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					APLASTIC ANAEMIA




     UNDER GUIDANCE OF
     DR. S.R.TALWELKAR
APLASTIC ANEMIA
 Aplastic anemia is a severe, life
  threatening syndrome in which
  production of erythrocytes, WBCs, and
  platlets has failed.
 Aplastic anemia may occur in all age
  groups and both genders.
 The disease is characterized by peripheral
  pancytopenia and accompanied by a
  hypocellular bone marrow.
HISTORY OF APLASTIC ANAEMIA.
 Paul Ehrlich (1854-1915) described 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.
AETIOLOGY.
 INHERITED(20%)
 ACQUIRED(80%)

    Idiopathic
    secondary cause
AETIOLOGY.
   INHERITED(20%)
o   Fanconi Anaemia
o   Dyskeratosis congenita
o   Shwachman-Diamond
    syndrome
o   Congenital
    megakaryocytic
    thrombocytopenia
    anaemia.
 ACQUIRED(80%)
o Idiopathic
o Secondary cause:

 Drug induced

       1)Drug which produce marrow depression
    Alkylating agent:
       Cyclophosphomide,melphalan and chlorambucil
    Anti metabolites: Mtx, 5FU, Azathioprine
    Anti-mitotic: Vincristine, Vinblastine
       2) Drug causing idiosyncratic marrow injury
    Chloramphenicol, nitrufurontoin, cotrimoxazole,
    Phenylbutazone, indomethazine, diclofenac
    Gold
        3) Chemical associated with AA
    Benzene, Arsenic, Alcohol
ACQUIRED

   Viral
     (Hepatitis,EBV,HIV,parvoB19)
o   Ionising radiation(>1.5 gy dose)
o   Toxins (pesticides, benzene, arsenic)
o   Pregnancy
o   PNH
   INHERITED BONE MARROW FAILURE
   SYNDROME
    Disease        Inheritance   Additional Lab     Associated tumour
                                    finding
Fanconi anaemia      AR           Chromosome       AML ,MDS ,SCC,brain
                     XR            breakage          and wilms tumor
  Dyskeratosis       AR          Telomere length     AML ,MDS ,SCC
   congenita         XR
                     AD
  Schwamann          AR               Serum               AML
   Diamond                         trypsinogen
   syndrome                         Pancreatic
                                  isomylase rise

   Congenital        AR                                   AML
Amegakaryocytic
thrombocytopenia
FANCONI’S ANEMIA.
 This common congenital form of aplastic
  anemia is an autosomal recessive inherited
  condition .
 Age : 7 to 9 yr ,also in adult. Sex : M=F

 Typical physical stigmata include short
  stature, skin hyperpigmentation, microcephaly,
  thumb or radius hypoplasia, urogenital
  abnormalities, and mental retardation.
 Lab.inv : mild macrocytosis,mild anisocytosis &
  anaemia > thrombocytopenia> Leucopenia. and
  increased HBF
 BM aspiration & biopsy :norm cellular to frank
  aplastic with dysplastic changes
 Fanconi’s anemia is confirmed by cytogenetic
  analysis of peripheral blood lymphocytes, which
  show chromosome breaks by mitomycin,
  diepoxybutane .
 Fanconi’s anemia associate with AML,MDS,SCC

 Curative Rx is stem cell transplantation

 Nearly 50% of patient may be controlled with
  androgen therapy.
DYSKERATOSIS CONGENITA

 Autosomal recessive, autosomal dominant,X-link
  recessive.
 Age : 5 to 10 yr ,also in adult. Sex : M>F

 C/F: Clasical triad inclued skin pigmentation ,
  nail dystrophy & leukoplakia.
 Also associate with pulmonary fibrosis.

 Lab.inv :Cytopenia and macrocytosis.

 Curative Rx is stem cell transplantation

 Androgen therapy,G-CSF
SHWACHMAN-DIAMOND SYNDROME

 Autosomal recessive.
 C/F: pancreatic insufficiency and BM failure.

