Warfarin
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Brand names, Trade names |
| 1.6 Manufacturers, Importers |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First-aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Colour |
| 3.3.2 State/Form |
| 3.3.3 Description |
| 3.4 Other characteristics |
| 4. USES/CIRCUMSTANCES OF POISONING |
| 4.1 Uses |
| 4.1.1 Uses |
| 4.1.2 Description |
| 4.2 High risk circumstance of poisoning |
| 4.3 Occupationally exposed populations |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Others |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination by route of exposure |
| 7. TOXICOLOGY |
| 7.1 Mode of Action |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.2.4 Workplace standards |
| 7.2.5 Acceptable daily intake (ADI) and other guideline levels |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 8. TOXICOLOGICAL ANALYSES & BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Toxicological analyses |
| 8.1.1.2 Biomedical analyses |
| 8.1.1.3 Arterial blood gas analysis |
| 8.1.1.4 Haematological analyses |
| 8.1.1.5 Other (unspecified) analyses |
| 8.1.2 Storage of laboratory samples & specimens |
| 8.1.2.1 Toxicological analyses |
| 8.1.2.2 Biomedical analyses |
| 8.1.2.3 Arterial blood gas analysis |
| 8.1.2.4 Haematological analyses |
| 8.1.2.5 Other (unspecified) analyses |
| 8.1.3 Transport of laboratory samples &specimens |
| 8.1.3.1 Toxicological analyses |
| 8.1.3.2 Biomedical analyses |
| 8.1.3.3 Arterial blood gas analysis |
| 8.1.3.4 Haematological analyses |
| 8.1.3.5 Other (unspecified) analyses |
| 8.2 Toxicological Analyses and Their Interpretation |
| 8.2.1 Tests on toxic ingredient(s) of material |
| 8.2.1.1 Simple Qualitative Test(s) |
| 8.2.1.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.1.3 Simple Quantitative Method(s) |
| 8.2.1.4 Advanced Quantitative Method(s) |
| 8.2.2 Tests for biological specimens |
| 8.2.2.1 Simple Qualitative Test(s) |
| 8.2.2.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.2.3 Simple Quantitative Method(s) |
| 8.2.2.4 Advanced Quantitative Method(s) |
| 8.2.2.5 Other Dedicated Method(s) |
| 8.2.3 Interpretation of toxicological analyses |
| 8.3 Biomedical investigations & their interpretation |
| 8.3.1 Biochemical analysis |
| 8.3.1.1 Blood, plasma or serum |
| 8.3.1.2 Urine |
| 8.3.1.3 Other fluids |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.3.4 Interpretation of biomedical investigations |
| 8.4 Other biomedical investigations |
| 8.5 Overall Interpretation |
| 8.6 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 Central Nervous System (CNS) |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Others |
| 9.4.7 Endocrine & reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ears, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid & electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Others |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other investigations |
| 10.3 Life supportive procedures |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases |
| 12. ADDITIONAL INFORMATION |
| 12.1 Availability of antidotes |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER (S), DATE (S) (INCLUDING UPDATES), COMPLETE ADDRESS (ES) |
1. NAME
1.1 Substance
Warfarin
1.2 Group
Coumarin derivative
1.3 Synonyms
Coumadin; Coumafene; Zoocoumarin
1.4 Identification numbers
1.4.1 CAS number
81-81-2 (unstated stereochemistry)
1.4.2 Other numbers
(R)-(+)-isomer CAS number: 5543-58-8
NIOSH RTECS GN4550000
1.5 Brand names, Trade names
1.6 Manufacturers, Importers
2. SUMMARY
2.1 Main risks and target organs
The target system is the haematological system, with
impairment of clotting. The main risks are associated with
potentially fatal gastrointestinal and intracerebral
haemorrhage.
2.2 Summary of clinical effects
If toxic amounts have been ingested, coagulation will be
impaired, with gum bleeding, epistaxis, ecchymosis,
haematomata, haematemesis, melenae, haematuria.
2.3 Diagnosis
The diagnosis is based on history of exposure (generally
by ingestion of a rodenticide); clinical evidence of
bleeding, which may appear 1 to 2 days post ingestion; and
abnormal prothrombin time.
