Aplastic anaemia

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APLASTIC ANAEMIA

• BY
• SYLVANUS AITKINS

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OVERVIEW

• DEFINITION
• TYPES AND ETIOLOGY
• PATHOPHYSIOLOGY
• LABORATORY FINDINGS
• TREATMENT

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DEFINITION

• APLASTIC ANAEMIA-Pancytopenia resulting from
  aplasia of the bone marrow.
• Aplastic anemia is a severe, life threatening
  syndrome in which production of erythrocytes,
  WBCs, and platelets has failed.
• Aplastic anemia may occur in all age groups and
  both genders.

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• The disease is characterized
• by peripheral pancytopenia
• and accompanied by a
• hypocellular bone
• marrow.

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Aplastic bone marrow

• Hypocellular with
• all elements down
• mostly fat ,stroma and few
• hematopoietic cells.
• Residual hematopoietic
• Cells are normal.
• No malignancy or fibrosis
• No megaloblastic hematopoiesis

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TYPES

• There are two types
• CONGENITAL APLASTIC ANAEMIA (Primary).
• ACQUIRED APLASTIC ANAEMIA.
• (Secondary).

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etiology

• ACQUIRED APLASTIC ANAEMIA
• Most cases of aplastic anemia are idiopathic and
  there is no history of exposure to substances
  known to be causative agents of the disease
• Exposure to ionizing radiation hematopoietic
  cells are especially susceptible to ionizing
  radiation. Whole body radiation of 300-500 rads
  can completely wipe out the bone marrow. With
  sublethal doses, the bone marrow eventually
  recovers.

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ACQUIRED APLASTIC ANAEMIA

• Chemical agents include chemical agents with a
  benzene ring, chemotherapeutic agents, and
  certain insecticides.
• Idiosyncratic reactions to some commonly used
  drugs such as chloramphenicol or quinacrine.

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ACQUIRED APLASTIC ANAEMIA

• Infections viral and bacterial infections such
  as infectious mononucleosis, infectious
  hepatitis, cytomegalovirus infections, and
  tuberculosis occasionally lead to aplastic
  anemia.
• Pregnancy (rare)

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ACQUIRED APLASTIC ANAEMIA

• Paroxysmal nocturnal hemoglobinuria this is a
  stem cell disease in which the membranes of RBCs,
  WBCs and platlets have an abnormality making them
  susceptible to complement mediated lysis.
• Other diseases preleukemia and carcinoma

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CONGENITAL APLASTIC ANAEMIA

• Fanconis Anemia
• Dyskeratosis Congenita
• Diamond-Blackfan Anemia
• Schwachman-Diamond Syndrome
• Others Amegakaryocytic Thrombocytopenia,
  Pearsons Syndrome, Severe Congenital
  Neutropenia, Dubowitz Syndrome, Familial Aplastic
  Anemia and more

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PRIMARY SECONDARY
Congenital (Fanconi non-Faconi types) Ionizing radiations accidental exposure(radiotherapy, radioactive isotopes, nuclear power stations)
Idiopathic. Chemicals benzene other organic solvents, TNT, insecticides, hair dyes, chlordane, DDT
Drugs -Those that regularly cause marrow depression(eg busulphan, cyclophosphamide, anthracyclines,
Those that occasionally or rarely cause marrow depression (eg chlormphenicol, sulphonamides, gold others)
Infection viral hepatitis (A or non-A, non-B)
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PATHOPHYSIOLOGY

• The primary defect
• Reduction in or depletion of hematopoietic
  pluripotent stem cells and a fault in the
  remaining stem cells or an immune rxn against
  them.
• This makes them unable to divide and
  differentiate sufficiently to populate the bone
  marrow ? decreased production of all cell lines
  hence peripheral pancytopenia.

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PATHOPHYSIOLOGY

• In rare instances it is the result of abnormal
  hormonal stimulation of stem cell proliferation
  or as a result of a defective bone marrow
  microenvironment (but normal donor stem cells are
  able to thrive in the recipients BM) or from
  cellular or humoral immunosuppression of
  hematopoiesis.

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HYPOCELLULAR BONE MARROW IN APLASTIC ANAEMIA
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LABORATORY AND CLINICAL FINDINGS

• ACQUIRED APLASTIC ANAEMIA
• Non-Severe
• A hypocellular bone marrow, but the cytopenias
  dont
• meet criteria for severe.
• Severe
• Bone marrow cellularity of lt25 and at least 2/3
  of
• Neutrophil count of lt0.5x109/L Platelet count
  of lt20x109/L
• Absolute reticulocyte count of lt60x109/L.
• Very Severe
• Similar to severe except that the neutrophil
  count is below
• 0.2x109/L.