 Lab.inv :Cytopenia (mainly neutropenia) and
  macrocytosis.
 BM aspiration & biopsy :normocellular to
  frank aplastic with dysplastic changes and
  cytogenetic abnormality include monosomy
  7,isochromosome 7,del 7q)
CONGENITAL MEGAKARYOCYTIC
THROMBOCYTOPENIC ANAEMIA.

 Autosomal recessive
 Age : 3 to 7 yr

 C/F: Increased bleeding tendency may progress
  to severe aplastic anemia
 Lab.inv :severe thrombocytopenia
  (<20,000/mm3),normal size and
  morphology.RBCs norm chronic normocytic &
  reduce. WBCs reduce.
 BM aspiration & biopsy :Normocellular or
  hypocllular with decrease megakaryocyte.
ACQUIRED APLASTIC
ANAEMIA(80%)
 Incidence: 2-5/million per year
 Incidence is higher in East.

 Male to female incidence = equal

 Disease of young adults, 2nd peak in 4th -5th
  decade of life.
 Idiopathic(75%)
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.

The first mechanism is direct hematopoietic
 injury by chemicals (eg, benzene), drugs, or
 radiation to both proliferating and quiescent
 hematopoietic cells.
The second mechanism, supported by clinical
  observations and laboratory studies, is immune-
  mediated suppression of marrow cell,
 Cytotoxic T cells are thought to mediate the
  suppressive effect on hematopoietic cells through
  the production of hematopoiesis-inhibiting
  cytokines such as interferon-γ and tumor necrosis
  factor-α.
 The mechanism for idiopathic, pregnancy
  associated, and some cases of drug-associated
  aplastic anemia is not clear but may involve
  immunologic processes as well.
HAEMATOPOIETIC STEM CELL.
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
PHYSICAL EXAMINATION
 Physical examination may show signs of
    Anemia, such as pallor and tachycardia,
    Thrombocytopenia: such as petechiae,
  purpura, or ecchymoses.
     Leukopenia:Overt signs of infection are
  usually not apparent at time of diagnosis.
 A subset of patients with aplastic anemia present
  with jaundice and evidence of clinical hepatitis.
 Findings of Lymphadenopathy or organomegaly
  should suggest an alternative diagnosis (eg,
  hepatosplenomegaly and supraclavicular
  Lymphadenopathy are observed more frequently in
  cases of leukemia and lymphoma than in cases of
  aplastic anemia).
LABORATORY STUDIES
   Determination of complete blood cell (CBC) count
    and peripheral smears:
                 Severe pancytopenia with relative lymphocytosis
                  (lymphocytes live a long time)
                 Normochromic, normocytic RBCs (may be
                  slightly macrocytic)
                 Mild to moderate anisocytosis and poikilocytosis
LABORATORY STUDIES
 The corrected reticulocyte count is uniformly low
  in aplastic anemia.
 The peripheral blood smear is often helpful in
  distinguishing aplasia from infiltrative and
  dysplastic causes. Teardrop poikilocytes and
  leukoerythroblastic changes suggest an
  infiltrative process.
LABORATORY STUDIES


 Patients with MDS often have certain
  characteristic abnormalities such as
  dyserythropoietic RBCs and neutrophils with
  hypogranulation, hypolobulation, or apoptotic
  nuclei.
 A leukemic process may result in evidence of
  blasts (myeloblasts) on the peripheral smear.
LABORATORY STUDIES
 Biochemical profile is useful in evaluating the
  etiology and in the differential diagnosis.
      The profile includes ; an analysis of kidney
  function; and liver function test and lactic
  dehydrogenase(LDH) levels.
 Serologic testing for hepatitis and other viral
  entities, such as EBV, CMV, and HIV may be
  useful.
 The Ham test, or the sucrose hemolysis test, is
  frequently performed to diagnose PNH.
 However, at present, the fluorescence-activated
  cell sorter (FACS) profile of PIGA anchor
  proteins, such as CD55 and CD59, may be more
  accurate than the Ham test for excluding PNH.
BONE MARROW ASPIRATION AND BIOPSY
 BM aspiration     : to assess cell morphology
 BM biopsy          : to assess cellularity and
                       architecture.