A sample of the rodenticide should be kept for toxicological
analysis (if feasible). The most relevant biomedical analysis
is coagulation studies including:
Determination of clotting factors
Prothrombin time (PT)
Activated partial thromboplastin time (PTT)
2.4 First-aid measures and management principles
All cases of warfarin ingestion should be taken to a
hospital for initial clinical and laboratory evaluation. If
ingestion was recent administer activated charcoal. Gastric
emptying is not necessary if activated charcoal can be given
promptly, and should be avoided in patients who are already
anticoagulated.
If more than 24 hours have elapsed since ingestion,
decontamination measures are not effective and the patient
should be monitored closely using prothrombin time (PT) and
plasma thromboplastin time (PTT).
Treatment is based on the administration of vitamin K1
(phytomenadione) as indicated by the prothrombin time.
Fresh frozen plasma or whole blood are indicated in cases of
acute bleeding.
Close clinical observation is essential to detect occult
bleeding or life-threatening haemorrhage.
In cases of suspected serious ingestion, vitamin K1 is
indicated before signs and symptoms of haemorrhage
appear.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
It may be synthesised naturally from coumarins present
in many plants, such as sweet clover. It is usually prepared
synthetically by the Michael condensation of benzylidene-
acetone with 4- hydroxy-coumarin (Budavari, 1996).
3.2 Chemical structure
(RS)-4-hydroxy-3-(3-oxo-1-phenylbutyl)coumarin (IUPAC
name)
4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one (CA
name)
Relative molecular mass = 308.3
Molecular Formula C19H16O4
Warfarin is a racemic mixture of the two optical isomers
(Tomlin, 1994).
3.3 Physical properties
3.3.1 Colour
The racemate forms colourless crystals.
3.3.2 State/Form
Solid at room temperature.
3.3.3 Description
Solubility in water: 17 mg/L (20°C)
Sodium salt, up to 400 mg/L
Dissolves in aqueous alkalis with the formation of
water soluble salts.
Moderately soluble in metanol, ethanol, and
isopropanol. Acetone 65 g/L, dioxane 100 g/L (Tomlin,
1994).
Melting Point 161 to 162°C (Tomlin, 1994).
3.4 Other characteristics
Very stable, even to strong acids
4. USES/CIRCUMSTANCES OF POISONING
4.1 Uses
4.1.1 Uses
Anticoagulant rodenticide.
Therapeutic anticoagulant.
4.1.2 Description
Control of rats and mice. Commercial baits are
usually in a concentration of 0.02% warfarin. They may
be formulated as corn-meal or oats, or other grains.
There is no tendency to bait shyness. Warfarin is no
longer popular as a rodenticide because rats and mice
have become resistant (Tomlin, 1994).
It is available as the sodium salt of the racemic
mixture for use as an anticoagulant, in oral doses of
2 to 25 mg daily.
4.2 High risk circumstance of poisoning
Children may ingest baits, but single ingestions rarely
lead to symptoms.
Mislabelled warfarinised grains and flours used as food are
likely to lead to haemorrhagic syndromes.
The therapeutic use of warfarin may produce adverse effects
and in overdose a haemorrhagic syndrome.
4.3 Occupationally exposed populations
Poisoning may occur in occupations involving chronic
exposure to warfarin, eg people manufacturing warfarin,
formulating baits or applying the rodenticide (WHO,
1995).
5. ROUTES OF ENTRY
5.1 Oral
This is the commonest route of entry.
5.2 Inhalation
Absorption occurs via the respiratory system.
5.3 Dermal
Moderately absorbed through intact skin.
5.4 Eye
No data available.
5.5 Parenteral
Warfarin as the sodium salt has been administered
intravenously as a therapeutic agent.
5.6 Others
No data available.
6. KINETICS
6.1 Absorption by route of exposure
Gastrointestinal absorption of warfarin is rapid and
complete.
Significant transcutaneous uptake of warfarin caused many
cases of a hemorrhagic syndrome in infants (Martin-Bouyer et
al., 1984).
