Aplastic Anemia

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Chapter 8

• Aplastic Anemia
• (Including Pure Red Cell Aplasia and Congenital
  Dyserythropoietic Anemia)

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1. Study Questions2. Homework Assignment3.
Exam for Unit IV
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Aplastic Anemia

• In Chapter 8, you will learn about aplastic
  anemia, including pure red cell aplasia and
  congenital dyserythropoietic anemia.  You will
  study the pathogenesis and etiologies of these
  disorders.  Laboratory results and treatment will
  be discussed.

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Definition of Aplastic Anemia

• Group of disorders characterized by severely
  hypocellular bone marrow, cellular depletion, and
  fatty replacement of bone marrow. Will see
  pancytopenia - decrease in all cell lines.
• Loss of functional bone marrow has variety of
  causes drugs, chemicals, radiation, infections,
  and immune destruction. Progenitor cells lose
  ability to renew themselves and produce progeny.

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Pathogenesis of Aplastic Anemia

• Basic defect is failure of blood cell production
  involving all cell lines. Bone marrow failure
  may result as consequence of failure of blood
  cell formation at level of stem cell or
  disturbance of bone marrow microenvironment
  (failure to respond to hormones).
• Has been classified as refractory or
  aregenerative anemia.

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Etiology of Aplastic Anemia

• May be acquired or congenital
• Acquired
• Vast majority of cases acquired and are primary
  (or idiopathic).
• Occurs more frequently after age 50.
• Is more frequently found in Far East.
• Secondary
• Rest of cases considered secondary resulting from
  exposure to chemicals or drugs, irradiation or
  infection.
• May be result of immune dysfunction.
• Hereditary cases extremely rare and usually
  grouped under Fanconis anemia.

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Acquired Aplastic Anemia
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Acquired Aplastic Anemia

• Idiopathic or primary
• Most often thought to be idiopathic (unknown
  cause) in nature
• 40-70 of the cases of acquired aplastic anemia
  seen in western populations are idiopathic

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Secondary Causes of Acquired Aplastic Anemia

• Variety of agents associated with development of
  secondary aplastic anemia
• Chemical Agents
• Drugs
• Ionizing Radiation
• Infections
• Miscellaneous Causes

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Chemical Agents 1 of 2

• Agents associated with aplastic anemia include
  benzene, insecticides, arsenic and weed killers.
  Most have benzene ring as part of structure. 
• Benzene known to cause aplastic anemia for over
  100 years. Still used in industry. Volatile,
  easily absorbed by inhalation.  Is solvent for
  rubber, fats, alkaloids.  Find in dyes and
  drugs.  Find in dry cleaning shops.

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Chemical Agents 2 of 2

• Bone marrow suppression reversible if exposure to
  benzene stopped and bone marrow not too severely
  depressed.  Anemia ranges from mild to severe.
  Ranges from mild anemia and thrombocytopenia to
  fatal pancytopenia.
• Benzene may inhibit DNA and RNA synthesis.
• May see accumulation of chromosomal abnormalities
  and development of acute leukemia.
• Diversity in individual susceptibility to benzene
  compounds.

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Drugs 1 of 2

• Wide variety of drugs may cause aplastic anemia.
• Antibiotic chloramphenicol and anti-inflammatory
  drug phenylbutazone best known.
• Toxicity of drug NOT related to dosage of drug.
  Hard to definitely connect drug as causative
  agent of aplastic anemia.
• Mechanism by which drug causes aplastic anemia
  unknown. Cannot identify which patients will
  develop anemia due to drug.
• Effects may be either reversible or irreversible.
  Usually reversible if on drug short time. Tends
  to be irreversible if on drug a long time. Which
  form aplastic anemia to develop is unpredictable.

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Drugs 2 of 2

• Chloramphenicol now only used when no other
  antibiotic will work.
• Other drugs which may case aplastic anemia
  include
• Chloramphenicol (antibiotic)
• Anticonvulsants
• Sulfonamides
• Chemotherapy drugs
• Knowing potential bone marrow side effects
  important.  Monitoring of patient very important.
  

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Ionizing Radiation

• Radiation destroys rapidly dividing cells of bone
  marrow. Is fairly predictable that high dose of
  radiation will lead to aplastic anemia. Is
  irreversible and fatal.
• Lesser doses may lead to reversible anemia,
  leukopenia, and thrombocytopenia.
• Gamma rays and x-rays cause most damage to bone
  marrow cells.
• Radiation disrupts chemical bonds and leads to
  formation of free radicals and other ions. Free
  radicals and other ions interact with DNA causing
  breaks or cross linking of DNA strands.
• Radiation may also have long term effects.
  Aplastic anemia may occur months to years after
  radiation exposure.

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Infections

• Many infections have myelosuppressive effects.
  Acute infections usually suppress bone marrow for
  10-14 days with minor effects on peripheral
  blood.
• Chronic infections may have more severe effects.
• Several viral infections (Epstein-Barr,
  cytomegalovirus, HIV) associated with aplastic
  anemia. 
• Hepatitis also has associations with development
  of refractory aplastic anemia.
• Actual mechanism unknown. Virus may either
  directly infect stem cell or may induce
  autoimmune response.
• Other infectious agents include TB and dengue
  fever.

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Miscellaneous Causes

• Aplastic anemia also associated with number of
  conditions of altered immunity, including
  pregnancy and graft-versus-host disease.
• May suggest autoimmune connection.
• Other causes include malnutrition, anorexia
  nervosa, pancreatic insufficiency, and paroxysmal
  nocturnal hemoglobinuria.

