Drug-induced hematologic disorders

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Drug-induced hematologic disorders Powered By Docstoc
hematologic disorders
         อ. วนรัตน์ อน ุสรณ์เสงี่ยม
                      16 พ.ย. 48
o Introduction
o Drug-induced aplastic anemia
o Drug-induced agranulocytosis
o   Drug-induced   hemolytic anemia
o   Drug-induced   oxidative hemolytic anemia
o   Drug-induced   megaloblastic anemia
o   Drug-induced   thrombocytopenia
o Idiosyncratic reaction and life threatening
o Depend on cell line affected, the specific
  drug, dose of drug, possibly genetic
o Diagnosis : clinical, blood test and
  - previously reported associations between
  the drug and the dyscrasia
  - the pattern of clinical association, e.g.,
  dose, history of administration
  - absence of other causes
Types of mechanism :
o An abnormal sensitivity to the drug or one
  of the drug’s metabolites by a stem cell
o Abnormal metabolism of the drug causing
  formation of a toxic metabolites
o An immune-mediated effect on the a
  mature cellular component of the blood or
  on the stem cell
o Genetic predisposition (e.g., oxidative
  hemolytic anemia)
Drug-induced aplastic anemia
o Pancytopenia with a hypocellular bone
  marrow and no gross evidence of increased
  peripheral blood cell destruction
o Diagnosis : meets two of the following
  * WBC count < 3,500/mm3
  * platelet count < 55,000/mm3
  * Hb < 10 g/dL with reticulocyte count <
 Drug-induced aplastic anemia
o Mechanism : dose-dependent toxic effect
  on hematopoiesis : antineoplastic agents
  : Idiosyncratic
  : drug- or metabolite-induced immune
  reaction that is specific to the stem cell :
  chloramphenicol (nitroso group interact
  with DNA or bacteria from GI tract may
  metabolize to marrow toxic metabolite)
 Drug-induced aplastic anemia
Treatment and monitoring
o Survival rate ~ 62%
o The suspected offending agent must be
o Blood transfusion, antimicrobial,
o Continue bone marrow suppression : bone
  marrow transplantation
 Drug-induced agranulocytosis
o Reduction in the mature myeloid cells in
  the blood to a total count of 2,000
  cells/mm3 or less
o Mortality rate 16%; increase when the
  petient develops bacteremia or renal
o Symptoms : fever, sore throat, malaise,
  weakness, chill; within 7-14 days after
  initiation of the drug
  Drug-induced agranulocytosis
o Mechanism :
   - type I reaction : immune mediated and
  involve the drug or drug metabolite,
  antibodies, neutrophil : penicillin
  - type II reaction : accumulated drug toxicity
  in hypersensitive individuals : phenothiazines
  - typer III reaction : combine
o Antithyroid drugs : PTU, methimazole
  - mechanism : unknown; antibody
  - may occur more frequently in older patients
  and within 2 months after initiation
Penicillin high dose : > 150
 Drug-induced agranulocytosis
Treatment and monitoring
o Removal of the offending drug; granulocyte
  count recover between 3-15 days
o Treatment some symptoms e.g., infection
o Autoimmune neutropenia : intravenous
  immune globulin
o GM-CSF, G-CSF : decrease the time
  period of neutropenia
 Drug-induced agranulocytosis
o No specific guideline for predicting the
  development of agranulocytosis and not
  correlate with blood counts :
  * patient counseling to ensure self-referral
  at the first signs of pharyngitis, fever
  after taking the high-risk drug
Drug-induced hemolytic anemia
o Hemolysis involves the destruction of red
  blood cells with lysis of the cell membrane
  and removal of red cell contents by
o Mechanism : immune or metabolic
o Immune hemolytic anemia :
  - adsorption of drug to RBC membrane :
  penicillin, cephalosporin, tetracycline,
  antineoplastic agents
Drug-induced hemolytic anemia
- innocent bystander phenomenon : quinidine,
- nonspecific binding of proteins : cephalosporin
- autoimmune : positive direct Coomb’s test :
     * methyldopa : 15-20% of patients, only 8%
will develop hemolysis
                    : hemolysis occurs after
initiation of drug from 18 months to 4 years
                    : positive direct Coomb’s test
occur after therapy 3-6 months and remain
positive 7-20 months after discontinue
Drug-induced hemolytic anemia
o Metabolic mechanism :
  - hereditary condition, mosr ofter
  associated with G6PD deficiency
  - conditions that occur drug-induced
  oxidative hemolytic anemia :
     * abnormal increase in oxidative stress
     * structural abnormalities of the RBC
  Hb molecule render the cells more
  susceptible to oxidant stress
Drug-induced hemolytic anemia
      * deficiency of reducing power in the RBC
  - excessive oxidant stress can denature Hb
  molecule and increase the RBC membrane
  rigidity, resulting in cell lysis
Treatment and monitoring :
o Removal of the offending drugs and
  supportive care
o The lysis will cease and blood picture returns
  to normal in 2-3 weeks
o Advise patient to avoid medication capable of
  inducing the hemolysis
       megaloblastic anemia
o Abnormal development of RBC precursors
  called megaloblasts in the bone marrow
o Mechanism :
  - by inhibiting the absorption or utilization
  of vitamin B12 or folate
  - by directly inhibiting DNA synthesis
  without depleting folate or vitamin B12
o Antineoplastic agents : action on DNA
      megaloblastic anemia
o Cotrimoxazole : occur most frequently in
  patients with a partial B12 or folate
o Phenytoin, pyrimidone, phenobarbital :
  inhibit folate absorption, or increasing
  the folate catabolism
       megaloblastic anemia
Treatment and monitoring
o Chemotherapy : no real therapeutic option
o Cotrimoxazole : folinic acid 5-10 mg up to
  four times a day
o Phenytoin, phenobarbital : folic acid
  supplement 1 mg daily but some clinicians
  suggest the supplement may decrease the
  effectiveness of the antiepileptic drugs
o Methotrexate : dose-dependent, use with
  calcium leucovorin
Drug-induced thrombocytopenia
o Mechanism :
  - direct toxicity in megakaryocytes in the
  bone marrow : antineoplastic agents,
  amrinone, amphotericin B
  - immune reaction : increase peripheral
  destruction of platelets : penicillins,
  trimethoprim, heparin
     * occurs 7-15 days after initiation of
  drug, large doses
Drug-induced thrombocytopenia
o Heparin-induced thrombocytopenia :
  * First : mild, occur 2-4 days after
  initiation of therapy; platelet count then
  slowly returns to normal; mechanism :
  sequestration of platelet
  * Second : severe form and may be
  associated with thrombosis; platelet drop
  6-12 days after starting heparin therapy
      * patient can develop thrombocytopenia,
Drug-induced thrombocytopenia
      * mechanism : antibody attach to the
  platelet-heparin complex, allowing the
  activation of arachidonic acid by platelets,
  then platelet aggregates and from a
o Gold salt : interaction with HLA antigens
  on platelet membrane, causing destruction
  of platelet by autoantibody
o Early symptoms : increased bruising,
  petechiae, ecchymosis, epistaxis
Drug-induced thrombocytopenia
Treatment and monitoring
o Removal of the offending drug and
  symptomatic treatment
o Heparin : antiplatelet drugs or low
  molecular weight heparin
o Corticosteroid : immune mechanism

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