6.2 Distribution by route of exposure
Data from its use as a therapeutic agent show the the
volume of distribution to be very small (0.1 to 0.2 L/kg). It
is predominantly bound (99%) to serum albumin and other
plasma proteins (Baselt & Cravey, 1994)
6.3 Biological half-life by route of exposure
The average half-life of warfarin was found to be 36
hours in healthy volunteers; a range of 20 to 80 hours has
been reported in volunteers (Hackett et al., 1985; O'Reilly
et al., 1980).
The half-life of warfarin after a massive overdose of 2000 mg
in an adult was 21.7 hours (Hackett et al., 1985). The half-
life in another patient who overdosed on an unknown amount
was 53 hours (Renowden et al., 1985).
6.4 Metabolism
Warfarin is metabolized by oxidation to 6-
hydroxywarfarin and 7-hydroxywarfarin (both inactive
anticoagulants), and by reduction to a pair of
diastereoisomeric alcohols (active) (Trager et al.,
1970).
6.5 Elimination by route of exposure
Less than 1% of a dose is excreted unchanged in urine,
and essentially no unchanged warfarin is found in the faeces
(O'Reilly et al., 1962). Urinary excretion accounted for 16
to 43% of a single dose of the drug over a 6 day period,
apparently as the 7-hydroxy metabolite (O'Reilly et al.,
1963).
7. TOXICOLOGY
7.1 Mode of Action
Warfarin acts by blocking liver prothrombin production
and by causing vascular injury at the capillary level
(Baselt & Cravey, 1994).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Precise toxic doses are difficult to
determine since there is considerable
interindividual variation in response.
Toxicity has resulted from ingesting amounts
ranging from 500 to 1000mg over several days
(Baselt & Cravey, 1994).
The lowest toxic dose in humans ranges from
10 mg/kg to 15 mg/kg (RTECS, 1991).
Large amounts of warfarin containing grain
bait do not usually produce significant
toxicity because of the small concentration
of the warfarin and poor absorption in large
amounts of grain. However, fourteen reported
cases of accidental poisoning in Korea
involved eating cornmeal containing 0.25%
warfarin included in rat bait. The corn meal
was eaten over a period of 15 days. All 14
became severely ill with hemorrhage; two of
the 14 died. The estimated dosage was 1 to 2
mg/kg/day (Baselt & Cravey, 1994)
Persons with a history of blood disorders
with bleeding tendencies would be expected to
be at increased risk from exposure.
The minimum lethal exposure would depend in
part on whether or not an individual is on
anticoagulant therapy; individuals on therapy
would be expected to react to lower exposures
than non-treated persons.
7.2.1.2 Children
Extrapolation from the amount needed
in adults to acutely and reliably prolong the
PT (40 milligrams) predicts a dose of about
0.5 milligram/kilogram in children that would
be considered potentially toxic. This dose
resulted in PTs between 18 and 30 seconds in
children receiving a single loading dose
after heart valve surgery (Carpentieri et
al., 1976).
A 20-month-old child ingested approximately
50 milligrams (4 milligrams/ kilogram) of
warfarin sodium and subsequently developed
prolonged PT. The child, however, remained
asymptomatic with no signs of bleeding or
bruising (Montanio et al., 1993).
Death can occur from significant
transcutaneous uptake of warfarin. In August,
1981, paediatric hospitals in Ho Chi Minh
City (formerly Saigon), Vietnam, reported 741
cases of a haemorrhagic syndrome in infants.
The cause of this phenomenon was identified
as talcum powder contaminated with warfarin
in concentrations between 1.7 and 6.5 %. One
hundred seventy-seven (177) of the 741
reported cases died (Martin-Bouyer et al.,
1984).
7.2.2 Relevant animal data
Acute oral LD50 for rats is 186 mg/kg, mice 374
mg/kg. Oral LD50 for rats 1, pigs 1, cats 3, dogs 3,
cattle 200 (all mg/kg daily for 5 days) (Tomlin,
1994).
7.2.3 Relevant in vitro data
No data available
7.2.4 Workplace standards
TLV-TWA (Threshold limit value-Time weighted
average) 0.1 mg/m3 in air (ACGIH, 1992).
