Transcript DRUG INDUCED BLOOD DISORDERS

 Introduction
 Epidemiology
 Drug-induced Aplastic anemia
 Drug-induced Hemolytic anemia
 Drug-induced Neutropenia and Agranulocytosis
 Drug-induced Thrombocytopenia
 Drug-induced Megaloblastic anemia
 Conclusion
 Hematologic disorders have long been a potential risk
of modern pharmacotherapy.
 Some agents causes predictable hematologic disease
(e.g., antineoplastics) but others induce idiosyncratic
reactions not directly related to the drugs
pharmacology.
 Drug-induced hematologic disorders are more common
in the elderly than in the young; the risk of death also
appears to be greater with increasing age.
 Drug-induced injuries of the blood are termed blood
dyscrasias.
 Drug-induced hematologic disorders can affect any
cell line, including white blood cells (WBCs), red
blood cells (RBCs) and platelets.
 The types of drug-induced blood dyscrasias presented
are
(a) Aplastic anemia
(b) Hemolytic anemia
(c) Agranulocytosis or neutropenia
(d) Thrombocytopenia
(e) Megaloblastic anemia
 Although rare, these disorders are important as they
are associated with significant morbidity and mortality.
 A report from the Netherlands estimated the incidence
of drug-induced agranulocytosis as 1.6 to 2.5 cases per
million inhabitants per year.
 An epidemiological study held in United states
estimated 14490 deaths in 1984 were attributable to
blood dyscrasias where aplastic anaemia was leading
cause of death, followed by thrombocytopenia,
agranulocytosis, and haemolytic anaemia. Similar
results were reported in epidemiologic studies
conducted in Thailand and Brazil
 However, incidence of drug-induced thrombocytopenia
is more frequent, with some reports suggesting that as
many as 5% of patients who receive heparin develop
heparin-induced thrombocytopenia.
 Aplastic anemia was the leading cause of death, followed
by thrombocytopenia, agranulocytosis, and hemolytic
anemia.
 The risk of agranulocytosis has been reported to be
higher in women than in men.
 Aplastic anemia occurs when the bone marrow fails
and production of red blood cells, white cells, and
platelets ceases (i.e. Pancytopenia).
 Drug induced aplastic anemia accounts for 7% to 86%
of total cases of aplastic anemia.
 Some authors have reported a peak incidence in
patients younger than 30 years of age, although others
report the highest incidence in those older than 60
years of age.
 Fatigue
 Headache
 Lethargy
 Neutropenia
 Fever
 Chills
 Infection
 Tachycardia
 Thrombocytopenia
 Easy bruisability
 Petechiae
 Bleeding
 Weakness
Acetazolamide
Etodolac
Captopril
Ibuprofen
Carbamazepine
Indomethacin
Chloramphenicol
Salicylates
Felbamate
Sulindac
Furosemide
Phenytoin
Gold salts
Sulfonamides:
Imatinib
Sulfisoxazole
Linezolid
Sulfasalazine
Methimazole
Mesalamine
NSAIDs:
Temozolomide
Diclofenac
Ticlopidine
 The cause of drug-induced aplastic anemia is damage
to the pluripotential hematopoietic stem cells, before
their differentiation to committed stem cells. This
damage effectively reduces the normal levels of
circulating erythrocytes, neutrophils and platelets.
 Three mechanisms have been proposed as causes of
damage to the pluripotential hematopoietic stem
cells.
 Direct, dose-dependent drug toxicity-
e.g. antineoplastics, chloramphenicol, radiation
 Idiosyncratic and operates through toxic metabolites
e.g. phenytoin, Carbamazepine, chloramphenicol
 Drug-or metabolite-induced immuno reaction specific
to the stem cell population.
 The
anti-neoplastic agents exemplify the dosedependent mechanism for the development of aplastic
anemia.
 Chloramphenicol, an antimicrobial agent, also causes a
bone marrow depression that is dose-dependent and
reversible.
 The most common cause of drug-induced aplastic
anemia is the development of an immune reaction.
 Genetic predisposition may also influence the
development of drug-induced aplastic anemia. Studies
in animals and a case report of chloramphenicolinduced aplastic anemia in identical twins suggest a
genetic predisposition to the development of druginduced aplastic anemia.
 Drug-induced aplastic anemia occurs due to either
direct cytotoxicity or an immunologic response.
 Both eventually lead to apoptosis of hematopoietic
stem cells.
 Chemotherapy, though its effect on DNA synthesis,
DNA replication, or both, is a classical example of
direct toxicity.
