Warfarin toxicity

Anticoagulant toxicity
managment

Warfarin Toxicity
• Overdose of the oral anticoagulant
warfarin
• or drug interactions with warfarin,
can lead to toxicity.
• Similarly, toxicity can result from
exposure to superwarfarins, which
are long-acting anticoagulants used
in rodenticides.

Etiology
• Coumarins inhibit hepatic synthesis of the
vitamin K ̶ dependent coagulation factors II,
VII, IX, and X and the anticoagulant proteins C
and S.
• Vitamin K is a cofactor in the synthesis of
these clotting factors.
• The vitamin K ̶ dependent step involves
carboxylation of glutamic acid residues and
requires regeneration of the used vitamin K
back to its reduced form.

• Coumarins and related compounds
inhibit vitamin K1 -2,3 epoxide
reductase, preventing vitamin K from
being reduced to its active form. The
degree of effect on the vitamin K ̶
dependent proteins depends on the
dose and duration of treatment with
warfarin.

• The oral bioavailability of warfarin and the
superwarfarins is nearly 100%.
• Warfarin is highly bound (approximately
97%) to plasma protein, mainly albumin.
• The high degree of protein binding is one
of several mechanisms whereby other
drugs interact with warfarin.
• It does not appear to be distributed to
breast milk in significant amounts.
• It crosses the placenta and is a known
teratogen.

• The duration of anticoagulant effect
after a single dose of warfarin is
usually 5-7 days.
• However, superwarfarin products
may continue to produce significant
anticoagulation for weeks to months
after a single ingestion.
• In one reported overdose case with
measured serum levels, the half-life
of brodifacoum was 56 days.

• Warfarin is metabolized by hepatic
cytochrome P-450 (CYP)
isoenzymes predominantly to
inactive hydroxylated metabolites,
which are excreted in the bile

Drugs that inhibit warfarin metabolism include
the following:
• Allopurinol/Amiodarone
• Azole antifungals/ Cephalosporin antibiotics
• Chloramphenicol/ Chlorpropamide
• Cimetidine/ Cotrimoxazole
• Macrolide antibiotics/ Omeprazole
• Penicillin antibiotics/ Quinolone antibiotics
• Statins (particularly lovastatin and pravastatin)
• Tolbutamide/Zafirlukast
• Zileuton
Antibiotics can inhibit the activity of vitamin K,
possibly due to decreased gastrointestinal (GI)
flora synthesis of vitamin K.

• An additive anticoagulant effect is
produced by the following drugs:
• Aspirin
• Clopidogrel
• Heparin
• Low ̶ molecular weight heparin
• Direct thrombin inhibitors (eg,
argatroban, lepirudin)

Drugs that interfere with protein
binding include the following:
• Clofibrate
• Diazoxide
• Miconazole (including intravaginal
use)
• Nalidixic acid (displaces protein
binding)
• Salicylates
• Sulfonamides
• Sulfonylureas

Drugs that can reduce PT by decreasing the
warfarin effect
• The following drugs cause inhibition of warfarin
absorption:
• Cholestyramine
• Sucralfate
• Colestipol
• The following drugs cause enhanced warfarin
metabolism:
• Barbiturates
• Carbamazepine
• Phenytoin
• Rifampin

The following foods have a very high
vitamin K content (> 200 mcg):
• Coriander
• Liver
• Parsley
• Red leaf lettuce
• Spinach
• Black/green teas
• Broocli
• Cucumber
• cabbage

Prognosis
1. Bleeding is the primary adverse effect of
warfarin toxicity and is related to:
• the intensity of anticoagulation,
• length of therapy,
• the patient's underlying clinical state, and
• use of other drugs that may affect
hemostasis or interfere with warfarin
metabolism.
• Fatal or nonfatal hemorrhage may occur
from any tissue or organ.

• Major bleeding complications include GI
hemorrhage, intracranial bleeding, and
retroperitoneal bleeding. Massive hemorrhage
usually involves the GI tract but may involve
the spinal cord or cerebral, pericardial,
pulmonary, adrenal, or hepatic sites.
• Generally, a single ingestion of warfarin (10-20
mg) does not cause serious intoxication.
• In contrast, chronic or repeated ingestion of
even small amounts of warfarin (2-5 mg/day)
eventually can lead to significant
anticoagulation, especially in the presence of
interacting drugs.