7.2.5 Acceptable daily intake (ADI) and other guideline
levels
No ADI has been established for warfarin.
7.3 Carcinogenicity
No data available.
7.4 Teratogenicity
Developmental effects have been reported when warfarin
has been administered as a therapeutic agent during
pregnancy. There are two types of defects dependent upon the
time of administration during pregnancy. The first, a
characteristic embryopathy decribed by the terms "warfarin
embryopathy" or "fetal warfarin syndrome", occurs from early,
first-trimester use. Fetal wastage and other abnormalities,
especially Central Nervous System anomalies, result from
treatment later during gestation (usually the second or third
trimesters) (WHO, 1995).
Nasal hypoplasia is the most consistant feature of warfarin
embryopathy. The other common feature is bone abnormalities
of the axial and appendicular skeleton. Other non-skeletal
abnormalities reported include opthalmological malformations,
low birth weight, mental retardation, hypotonia and ear
abnormalities (WHO, 1995)
Wafarin was found to be embryotoxic and teratogenic to Wistar
rats when administered by gavage in single doses or
repeatedly throughout the periods of pre-implantation (1 to 7
days of gestation) and organogenesis (8 to 16 days), and also
throughout the whole gestation (1 to 21 days) at a wide range
of dose levels (0.04 to 8 mg/kg body weight) (WHO,
1995).
7.5 Mutagenicity
No data available.
7.6 Interactions
Multiple drug interactions are known to alter the
anticoagulant effect of coumarins. A decreased anticoagulant
effect has been reported for barbiturates, carbamazepine,
cholestyramine, glutethimide, oral contraceptives and
rifampicin. An increased anticoagulant effect has been
reported with allopurinol, chloral hydrate, cimetidine,
disulfiram, indomethacin, quinidine, salycilates and
sulfonamides (Olson, 1994).
8. TOXICOLOGICAL ANALYSES & BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples & specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples &specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations & their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical investigations
8.5 Overall Interpretation
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Symptoms of poisoning usually occur after
repeated ingestions of warfarin. The degree of
haemorrhage depends on individual response, pre-
existing liver disease and current drug treatment.
After a variable period of time (between 1 and 7
days), external bleeding and internal haemorrhage may
occur from any site. Signs may include epistaxis,
gingival bleeding ( and in other miscellaneous
mucocutaneous sites), petechial rash, ecchymoses,
large haematomas (including intra-articular),
haematuria and melaena.
9.1.2 Inhalation
Effects are similar to those of ingestion.
9.1.3 Skin exposure
Human warfarin intoxication by dermal
absorption has been described after prolonged (>24
hours) upper extremity contact with an oil-based
warfarin solution. Two days post exposure, haematuria
and subcutaneous haematomas appeared, followed by
epistaxis and mucocutaneous bleeding from the mouth
(Fristedt & Sterner 1965)
9.1.4 Eye contact
No data available.
9.1.5 Parenteral exposure
Warfarin as the sodium salt has been
administered intravenously as a therapeutic agent and
in an overdose situation would presumably produce
effects similar to those of ingestion.
9.1.6 Other
No relevant data available.
9.2 Chronic poisoning
9.2.1 Ingestion
Repeated ingestion of warfarin causes the same
haemorrhagic risks as acute exposure because of the
cumulative effects on serum concentrations of the
clotting factors.
9.2.2 Inhalation
Poisoning by inhalation can occur and symptoms
are similar to those of ingestion.
9.2.3 Skin exposure
Haematomas, epistaxis, punctate haemorrhages of
the palate and mouth, bleeding from the lower lip have
been reported following prolonged percutaneous
exposure (Proctor et al., 1988).
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
No data available.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Symptoms of poisoning usually occur after repeated
ingestions of warfarin. The degree of haemorrhage depends on
individual response, pre-existing liver disease and current
drug treatment. After a variable period of time (between 1
and 7 days), external bleeding and internal haemorrhage may
occur from any site. Death is usually due to shock from
intracranial haemorrhage or massive gastrointestinal
bleeding (WHO, 1995).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Hypotension may occur as a result of
haemorrhage due to warfarin therapy (Papagiannis et
al., 1995).
