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WARFARIN TOXICITY MANAGEMENT
10 : 6
Subir Kumar Banerjee, Kaushik Saha, Somnath Maitra, Kolkata
ABSTRACT
Warfarin also known as coumadin belongs to a class of medications known as anticoagulation. It
is used to prevent blood clots in certain medical conditions. Warfarin works by preventing platelets
from sticking together to form blood clots.
Warfarin can cause serious bleeding especially when it is taken without proper monitoring. INR
is supposed to be the best method for monitoring of warfarin. Management of warfarin toxicity is
done by stoppage of warfarin initially and then administration of Vit-K, FFP, Factor Concentrate and
Prothrombin complex concentrate.
INTRODUCTION
The coumarin derivative warfarin, which was licensed in the United States in 1954 as the first human
anticoagulant,1 remains the most commonly used oral anticoagulant in North America and the United
Kingdom.2,3 Warfarin exerts its anticoagulant effect by acting as a vitamin K antagonist and inhibiting
the biosynthesis of vitamin K-dependent procoagulant factors II, VII, IX and X.2,4,5 The maximum
dose effect occurs up to 48 hr after administration of a single dose and persists for the next 5 days.6
Nonetheless, in 1995 the Agency for Healthcare Policy and Research (AHCPR)7 reported that warfarin
is greatly underutilized for stroke prevention. The AHCPR noted that physicians are reluctant to
prescribe warfarin, in part because they are not familiar with techniques for administering the drug
safely and fear that the drug will cause bleeding. Patients treated with warfarin do require close
monitoring to avoid bleeding but it has been shown that the drug prevents 20 strokes for every
bleeding episode that it causes.
Warfarin overdose results from the administration of inappropriately high doses, altered protein
binding, decreased vitamin K intake, reduced synthesis or increased clearance of vitamin K-dependent
clotting factors and the simultaneous use of other drugs (e.g. Erythromycin, fluconazole, amiodarone,
propranalol, proxicam, and omeprazole) that compete with warfarin for protein binding.8
Warfarin therapy is challenging because of substantial individual variations in dosage requirements
that make over-anticoagulation common.2,8 In addition, because warfarin has a narrow therapeutic
window, treatment frequently results in bleeding, sometimes major or life-threatening.9 Major
bleeding, typically involving the gastrointestinal or urinary tracts or soft tissue, occurs in up to
6.5% of anticoagulated patients per year.10 The incidence of fatal bleeding, primarily Intracranial
hemorrhage (ICH), is approximately 1% annually.10-14 The risk of hemorrhage increases with the
intensity of warfarin anticoagulation; the variable most consistently associated with bleeding risk is
elevation of the international normalized ratio(INR), a standardized prothrombin time.2,3 For most
warfarin indications, the target maintenance INR is 2.0 to 3.10,15 However, the risk of bleeding is
heightened even at low anticoagulation intensity (INR < 2.0),13 and increases exponentially when
the INR exceeds 5.0.12,13
The goal of urgent warfarin reversal is to elevate or replace vitamin K-dependent clotting factors.16 The
method used is determined by the INR and the clinical seriousness of the bleeding event.2,16 Oral doses
532
Warfarin Toxicity Management
of vitamin K achieve partial reversal within 24 hr. whereas
intravenous (IV) administration reverses anticoagulation
within 4-8 hr.2,16 High doses will not further shorten the time
to anticoagulation reversal but may lower INR more than is
necessary and cause warfarin resistance that persists for up
to 1 week.17
There is general consensus that major or life-threatening
bleeding requires rapid and complete warfarin reversal.2,18
Fresh frozen plasma (FFP) is widely available and provides fast,
partial reversal of the coagulopathy through the replacement
of exogenous factors II,VII, IX, and X (F II, F III. FIX and
FIX.19 FFP is considered the general standard of care in the
United States, and although the optimal dose has not been
established, FFP is most often administered in a dose of 15
ml/kg.20 Volume overload may make it difficult to administer
an adequate FFP dose, particularly since patients often have
compromised cardiovascular systems.2,3,,21 FFP contains
isohemagglutinins and must be blood group specific.22 It also
must be thawed before use, which can delay treatment, and
infection transmission is a potential risk.3 In patients with
very dependent factors, replacement of hemostatic levels of
these factors cannot be achieved with tolerable doses of FFP.
Furthermore, the administration of FFP in recommended
doses is often insufficient to normalize FIX levels.18
MANAGEMENT OF PATIENTS WITH WARFARIN
TOXICITY
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; 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.
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).23 In contrast, the INR declines
substantially within 24 hours after treatment with vitamin
K1.24
Even when the INR is excessively prolonged, the absolute
daily risk of bleeding is low, leading many physicians to
manage patients with INR levels as high as 5 to 10 by stopping
warfarin expectantly, unless the patient is at intrinsically high
risk of bleeding or bleeding has already developed. Ideally,
vitamin K1 should be administered in a dose that will quickly
lower the INR into a safe but not subtherapeutic range without
causing resistance once warfarin is reinstated or exposing the
patient to the risk of anaphylaxis. Though effective, high doses
of Vitamin K1 (e.g. 10 mg) may lower the INR more than
necessary and lead to warfarin resistance for up to a week.