 An immunologic response causing aplastic anemia is
idiosyncratic, and it occurs when drug metabolites
form complexes with cellular proteins within bone
marrow cells (hapten protein complexes).
 Evaluation of patients with suspected aplastic anemia
should begin with a complete blood count (CBC).
 A bone marrow biopsy may be required to verify that
RBC production has ceased and to confirm the
diagnosis.
 A diagnosis of aplastic anemia can be made by the
presence of two of the following criteria:
 a WBC count of 3500/mm3 or less,
 a platelet count of 55,000/mm3 or less, or
 a hemoglobin value of 10g/dl or less with a reticulocyte
count of 30,000/mm3 or less.
 Severe aplastic anemia is defined by at least two of the
following three peripheral findings:
 Neutrophil count of less than 500/mm3,
 Platelet count of less than 20000/mm3, and
 Anemia with a corrected reticulocyte index of less than
1%.
RISK FACTORS:
Drug induced aplastic anemia is rare, and risk
factors are not well defined.
 exposure to pesticides and chemicals
 exposure to specific drugs known to cause the disorder
 occupational radiation exposure
 viral exposure (e.g. hepatitis A)
 The major causes of mortality in patients with
aplastic anemia are infections and bleeding.
 One case series estimated the mortality rate for
patients with drug-induced aplastic anemia to be
51%.
 One study showed that 62% of deaths were due to
infections, consisting mostly of bacterial and fungal
pathogens.
 Drug-induced
aplastic anemia is rare and
unpredictable, so prevention is challenging.
 Whenever possible, drugs known to cause aplastic
anemia should be avoided.
 When avoidance is not possible, careful hematologic
monitoring should be routinely conducted.
 Patients should be educated regarding the signs an
symptoms of aplastic anemia.
Goals of therapy:
 To improve peripheral blood counts so that patients do not
require transfusions and are not at the risk of infections.
Principles of therapy:
 The first step in treatment involves discontinuation of the
causative agent and administration of immunosuppressive
agents which may include cyclosporine, azathioprine, or
cyclophosphamide.
 Then provide adequate supportive care, including
symptomatic treatment of infection and transfusion
support with erythrocytes and platelets. Fever of unknown
origin should be aggressively managed in patients on
immunotherapy.
 Hematopoietic Stem cell transplantation (HSCT).
 Immunosuppression
- Current options for this
approach
include
antithymocyte
globulin,
antilymphocyte
globulin,
cyclosporine,
and
glucocorticoids
 Granulocyte colony-stimulating factor (G-CSF),
granulo-cytemacrophage colony-stimulating factor
(GM-CSF), and interleukin- 144 have also been
investigated in the treatment of aplastic anemia.
Prospective evaluations are required further to
determine the role of G-CSF in aplastic anemia.
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Collection - Stem cells are collected from bone
marrow or blood of donor.
Processing - Bone marrow or peripheral blood is
taken to laboratory where the stem cells are
concentrated and prepared for the freezing process.
Cryopreservation – Bone marrow or blood is
preserved by freezing to keep stem cells alive until
they are transfused into patient’s blood stream.
Chemotherapy – High dose chemotherapy or
radiation therapy is given to the patient.
Infusion – The stem cells are infused.
 Antithymocyte globulin:
40 mg/kg per day for 4 days to 15 to 20 mg/kg per day
for 8 to 14 days
 Methylprednisolone:
1 mg/kg per day for 4 weeks
 Cyclosporine:
4 to 6 mg/kg per day to 10 to 12 mg/kg per day
 Hemolytic anemia is a normocytic anemia that
occurs when red blood cells are prematurely
destroyed (hemolysis), which can occur either
because of defective RBCs or abnormal changes in
the RBCs.
 Estimates of the annual incidence of drug-induced
hemolytic anemia in the general population range
from 1.1 to 1.6 cases per million people.
 Intravascular hemolysis
 Extravascular hemolysis
 Fatigue
 Headache
 Lethargy
 Tachycardia
 Weakness
Acetaminophen
Fluoroquinolones:
NSAIDs:
ACE inhibitors
Ciprofloxacin
Diclofenac
Carbamazepine
Levofloxacin
Ibuprofen
Cephalosporins:
H2-antagonists:
Indomethacin
Cefazolin
Cimetidine
Salicylates
Cefotaxime
Famotidine
Piperacillin / tazobactam
Cefotetan
Ranitidine
Probencid
Cefoxitin
Nizatidine
Procainamide
Ceftizoxime
Ketoconazole
Quinidine
Ceftriaxone
Lansoprazole
Quinine
Cefuroxime
Levodopa
Rifabutin
Cephalothin
Isoniazid
Rifampin
Ceftazidime
Methyldopa
Triamterene
 The causes of drug-induced hemolytic anemia can be
divided into two categories:
 Immune (they may suppress regulator cells, which
allow the production of autoantibodies)
 Metabolic (induction of hemolysis by metabolic
abnormalities in the RBCs)
 Drug induced autoantibody production E.g. Methyldopa
 Innocent bystander autoantibody production E.g. Quinine,
Quinidine
 Hapten induced hemolysis E.g. Penicillin, Cephalosporin
 Non-immunological protein adsorption E.g.