9.4.2 Respiratory
Dysphonia, dysphagia, dyspneoa and inability to
clear secretions have been reported (Boster & Bergin,
1983).
9.4.3 Neurological
9.4.3.1 Central Nervous System (CNS)
Weakness, confusion, or signs of
increased intracranial pressure secondary to
bleeding may occur. Cerebrovascular accidents
may occur in severe poisoning cases (WHO,
1995).
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
Haemarthrosis may occur and cause
joint pain.
9.4.4 Gastrointestinal
Haematemesis and malena may occur (WHO, 1995).
9.4.5 Hepatic
Although the liver is the site of metabolism of
warfarin, no observable clinical effects are apparent,
except coagulopathy.
9.4.6 Urinary
9.4.6.1 Renal
Haematuria may be clinically evident
(WHO, 1995).
9.4.6.2 Others
No data available.
9.4.7 Endocrine & reproductive systems
No data available.
9.4.8 Dermatological
Petechial rashes may be seen.
9.4.9 Eye, ears, nose, throat: local effects
Epistaxis and gum bleeding (WHO, 1995).
9.4.10 Haematological
Coagulation is impaired after ingestion of
significant quantities of warfarin. The usual
haematological symptoms gingival bleeding, epistaxis,
ecchymoses, haematoma, and haematuria. There may be
internal bleeding (WHO, 1995).
9.4.11 Immunological
No data available.
9.4.12 Metabolic
No data available.
9.4.12.1 Acid-base disturbances
No data available.
9.4.12.2 Fluid & electrolyte disturbances
No data available.
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
No data available.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Developmental effects have been reported when
warfarin has been administered as a therapeutic agent
during pregnancy. There are two types of defects
dependent upon the time of administration during
pregnancy. The first a characteristic embryopathy
decribed by the terms "warfarin embryopathy" or "fetal
warfarin syndrome", occurs from early, first-trimester
use. Fetal wastage and other abnormalities, especially
CNS anomalies, result from treatment later during
gestation (usually the second or third trimesters)
(WHO 1995).
Nasal hypoplasia is the most consistant feature of
warfarin embryopathy. The other common feature is bone
abnormalities of the axial and appendicular skeleton.
Other non-skeletal abnormalities reported include
opthalmological malformations, low birth weight,
mental retardation, hypotonia and ear abnormalities.
(WHO, 1995).
9.5 Others
9.6 Summary
10. MANAGEMENT
10.1 General principles
All cases of warfarin ingestion should be taken to a
hospital for initial clinical and laboratory evaluation. If
ingestion was recent administer activated charcoal. Gastric
emptying is not necessary if activated charcoal can be given
promptly, and should be avoided in patients who are already
anticoagulated.
If more than 24 hours have elapsed since ingestion,
decontamination measures are not effective and the patient
should be monitored closely using prothrombin time (PT) and
plasma thromboplastin time (PTT).
Treatment is based on the administration of vitamin K1
(phytomenadione) as indicated by the prothrombin time.
Fresh frozen plasma or whole blood are indicated in cases of
acute bleeding.
Close clinical observation is essential to detect occult
bleeding or life-threatening haemorrhage.
In cases of suspected serious ingestion, vitamin K1 is
indicated before signs and symptoms of haemorrhage appear
(Olson 1994)
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Collect a sample of the product, blood/ urine/faeces.
10.2.2 Biomedical analysis
Prothrombin time (PT) monitoring is essential.
For the first 5 to 6 days it should be done at least
daily, and repeated even if results were normal upon
admission. Prothrombin time may initially be normal,
even in a severe poisoning because vitamin K-dependent
clotting factors have a long half-life and are still
circulating several hours after warfarin starts its
effect.
Activated partial thromboplastin time (PTT) is
abnormal.
Coagulation tests in general may be normal (e.g.
coagulation time, thromboelastogram).
Haemoglobin
Red blood count
Urinalysis (haematuria)
Stools
10.2.3 Toxicological analysis
Although a sensitive HPLC technique exists, it
is not clinically useful.