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Congenital Aplastic Anemia(Fanconis Anemia)
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Fanconis Anemia 1 of 2

• Characterized by hematologic abnormalities
  present since birth. Is inherited.
• Is autosomal recessive.
• Usually have variety of physical abnormalities
  skeletal defects (malformed thumbs), cutaneous
  hyperpigmentation (brown skin), renal
  abnormalities, microcephaly, mental retardation
  and poor growth.
• Have pancytopenia which becomes progressively
  worse as patient ages.

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Fanconis Anemia 2 of 2

• Usually symptomatic between ages 5 and 10.
• Fanconis aplastic anemia characterized by number
  of chromosomal abnormalities.
• Untreated patients usually die of infections or
  hemorrhage.
• Most patients treated with bone marrow
  transplantation.
• Other forms congenital aplastic anemia exist, but
  extremely rare.

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Clinical Manifestations

• Usually insidious disease because of gradual
  decrease in bone marrow production .
• May occur in any age group.
• Symptoms of progressive fatigue, dyspnea and
  palpitations. Occasionally see bleeding or
  infections. Patient presents pallor due to
  anemia and evidence of thrombocytopenia
  (petechiae, purpura, ecchymoses and mucosal
  bleeding). 
• Infections occur later in disease.

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Laboratory Examination 1 of 2

• CBC shows pancytopenia. Hemoglobin usually lt 7
  g/dL. Anemia usually normochromic and normocytic
  with moderate anisocytosis and poikilocytosis.
• Retic count usually decreased.
• No specific RBC morphology on peripheral smear.
  Platelet estimate is decreased. Will see
  relative increase in lymphocytes with
  corresponding decrease in myeloid cells and
  monocytes. Usually do not see left shift.

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Laboratory Examination 2 of 2

• When thrombocytopenia is present, bleeding time
  is prolonged and clot retraction is poor.
• To confirm diagnosis, must perform bone marrow.
  Bone marrow aspirate is hypocellular and may be a
  dry tap.  May require several biopsies to confirm
  diagnosis.

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Treatment, Clinical Course and Prognosis

• Untreated aplastic anemia has extremely poor
  prognosis. Rare to have spontaneous recovery.
• Until early 1970s, treatment was supportive
  transfusions, treatment with androgen and
  anabolic steroids. Key was to find cause and
  eliminate it. Course usually progressive with
  five year mortality rate of 70.
• Today, treatment of choice for patients under 50
  is bone marrow transplantation. Have long-term
  survival rates of 60-80.
• If unable to receive bone marrow transplant,
  immunomodulatory therapy utilized. Uses drugs to
  inhibit immune attack on bone marrow stem cells.

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Pure Red Cell Aplasia
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Pure Red Cell Aplasia 1 of 2

• Uncommon disorder in which erythroid cells in
  bone marrow are selectively decreased. See
  anemia without other associated cytopenias.
• May be acquired or congenital.  Usually occurs
  after age 40.
• Have a severe, chronic, normocytic to slightly
  macrocytic anemia.
• Reticulocyte count decreased. No evidence of
  hemolysis or hemorrhage.

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Pure Red Cell Aplasia 2 of 2

• White cells and platelets normal.  Have normal
  differential.  Bone marrow shows normal
  cellularity with absence of erythroid precursor
  cells. Erythropoietin levels markedly increased.
  
• Acquired causes of pure red cell aplasia most
  commonly seen. May be either acute or chronic in
  onset and duration.

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Congenital Red Cell Aplasia

• Named Diamond-Blackfan anemia.
• Characterized by moderate to severe chronic
  anemia (normochromic, normocytic) that appears in
  early infancy.
• Normal white cells and platelets.
• Mode of inheritance unknown. Wide variations in
  age of onset, severity of disease, and course of
  disease.
• May see spontaneous remission. Usually treated
  with steroids. May become transfusion dependent.
  Poor prognosis.

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Acquired Red Cell Aplasia 1 of 2

• Aplastic crisis in hemolytic disorders (sickle
  cell and spherocytosis).
• Infection by Parvovirus B19 may cause aplastic
  crisis. Patient usually recovers spontaneously.
• Idiosyncratic reaction to drug therapy.  Drugs
  include sulfamides and anticonvulsants. Anemia
  corrects itself once drug discontinued.
• Malnutrition.

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Acquired Red Cell Aplasia 2 of 2

• Chronic Infection.
• Vitamin deficiency.
• Thymoma or other neoplasms. Removal of thymic
  tumor may cause reversal of anemia.
• Idiopathic.
• Chemistry tests reveal increase in serum iron,
  erythropoietin and 90 saturation of transferrin.
  
• Treatment is usually RBC transfusions.

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Congenital Dyserythropoietic Anemia (CDA)
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Congenital Dyserythropoietic Anemias (CDAs) 1
of 2

• Rare group of familial disorders in which anemia
  and ineffective erythropoiesis associated with
  bizarre binuclear and multinuclear erythroblasts.
  
• Have three types of CDAs.  All types
  characterized by anemia, erythroid hyperplasia,
  and indirect hyperbilirubinemia or mild jaundice.
  
• CDA Type I characterized by mild to moderate
  macrocytic anemia with marked anisocytosis and
  poikilocytosis. Bone marrow shows 1-3
  erythroblasts, megaloblastic maturation, and
  small number of binucleated erythroblasts with
  chromatin bridges. Inherited as autosomal
  recessive.

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Congenital Dyserythropoietic Anemias (CDAs) 1
of 2

• CDA Type II characterized by mild to severe
  normocytic anemia with 10-50 binucleated or
  multinucleated erythroblasts. Is autosomal
  recessive inheritance.  Red cells will lyse in
  acidified serum. Do NOT lyse in sugar water
  test. Also noted that Type II CDA cells strongly
  agglutinated by anti-i. Usually benign disease.
• CDA Type III presents as mild to moderate
  macrocytic anemia.  30-50 of erthroblasts
  multinucleated. Inherited as autosomal dominant.