Cephalosporin
DIAGNOSIS:
 The direct coombs test (or direct anti–human globulin
test), used to determine the presence of antibodies on red
cells.
RISK FACTORS:
 Infections, particularly in those with hereditary disorders
 Presence of rare inherited disorders
 G6PD deficiency
 Hereditary spherocytosis
 Sickle cell anemia
 Thalassemias
 Exposure to traumatic and micro-angiographic conditions
 Valve replacement
 Graft rejection
MORTALITY AND MORBIDITY:
 It results in significant morbidity as a result of fatigue,
shortness of breath, dizziness, arrhythmia, and heart
failure. A case series suggests that the mortality rate is
approximately 4%.
PREVENTION:
 Since, it is frequently related to G6PD deficiency, careful
screening of patients for this deficiency can be an
important preventive step.
 G6PD testing should be done whenever the use of drugs
known to cause hemolytic anemia is being
contemplated.
 The first step includes the removal of the offending
agent and supportive care.
 RBC transfusion for patients with low hemoglobin and
hemodialysis for those in whom acute renal failure
develops may be necessary in some clinical situations.
 Steroids and intravenous immunoglobulin have been
used in serious cases.
 A recent development in the treatment of
autoimmune hemolytic anemia is the use of the
chimeric, human anti-CD20 monoclonal antibody
rituximab.
 A hereditary condition, accompanies a glucose-6-
phosphate dehydrogenase (G6PD) enzyme deficiency,
can also occur because of other enzyme defects.
(reduced nicotinamide adenine dinucleotide phosphate
[NADPH], methemoglobin reductase or reduced
glutathione peroxidase)
Drugs Associated with Oxidative Hemolytic Anemia
Dapsone
Nitrofurantion
Ascorbic acid
Primaquine
Metformin
Sulfacetamide
Methylene blue
Sulfamethoxazole
Nalidixic acid
Sulfanilamide
 Removal of
the offending drug is the primary
treatment for drug-induced oxidative hemolytic
anemia.
 Usually no therapy is necessary, as most cases of druginduced oxidative haemolytic anemia are mild in
severity.
 Patients with these enzyme deficiencies should be
advised to avoid medications capable of inducing the
hemolysis.
 Neutropenia is defined as an absolute neutrophil
count (ANC) of <500 cells per cubic millimeter.
 When non-cytotoxic drugs cause a decline in
neutrophil count, the condition is termed
agranulocytosis.
 Agranulocytosis is defined as a drug-mediated
reduction in the peripheral absolute neutrophil count
to <500 cells per cubic millimeter due to immunologic
or cytotoxic mechanisms.
 It occurs more frequently in females than in males,
with an overall estimated incidence of 1.6 to 3.4
million persons per year.
 Sore throat
 Bronchitis
 Pharyngitis
 Sinusitis
 Stomatitis
 Myalgias
 Fever
 Malaise
 Weakness
 Chills
 Lethargy
Abacavir
Acetaminophen
Acetazolamide
Allopurinol
Aminoglutethamide
Amoxapine
Aspirin
β-lactam antibiotics
Brompheniramine
Captopril
Carbamazepine
Carbimazole
Cephalosporins
Clindamycin
Chloramphenicol
Chlorpropamide
Chloroquine
Cimetidine
Dapsone
Desipramine
Digoxin
Dipyridamole
Erythromycin
Ethosuximide
Flucytosine
Furosemide
Ganciclovir
Gentamicin
Griseofulvin
Hydralazine
Isoniazid
Levodopa
Mebendazole
Methyldopa
Nifedipine
Nitrofurantoin
NSAIDs
Olanzapine
Penicillamine
Phenothiazines
Phenytoin
Potassium perchlorate
Procainamide
Propafenone
Propranolol
Chlorpheniramine
Imipramine
Propylthiouracil
Pyrimethamine
Quinidine
Quinine
Ranitidine
Spironolactone
Streptomycin
Sulfasalazine
Tamoxifen
Ticlopidine
Tocainamide
Trimethoprim
Valproic acid
Vancomycin
Zidovudine
Drug-induced agranulocytosis can be classified into
three types,
 Type I (immune-mediated)
 Type-II (direct toxicity)
 Type-III (combination of Type I and II)
 The evaluation of patients should focuses on the
clinical history and physical examination.