 Aspiration is dry tap or samples may appear hypo
  cellular because of technical reasons (eg,dilution with
  peripheral blood), or they may appear hypercellular
  because of areas of focal residual hematopoiesis.
 Bone marrow biopsy is performed in addition to
  aspiration to assess cellularity both qualitatively and
  quantitatively.
 In aplastic anemia, the specimens are hypocellular.
 The specimen is considered hypocellular if it is
  <30% cellular in individuals aged <60 years or if
  it is <20% in those aged >60 years.
 A relative or absolute increase in mast cells,
  plasma cells may be observed around the
  hypoplastic spicules.
 A proportion of marrow lymphocytes >70% is
  correlated with poor prognosis in aplastic
  anemia. Some dyserythropoiesis with
  megaloblastosis may be observed in aplastic
  anemia.
NORMAL    APLASTIC
ANAEMIA
HYPOCELLULAR BONE MARROW IN
APLASTIC ANEMIA
    FAT SPACES   RESIDUAL MARROW
Iron deposition
in marrow.
HISTOLOGIC FINDINGS
 Histologic findings of aplastic anemia include
  hypocellular bone marrow with fatty replacement
  and relatively increased nonhematopoietic
  elements, such as plasma cells and mast cells.
 Careful examination to exclude metastatic tumor
  foci on biopsy
STAGING

Staging of aplastic anemia is based on the criteria of the
 International Aplastic Anemia Study Group:

 1) Severe aplastic anaemia(SAA)
             Bone marrow cellularity <25%
             Two of three peripheral blood criteria;
      a)Absolute neutrophils (ANC)– < 500/mm3 .
      b)Platelets – < 20,000mm3
      c)Reticulocytes – Less than 60,000mm3 or<1%
                         corrected
2)Very Severe aplastic anaemia(VSAA)
    Same as SAA with ANC Less than
    200/mm3
3)Nonsevere (moderate)aplastic anaemia
     Bone marrow cellularity <25%
     Peripheral cytopenia do not fulfill criteria
     for SAA
DIFFERENTIAL DIAGNOSIS
HYPOCELLULAR MARROW
 Aplastic Anaemia

 Hypoplastic MDS

 Post chemotherapy

 Aplastic crisis in hemoloytic anaemia

 Congenital marrow failure syndrome
CELLULAR MARROW WITH DEFICIENCY /
  SYSTEMIC DISEASE
 Deficiency of B12 or folic acid

 Hypersplenism

 Kala azar

 SLE

 Sjogren

 Sarcoidosis

 Metastatic solid tumour

 Alcoholism

 Storage disease
PRIMARY MARROW DISEASE WITH
  CELLULAR MARROW
 Aleukemic leukemia

 Hairy cell leukemia

 MDS

 Marrow fibrosis

 PNH
D/D
   One or more of the following signs in patient with
    pancytopenia suggest diagnosis other than
    aplastic anemia.
               Splenomegaly
               Hepatomegaly
               Lymphadenopathy
               Bone tenderness
               Immature RBC and WBC
                            precursors in blood.
     PNH ASSOCIATION WITH APLASTIC
               ANEMIA
   PNH patients have a 10-20% chance of developing
    Aplastic Anemia, and 5% of AA patients eventually
    develop PNH.

   In upto 70% of patients with acquired Aplastic
    Anemia, mutated PNH clones are found in their blood
     Pathophysiological link between the two disorders.
AA ASSOCIATION WITH HEPATITIS



 Hematopoietic failure developing within 6
  months (usually several weeks) of episode of
  hepatitis
 Accounts for 5-10% off aplastic anemia cases

 Most often in previously healthy adolescent boys
  and young men
 Infectious cause is unknown(non A non B non C
  non G),
– Serology negative for known hepatitis viruses
TREATMENT : APLASTIC ANEMIA
 Remove Offending Agents
 Supportive care
       Selective transfusion therapy to avoid sensitization
   Definitive therapy
     Immunosuppressive therapy
     Allogeneic bone marrow transplantation
DEFINITIVE THERAPY:
IMMUNOSUPPRESSION
 Immunosuppression is NOT curative
 Goal is sustained remission
       20-36% have recurrent aplastic anemia
       20-36% develop clonal disorder, PNH, MDS or acute
        leukemia
   Combination therapy is best
       Antithymocyte globulin (ATG)
         Toxic side effect is serum sickness, tx with steroid
         Can lower platelet counts, transfuse plt.

