomal damage by DNA cross linking agents. Increased sensitivity of the cells to chromosomal damage by DNA cross linking agents. 5 genes are responsible A  E. 5 genes are responsible A  E. IV54 mutation, is associated with multiple dysmorphism, severe pancytopenia, higher incidence of AML. IV54 mutation, is associated with multiple dysmorphism, severe pancytopenia, higher incidence of AML.

15. Inherited Anemia Clinical Features: Skeletal and skin anomalies seen at birth e.g., microcephally. Skeletal and skin anomalies seen at birth e.g., microcephally. Manifestations of marrow failure, usually later at age 5-10 yrs. Present as anemia, mucusal bleeding e.g. nasal. Manifestations of marrow failure, usually later at age 5-10 yrs. Present as anemia, mucusal bleeding e.g. nasal. Chromosomal breaks. Chromosomal breaks.

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

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