 A CBC should be obtained.
 Bone marrow aspiration and biopsy with immunologic
and cytogenetic evaluation is indicated for
neutropenia with an undefined cause.
 Patients presenting with neutropenia who have not
received cytotoxic chemotherapy require a thorough
review of systems for evidence of a recent viral
infection and a careful medication history.
 Advanced age
 Previous exposure to chemotherapy or radiation
 Poor nutrition
 End-organ dysfunction
 Autoimmune disease
 Genetic predisposition
 Leukopenia during initiation of therapy
 Mononucleosis
 Multi-agent chemotherapy regimens
 Polypharmacy
 Renal insufficiency
MORTALITY AND MORBIDITY:
 The overall mortality rate in agranulocytosis is 16%; the rate
increases when they develop bacteremia or renal failure.
 Mortality rates due to clozapine-induced agranulocytosis have
been reported to be 0.016% to 0.017% in two studies that
included over 24000 patients.
PREVENTION:
Neutropenia due to cytotoxic chemotherapy:
 Dose modification
 Prophylactic administration of filgrastim or Sargramostim
Agranulocytosis:
 Avoid drugs that previously caused agranulocytosis
Agranulocytosis due to clozapine:
 Weekly monitoring of white cell count
 The primary treatment of drug-induced agranulocytosis
is the removal of the offending drug.
 Sargramostim (GM-CSF) and filgrastim (G-CSF) have
been used to shorten the duration of neutropenia.
 The time to recovery of the granulocyte count ranged
from 3 to 15 days.
Sargramostim:
250mcg/kg/ day IV or SC over 4 hours
Monitoring parameters: Renal functions
Hepatic functions
Hydration status
Body weight
CBC
Filgrastim:
5 mcg/kg/day IV or SC
Monitoring parameters: ARDS
Alveolar haemorrhage,
Allergic reactions,
Cutaneous vasculitis
Splenic rupture
 Thrombocytopenia is typically defined as a platelet
count below 1, 50,000/mm3 .
 It is estimated to be approximately 10 cases per 1 million
people per year.
 The risk of thrombocytopenia in patients receiving
Trimethoprim-Sulfamethoxazole is reported to be 38
occurrences per 1 million users and in patients receiving
quinine or Quinidine, the risk is reported to be 26
occurrences for every 1 million users.
 Orally administered Inamrinone has been shown to
cause thrombocytopenia in up to 18.6% of patients.
 Systemic symptoms:
 Dizziness
 Chills
 Fever
 Nausea / vomiting
 Fatigue
 Moderate thrombocytopenia (20,000 to 1,50,000
platelets /mm3)
 Ecchymosis
 Microscopic hematuria
 Purpura
 Petechiae
 Severe thrombocytopenia (<20,000 platelets/mm3)
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CNS hemorrhage
Hematochezia
Gross hematuria
Florid Purpura
Gingival bleeding
Epistaxis
Retroperitoneal bleeding
Menorrhagia
 Heparin-induced thrombocytopenia-specific
symptoms
 Upper and lower deep-vein thrombosis or pulmonary
embolism
 Skin necrosis
 Gangrene
 Anaphylaxis
Abciximab
Acetaminophen
Adefovir dipivoxil
Alprenolol
Aminoglutethimide
Amiodarone
Aminosalicylic acid
Amphotericin B
Ampicillin
Captopril
Carbamazepine
Chlordiazepoxide
Chlorothaizide
Chlorpromazine
Chlorpropamide
Cimetidine
Danazol
Diazepam
Deferoxamine
Diclofenac
Digoxin
Fluconazole
Glyburide
Gold salts
Haloperidol
Heparin
Ibuprofen
Isoniazid
Methyldopa
Minoxidil
Nalidixic acid
Naproxen
Naphazoline
Oxprenolol
Phenytoin
Piperacillin
Procainamide
Quinidine
Quinine
Ranitidine
Rifampin
Simvastatin
Sulfasalazine
Sulindac
Tamoxifen
Terbinafine
Thiathixone
Ticlopidine
Tirofiban
Tocainide
Trimethoprim
Valproate
Vancomycin
There are three types of drug-induced thrombocytopenia:
 Direct toxicity reactions, E.g. chemotherapeutic
agents, amrinone, pesticides, organic solvents
 Hapten-type immune reactions, E.g. Penicillin,
Abciximab, gold salts, Heparin
 Innocent bystander type immune reactions.