       Cyclosporine
       High dose corticosteroids
DEFINITIVE THERAPY: BMT
 Therapy choice influenced by age and
 disease severity
    <20 years old
        Allogeneic BMT if matched sibling available
          50-80% cure rate, with low incidence clonal disorders
          unrelated donor, but survival only half then matched sib

    20-45 years old
        Allogeneic BMT
    >45 years old
      ?Immunosuppression only
      ?BMT
PROGNOSIS
 The natural history of aplastic anemia suggests
  that one fifth of patients may spontaneously
  recover with supportive care;
 Prognosis depends upon severity of marrow
  damage.
 25% patient die within 4 month of onset of
  syndrome.
 50% patient die within 12 month of onset of
  syndrome.
 71% patient die within 5 year of onset of
  syndrome.
POOR PROGNOSTIC FACTORS
 Low retic. Count
 Low neutrophil count

 Very Low platelet count

 Lower % of myeloid cell in marrow

 Shorter interval between onset of symptom and
  visit to physician
 Male gender

 Age and etiology do not affect the prognosis

 Acute and fulminating clinical course associated
  with rapid progression to death
Thank you
INVESTIGATIONS.
 FBC
 Reticulocyte count
 Blood film.
 B12/folate.
 Liver function tests
 Virology
 Bone marrow aspirate & trephine
 PNH screen.
APLASTIC ANEMIA
 Pathophysiology:
     The primary defect is a reduction in or
      depletion of hematopoietic precursor stem cells
      with decreased production of all cell lines.
      This is what leads to the peripheral
      pancytopenia.
       This may be due to quantitative or qualitative
        damage to the pluripotential stem cell.
       In rare instances it is the result of abnormal
        hormonal stimulation of stem cell proliferation
       or the result of a defective bone marrow
        microenvironment
       or from cellular or humoral immunosuppression of
        hematopoiesis.
Pathophysiology of aplastic anemia
APLASTIC ANEMIA
     Etiology
         Acquired
            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.
            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.
APLASTIC ANEMIA
        Infections – viral and bacterial infections such as infectious
         mononucleosis, infectious hepatitis, cytomegalovirus
         infections, and miliary tuberculosis occasionally lead to
         aplastic anemia
        Pregnancy (rare)
        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
APLASTIC ANEMIA
     Congenital disorders
        Fanconi’s anemia – the disorder usually becomes
         symptomatic ~ 5 years of age and is associated with
         progressive bone marrow hypoplasia. Congenital
         defects such as skin hyperpigmentation and small
         stature are also seen in affected individuals.
        Familial aplastic anemia – a subset of Fanconi’s
         anemia in which the congenital defects are absent.
     Clinical manifestations

        Fatigue
        Heart palpitations
        Pallor
        Infections
        Petechiae
        Mucosal bleeding
APLASTIC ANEMIA
     Lab findings
        Severe pancytopenia with relative lymphocytosis
         (lymphocytes live a long time)
        Normochromic, normocytic RBCs (may be slightly
         macrocytic)
        Mild to moderate anisocytosis and poikilocytosis

        Decreased reticulocyte count

        Hypocellular bone marrow with > 70% yellow marrow

     Treatment – in untreated cases the prognosis is poor

        Remove causative agent, if known

        Multiple transfusions

        Bone marrow transplant
RELATED DISORDERS
   Disorders in which there is peripheral
    pancytopenia, but the bone marrow is
    normocellular, hypercellular, or infiltrated with
    abnormal cellular elements
       Myelopthesic anemia – replacement of bone marrow
        by fibrotic, granulomatous, or neoplastic cells
BONE MARROW ASPIRATE IN
APLASTIC ANAEMIA
 Hypocellular
 Abnormal cytogenetics in 12% patients