10.2.4 Other investigations
Specific organ evaluation for bleeding as
clinically indicated.
10.3 Life supportive procedures
Life-saving procedures are indicated if serious
complications arise.
Symptomatic treatment for bleeding is the administration of
fresh frozen plasma or fresh whole blood for correcting
coagulopathy.
10.4 Decontamination
If more than 24 hours have elapsed since exposure,
decontamination measures are not effective and the patient
should be monitored closely using prothrombin time (PT) and
plasma thromboplastin time (PTT).
If ingestion was recent administer activated charcoal.
Gastric emptying is not necessary if activated charcoal can
be given promptly, and should be avoided in patients who are
already anticoagulated.
10.5 Elimination
There is no role for enhanced elimination procedures
(Olson 1994).
10.6 Antidote treatment
10.6.1 Adults
Phytomenadione (vitamin K1) should be
administered. If prothrombin time is significantly
reduced vitamin K1 should be administered
intravenously starting with 10mg each 6 hours (40
mg/day). The intramuscular route may be chosen under
appropriate clinical settings. The dosage should be
adjusted according to the prothrombin time.
10.6.2 Children
Indication and dosage is the same as in
adults.
10.7 Management discussion
There is no concensus on the appropriate administration
schemes for vitamin K. Some authors give oral vitamin K
prophylactically in cases where ingestion is uncertain. The
usual route for treatment is intravenous, although in some
cases it has been given intramuscularly or subcutaneously.
The use of phenobarbital as an hepatic microsomal enzyme
inducer is controversial.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
A farmer whose hands were intermittently wetted with an
0.5% solution of warfarin over a period of 24 days developed
gross haematuria 2 days after the last contact with the
solution. The following day, spontaneous haematomas appeared
on the arms and legs. Within 4 days, other effects included
epistaxis, punctate haemorrhages of the palate and mouth, and
bleeding from the lower lip. Four days later, after treatment
for 2 days with vitamin K1, haematologic indices had returned
to the normal range (Proctor et al., 1988).
Fourteen members of a family in the Republic of Korea were
poisoned by eating warfarin-containing maize meal. The first
symptoms appeared 7 to 10 days after the beginning of
exposure and were followed by massive bruises or haemtomata
on the buttocks in all cases (WHO, 1995).
In August, 1981, paediatric hospitals in Ho Chi Minh City
(formerly Saigon), Vietnam, reported 741 cases of a
haemorrhagic syndrome in infants. The cause of this
phenomenon was identified as talcum powder contaminated with
warfarin in concentrations between 1.7 and 6.5 percent. One
hundred seventy-seven (177) of the 741 reported cases died
(Martin-Bouyer et al., 1984).
A 73-year-old woman suffered from recurrent episodes of
hypothrominaemia. Clotting tests and further investigation
showed that this was due to a warfarin rodenticide
intentionally mixed in the woman's cough syrup by her
daughter-in-law (WHO, 1995).
A 39-year-old female presented with symptoms of headache,
dyspneoa, nausea, vomiting, and double vision. She had been
administering weekly applications of a warfarin-type rat
poison, with her bare hands, to areas of her house. She
would not routinely wash her hands afterwards. The patient's
PT and PTT were prolonged (31.1 and 59.9 seconds
respectively). A CT scan of her head revealed an
intercerebellar haematoma (Abell et al., 1994).
11.2 Internally extracted data on cases
11.3 Internal cases
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes
12.2 Specific preventive measures
12.3 Other
13. REFERENCES
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14. AUTHOR(S), REVIEWER (S), DATE (S) (INCLUDING UPDATES),
COMPLETE ADDRESS (ES)
Authors: Prof R Merad
Centre Anti-Poisons
Algiers
February, 1988
Steven K Galson
IPCS/WHO
Geneva
April, 1989
Peer review: Strasbourg, France, April 1990
Newcastle-upon-Tyne, January 1991
Revision: Dr W A Temple
National Toxicology Group
University of Otago
Dunedin
New Zealand
February, 1997
Editor: M.Ruse
Finalised: IPCS, Geneva, April 1997