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FANCONIs ANAEMIA

• Autosomal recessive disorder.
• The disorder usually becomes symptomatic 5 -10
  years of age and is associated with progressive
  bone marrow hypoplasia.
• Genetically and phenotypically heterogeneous (7
  different complimentation grps termed FAA to FAG
  but only the genes of FAA, FAC, FAF FAG have
  been indentified)
• common features of
• In vitro and in vivo sensitivity to DNA
  cross-linking agents
• Defective DNA repair
• Congenital malformations
• Progressive BM failure
• Predisposition to AML (10)

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FABCONIs ANAEMIA

• Cell from FA patients show an
• abnormally high frequency of
• spontaneous chromosomal breakage
• Chromosomal rearrangements reflect a loss of
  fidelity in repairing
• double strand DNA breaks.
• These lesions are corrected normally
• by 2 primary pathways
• NHEJ (non homologous end joining)
• HRR (homologous recombinational repair)
• Absence of either pathway results in
• genomic instability and increased
• radiosensitivity.
• Dx test is elevated breakage after incubation
• of periheral blood lymphocytes with

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FANCONIs ANAEMIA

• CLINICAL MANIFESTATIONS
• Fatigue
• Palpitations
• Pallor
• Infections
• Petechiae
• Mucosal bleeding
• Altered skin pigmentation (hyper- or hypo)
• Short stature (growth retardation)
• Skeletal anomalies (absent radii or thumbs)

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FANCONIS ANAEMIA

• Lab findings
• Peripheral Blood
• Pancytopenia and macrocytic RBCs.
• Bone Marrow
• hypocellularity, loss of myeloid and erythroid
  precursors and megakaryocytes.

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Other findings

• - Hemoglobin F is increased
• - Skeletal and structural defects can be detected
  by X-rays, ultrasounds and MRI machines
• - Genetic diagnosis can be made using molecular
  methods
• - Diagnostic test addition of mutagenic agent
  (such as diepoxybutane) to bone marrow causes
  chromosome breakage.

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TREATMENT

• Androgens /or Stem cell transplantation.
• Blood count improves with androgens but
  disturbing side effects especially in children eg
  virilization liver disease.
• Remission rarely lasts gt2yrs
• Stem cell transplantation may cure the patient.

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DYSKERATOSIS CONGENITIA DC

• Found predominately in males
• Can be X-linked recessive, autosomal recessive or
  autosomal dominant.
• X-linked recessive mutation in DKC1 gene
• Autosomal recessive no identified gene mutation
• Autosomal dominant mutation in TERC/TERT gene

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CLINICAL FINDINGS

• Abnormal skin pigmentation atrophy, nail
  dystrophy mucosal leukoplakia
• - pulmonary complications
• - learning difficulties
• - mental retardation

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LABORATORY FINDINGS

• - Peripheral Blood Pancytopenia and macrocytic
  RBCs.
• - Bone Marrow hypocellularity, loss of myeloid
  and erythroid precursors and megakaryocytes.

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IDIOPATHIC ACQUIRED APLASTIC ANAEMIA

• Most common type of Aplastic Anaemia.
• Mechanism is unknown but shows good response to
  antilymphocyte globulin (ALG) cyclosporine A.
• This suggests autoimmune T-cell mediated damage
  against structurally fxnally altered stem
  cells.

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CLINICAL FINDINGS

• Fatigue or Shortness of breath
• Gingival bleeding petechiae, oral blood
  blisters hematuria heavy menses.
• Recurrent bacterial infections
• Sepsis, pneumonia, UTI
• Invasive fungal infections
• Physical exam above findings, but otherwise
  normal, no splenomegaly

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PURE RED CELL APLASIA

• Pure red cell aplasia is characterized by a
  selective decrease in erythroid precursor cells
  in the bone marrow. WBCs and platelets are
  unaffected.
• Acute/transient form chronic form

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CLASSIFICATION OF PURE RED CELL APLASIA

• Transient form
• Parv B19 infects red cell precursors via P
  antigen
• Leads to transient rbc aplasia rapid onset of
  severe anemia in patients with pre-existing
  conditions that shorten rbc life span (eg sickle
  cell ds, hereditary spherocytosis).
• Also with drug therapy and in norm infants
  children with hx of viral infection in the
  preceding 3 months.
• Chronic form
• Acquired form may occur with or without ds or
  ppting factor. May be seen with autoimmune
  disorders .
• immunosuppression with corticosteroids,
  cyclosporin, azathioprine or ALG is helpful.

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ETIOLOGY

• Acquired
• Transitory with viral or bacterial infections
  (Parvovirus B19, tuberculosis, mumps, hepatitis)
• Patients with hemolytic anemias may suddenly halt
  erythropoiesis
• Patients with thymoma T-cell mediated
  responses against bone marrow erythroblasts or
  erythropoietin are sometimes produced.
• Drugs
• Alpha-interferons, diphenylhydantoin, isoniazid,
  lamivudine, phenytoin, chloramphenicol
• Other
• Collagen vascular diseases, thymoma,
  myelodysplastic
• Syndrome.

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ETIOLOGY

• CONGENITAL
• Diamond-Blackfan syndrome
• Inherted as recessive condition
• seen in young children and is progressive.
• probably due to an intrinsic or regulatory defect
  in the committed erythroid stem cell. Mutation of
  a gene on chromosome 19 that encodes a ribosomal
  protein may be implicated.
• a/w with somatic disorders eg of face or heart

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DIAMOND- BLACKFAN ANAEMIA

• Most patients are diagnosed in the first two
  years of life
• Autosomal recessive inheritance
• Three different genes are responsible. Two have
  been identified RPS10 and RPS24
• Clinical findings - short stature
• - abnormal thumbs
• -other physical anomalies

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LABORATORY FINDINGS

• Lab findings
• -Peripheral Bloodlow RBC count macrocytic RBCs.
  Normal WBC platelet counts. Low ret count.
• -Bone Marrownormocellular with a deficiency of
  erythroid precursors.

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DIAGNOSIS

• Bone marrow aspirate and biopsy
• History of exposures
• Serological testing HIV, hepatitis EBV,
  parvovirus
• ?red cell CD59 for PNH if history suggestive
• Determine severity of aplastic anemia
• Severe cases

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• GRACIAS