 Trisomy 6, 8, or 15 most common, similar
  outcome to no clone.
 Monosomy 7 may have poor outcome, suggests
  possible hypoplastic MDS.
MARROW TREPHINE
RELATED DISORDERS
    Myelodysplastic syndromes – are primary, neoplastic
     stem cell disorders that tend to terminate in acute
     leukemia. The bone marrow is usually normocellular, or
     hypercellular with evidence of qualitative abnormalities
     in one or more cell lines resulting in ineffective
     erythropoiesis and/or granulopoiesis and/or
     megakaryopoiesis. The peripheral smear shows
     dysplastic (abnormality in development) cells including
     nucleated RBCs, oval macrocytes, pseudo-Pelger-Huet
     PMNs (hyposegmented neutrophils) with
     hyperchromatin clumping, hypogranulated neutrophils,
     and giant bizarre platlets.
    Hypersplenism – why can this lead to pancytopenia?
PURE RED CELL APLASIA
 Pure  red cell aplasia is characterized by a
 selective decrease in erythroid precursor
 cells in the bone marrow. WBCs and
 platlets are unaffected.
     Acquired
       Transitory with viral or bacterial infections
       Patients with hemolytic anemias may suddenly halt
        erythropoiesis
       Patients with thymoma – T-cell mediated responses
        against bone marrow erythroblasts or erythropoietin
        are sometimes produced.
PURE RED CELL APLASIA
    Congenital
        Diamond-Blackfan syndrome – occurs in young children
         and is progressive. It is probably due to an intrinsic or
         regulatory defect in the committed erythroid stem cell.
OTHER HYPOPROLIFERATIVE
ANEMIAS
 Renal disease – due to decreased erythropoietin
 Endocrine deficiencies – may lead to decreased
  erythropoietin production. For example:
  hypothyroidism leads to decreased demand for
  oxygen from tissues; decreased androgens in
  males; decreased pituitary function
PATTHOPHYSIIOLLOGY – IIMMUNE SYSTTEM

 1Support for immune destruction off stem cells..
  Patients respond to immunosuppressive therapy
 2.. See increased number off activated CD8
  lymphocytes in bone marrow
 3.. T-lymphocytes from patients inhibit
  hematopoiesis when cultured within marrow
  Depleting these cells restores cell production
 4.. IFN-gamma,, TNF,, and IL-2 elevatted in
  pattients Known to suppress proliferation and
  induce apoptosis of stem cells
 With immunosuppression cytokine levels drop

 5.. HLA-DR2 in 58% vs.. 28% off normal
  population
B.M IN APLASTIC ANEMIA

   For diagnosis of aplastic anemia......
        at least TWO of following
               - granulocytes < 500 cells / cumm
               - platelets     < 20,000 cells / cumm
               - absolute reticulocyte count.< 1%
        in addition to
               bone marrow cellularity < 25% of
      normal
              is required.
 BM aspiration    : to assess cell morphology
 BM biopsy        : to assess cellularity and
                    architecture.



   - IN APLASTIC / HYPOPLASTIC PARTICLES
Mainly fat cells, plasma cells, reticulum cells and
 lymphocytes present

    -IN CELLULAR AREAS
Redused fat cells, increased haemopoetic cells,
 dyserythropoesis, decreased megakaryocytes are
BM BX OF AA.
TREATMENT
TREATMENT



 Alleviate the underlying disorder or prevent
  further exposure to the causal agent
 If platelet count is less than 10,000 cells/μl,
  platelet transfusions are used to increase the
  number of platelets in circulation.
 Packed RBC’s should be administered to increase
  the Hb level
 Administering broadspectrum antibiotics
 Bone marrow transplant or immunosuppressive
  therapy
 Antithymocyte globulin (ATG) but slightly less
  effective
 Androgen therapy
INTRODUCTION

 Aplastic anemia is a rare, non-contagious and
  often life-threatening disorder that results from
  the unexplained failure of the bone marrow to
  produce red blood cells, white blood cells and
  platelets.
 A decrease in the production of blood cells means
  that patients are more susceptible to bleeding,
  fatigue and infections.

				
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