E.g. Quinine
 Decreased megakaryocytes on bone-marrow biopsy
and pancytopenia are indicative of thrombocytopenia
due to decreased platelet production.
 Splenomegaly can lead
to thrombocytopenia
secondary to platelet re-distribution in splenic
vascular beds.
 The laboratory evaluation of patients with suspected
drug-induced thrombocytopenia may include
glycoprotein-specific platelet antibody assays and an
evaluation of drug-dependent increase in plateletassociated IgG.
 Heparin, LMWH
 History of HIT
 Previous exposure to heparin or LMWH
 Valproic acid
 Advanced age
 Concurrent use of aspirin
 High serum Valproic acid concentrations
 The use of corticosteroid therapy in the treatment of
drug-induced thrombocytopenia is controversial.
 In gold salt–induced thrombocytopenia, prednisone in a
dose of 60 mg daily is beneficial in correcting the
thrombocytopenia.
 Abciximab-induced acute profound thrombocytopenia is
effectively treated with platelet transfusion, if clinically
indicated.
 In the case of heparin-induced thrombocytopenia with
thrombosis, all forms of heparin must be discontinued,
and anticoagulation with Argatroban or the recombinant
Hirudin, Lepirudin initiated.
 Macrocytic anemias are characterized by an increase
in the average volume of the RBC (an increased MCV)
and increase in the diameter and thickness of the
erythrocyte.
 Megaloblastic anemias are produced by disorders of
DNA synthesis, most commonly as a of folic acid and
vitamin B12 deficiencies.
 The incidence of macrocytosis with Zidovudine agent
has been reported to be as high as 80%.
 Methotrexate, an irreversible inhibitor of dihydrofolate
reductase, causes megaloblastic anemia in 3% to 9% of
patients.
 Fatigue
 Headache
 Lethargy
 Tachycardia
 Weakness
CAUSES:
Azathioprine
Leflunomide
Metformin
Phenytoin
Sulfonamides:
Sulfisoxazole
Sulfasalazine
Mesalamine
Trimethoprim-Sulfamethoxazole
Zidovudine
 Drug-induced macrocytosis is the result of inhibition of
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DNA synthesis and replication that ultimately leads to
abnormal erythrocytosis and the production of
megaloblasts.
The normal proliferation of red cells requires adequate
folate and vitamin B12.
Folate is necessary for efficient thymidilate synthesis and
production of DNA.
Trimethoprim and methotrexate disrupt the folate pathway
by inhibiting dihydrofolate reductase, while phenytoin may
decrease the absorption of folate or facilitate its clearance.
Zidovudine appears to interfere with the synthesis of heme
proteins, possibly by inhibiting DNA polymerase.
 Patients with macrocytic anemia present an elevated
MCV in the presence of low hemoglobin.
 The diagnostic evaluation of patients with suspected
drug-induced macrocytic anemia must include
determination
of
folate
and
vitamin
B12
concentrations.
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Major risk factors include a diet low in vitamin B12,
chronic alcoholism, and malabsorption syndromes.
Abdominal or intestinal surgery that effects intrinsic
factor production or absorption
Diet low in vitamin B12
Chronic alcoholism
Crohn’s disease
Intestinal malabsorption syndromes
Pernicious anemia
MORTALITY AND MORBIDITY:
 Drug-induced macrocytic anemia is usually relatively
benign and generally does not result in significant
morbidity and mortality.
PREVENTION:
 Primary prevention of drug-induced macrocytic
anemia involves avoidance of agents known to cause
the disorder.
 Careful hematologic monitoring is recommended.
 If drug-induced megaloblastic anemia results from
cotrimoxazole, a trial course of folinic acid, 5 to 10 mg
up to four times a day, may correct the anemia.
 Folic acid supplementation of 1 mg every day often
corrects the drug-induced megaloblastic anemia
produced by either Phenytoin or Phenobarbital.
 Drug-induced
hematologic disorders are rare but
potentially life-threatening conditions.
 Clinicians should recognize the medications with the
potential of causing hematologic disorders, and educate
patients to recognize the symptoms associated with such
events.
 Frequent laboratory monitoring of patients taking
medications associated with severe hematologic events
can facilitate diagnosis and treatment.
 Identifying the etiology of the event and documenting the
causative agents may serve to prevent a recurrence
secondary to the use of a related medication.