• Patients with hepatic dysfunction,
malnutrition, or a bleeding diathesis are
at the greatest risk of toxicity from
warfarin use.
• Superwarfarins are extremely potent
and can produce prolonged effects
even after a small ingestion; as little as
1 mg in an adult can cause
coagulopathy.

• Do not expect to see physical evidence
of bleeding after an acute ingestion for at
least 24 hours.
• More common findings of excessive
anticoagulation are subconjunctival
hemorrhage, epistaxis, vaginal bleeding,
bleeding gums, or hematuria.
• In all patients, if prolongation of the PT is
observed after an acute ingestion, it may
appear in as early as 8-12 hours;
however, peak effects commonly are
delayed until at least 1-2 days

Workup
• Blood levels of warfarin are neither
readily available nor helpful.
• Specific levels of superwarfarin
rodenticides (eg, brodifacoum) may
be useful in cases in which the
ingestion is denied or for purposes of
estimating the necessary duration of
vitamin K1 therapy.
• However, most reference laboratories
do not perform this analysis.

• The anticoagulant effect is best
quantified by baseline and daily
repeated measurement of the
prothrombin time (PT) and the
International Normalized Ratio
(INR).
• If intracranial bleeding is suspected,
obtain a noncontrast computed
tomography (CT) scan of the head

• There is a close relation between the
INR and risk of bleeding. The risk of
bleeding increases when the INR
exceeds 4, and the risk rises sharply
with values > 5.
• Three approaches can be taken to
lower an elevated INR.

• The first step: is to stop warfarin;
• the second is to administer vitamin K1;
Significant superwarfarin poisoning may
require many weeks of vitamin K1
therapy.
• and the third and most rapidly effective
measure is to infuse fresh plasma or
prothrombin concentrate.
• The choice of approach is based largely
on clinical judgement because no
randomized trials have compared these
strategies with clinical end points.

• Administer activated charcoal for
recent (within the last 1 - 2 hours)
clinically significant ingestions (only in
acute ingestion).

• After warfarin is interrupted, the INR
falls over several days (an INR
between 2.0 and 3.0 falls to the
normal range 4 to 5 days after
warfarin is stopped).
• In contrast, the INR declines
substantially within 24 hours after
treatment with vitamin K1

• 10 mg of vitamin K1given by slow
intravenous infusion; This can be
repeated, according to the INR,.
• If warfarin is to be resumed after
administration of high doses of
vitamin K, then heparin can be given
until the effects of vitamin K have
been reversed and the patient again
becomes responsive to warfarin.

• Phytonadione (Vitamin K1) can overcome
competitive block produced by warfarin and
other, related anticoagulants. (Note that
vitamin K3 [menadione] is not effective for this
purpose.) The clinical effect is delayed for
several hours while liver synthesis of clotting
factors is initiated and plasma levels of clotting
factors II, VII, IX, and X are gradually restored.
• Vitamin K1 is not to be administered
prophylactically; use only if evidence of
anticoagulation exists. The required dose
varies with the clinical situation, including the
amount of anticoagulant ingested and whether
it is a short-acting or long-acting anticoagulant.

• Early PCC products, including those
currently available in the United
States, contain factors II, IX and X.
Newer products include factor VII.
Some contain protein C and protein
Z, antithrombin II, and /or heparin.
Across 4-factor products however,
there appears to be rapid reversal of
coagulopathy within 10-30 minutes

• Recombinant factor VIIa has been shown
to correct INR within hours.
• the potential benefits of rFVIIa or PCC over
FFP include rapid Administration (because
rFVIIa and PCC do not have to be
thawed), smaller infusion volumes, and
decreased risk of transfusion-associated
adverse reactions.
• Studies have shown improvement only of
secondary end points, such as intracranial
hematoma size, total volume of blood
products, and time to operative intervention

Heparin toxicity
• when clinical circumstances
(bleeding) require reversal of
heparinization, protamine sulfate
(1% solution) by slow infusion will
neutralize heparin sodium.
• No more than 50 mg should be
administered, very slowly in any 10
minute period.

• Administration of protamine sulfate
can cause severe hypotensive and
anaphylactoid reactions.
• Because fatal reactions often
resembling anaphylaxis have been
reported, the drug should be given
only when resuscitation techniques
and treatment of
anaphylactoid shock are readily
available.

Streptokinase toxicity
• 1- aminocaproic acid; tissue
plasminogen activator inhibitor.
• 2- fibrinogen infusion
• Fresh whole blood

Warfarin toxicity

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