Vitamin K1 can be administered intravenously, subcutaneously,
or orally, intravenous injection produces a rapid response but
may be associated with anaphylactic reactions, and there is no
proof that this rare but serious complication can be avoided
by using low doses. The response to subcutaneous vitamin K1
is unpredictable and sometimes delayed.23,25 In contrast, oral
administration is predictably effective and has the advantages
of convenience and safety over parenteral routes. In patients
with excessively prolonged INR values, vitamin K1, 1 mg to
2.5 mg orally, more rapidly lowers the INR to < 5 within 24
hours than simply withholding warfarin.26 In a prospective
study of 62 warfarin-treated patients with INR values between
4 and 10, warfarin was omitted, and vitamin K1, 1 mg was
administered orally. 23,27 After 24 hours, the INR was lower in
95%, <4 in 85% and < 1.9 in 35%. None displayed resistance
when warfarin was resumed. These observations indicate that
oral vitamin K1 in low doses effectively reduced the INR in
patients treated with warfarin. Oral vitamin K1 1.0 to 2.5 mg,
is sufficient when the INR is between 4 and 10, but larger
doses (5 mg) are required when the INR is > 10.
Oral vitamin K1 is the treatment of choice unless very rapid
reversal of anticoagulation is critical, when vitamin K1 can be
administered by slow intravenous Infusion (5 to 10 mg over 30
minutes). In 2001, the American College of Chest Physicians
published the following recommendations for managing
patients on coumarin anticoagulations who need their INRs
lowered because of either actual or potential bleeding.28
1. When the INR is above the therapeutic range but <5, the
patient has not developed clinically significant bleeding,
and rapid reversal is not required for surgical intervention, the dose of a warfarin can be reduced or the next
dose omitted and resumed (at a lower dose) when the
INR approaches the desired range.
2. If the INR is between 5 and 9 and the patient is not
bleeding and has no risk factors that predispose to bleeding, the next 1 to 2 doses of warfarin can be omitted and
warfarin reinstated at a lower dose when the INR falls
into the therapeutic range. Alternatively, the next dose of
warfarin may be omitted and vitamin K1 (1 to 2.5 mg)
given orally. This approach should be used if the patient
is at increased risk of bleeding.
3. When more rapid reversal is required to allow urgent
surgery or dental extraction, vitamin K1 can be given
orally in a dose of 2 to 5mg anticipating reduction of the
INR within 24 hours. An additional dose of 1 to 2 mg
vitamin K can be given if the INR remains high after 24
hours.
4. If the INR is > 9 but clinically significant bleeding has
not occurred, Vitamin K1, 3 to 5 mg, should be given
orally, anticipating that the INR will fall within 24 to 48
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Medicine Update 2012  Vol. 22
hours. The INR should be monitored closely and vitamin K repeated as necessary.
1. When rapid reversal of anticoagulation is required because of serious bleeding or major warfarin overdose
(e.g. INR >20), vitamin K1 should be given by slow
intravenous infusion in a dose of 10 mg, supplemented
with transfusion of fresh plasma or prothrombin complex concentrate, according to the urgency of the situation. It may be necessary to give additional doses of
vitamin K1 every 12 hours.
2. In cases of life-threatening bleeding or serious warfarin
overdose, Prothrombin complex concentrate replacement therapy is indicated, Supplemented with 10 mg of
vitamin K1 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.
•
If INR > 8.0 and no bleeding or minor bleeding then :
•
stop warfarin
•
restart warfarin when INR < 5.0
•
If other risk factors for bleeding then give 0.5-2.5
mg
If major bleeding then :
•
An algorithm for the management of bleeding and excessive
anticoagulation was included in the 1998 anticoagulation
guidelines:23
•
If 3.0 <INR < 6.0 (target INR 2.5) then :
•
reduce warfarin dose/stop warfarin
•
restart warfarin when INR <5.0
•
If 4.0 < INR < 6.0 (target INR 3.5)
•
reduce warfarin/stop warfarin
•
restart warfarin when INR < 5.0
•
If 6.0 < INR < 8.0 and no bleeding or minor bleeding
then :
•
stop warfarin
•
restart when INR < 5.0
stop warfarin
Managing bleeding and excessive anticoagulation
•
reversal of anticoagulation with vitamin K is achieved
more rapidly with intravenous administration than oral
administration
•
in the original guideline an option of 5 mg of Vitamin K
orally or intravenously was recommended for patients
with major bleeding,1 in addition to factor replacement
therapy with either a factor concentrate or fresh frozen
plasma (FFP). The updated guideline5 now considers
that, in patients with major bleeding, reversal with intravenous vitamin K is preferable. A dose of either 5 or
10 mg is recommended. Complete and rapid reversal
of over-anticoagulation is more readily achieved with a
factor concentrate than with FFP.
Intravenous vitamin K should be given if reversal is to
be sustained. The guideline recommends that reversal of
anticoagulation in patients with major bleeding requires
administration of a factor concentrate in preference to
FFP, when this is available and administration of intravenous rather than Oral Vitamin K and administration of
intravenous rather than oral vitamin K.28
3. 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.29
4. Recombinant factor VIIa has been shown to correct INR
within hours.30,31,32 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.31-34
Of oral vitamin K
Unexpected bleeding at therapeutic levels :
•
Investigate for possible cause e.g. alimentary or renal
disease.
SUMMARY
Judicious use of warfarin in treating and preventing blood
clots, especially in deep vein thrombosis and pulmonary
thromboembolism should be the first cautious steps to keep
warfarin toxicity at a distance. INR is by for the best method
for monitoring warfarin toxicity. The management should be
initiated promptly. Stoppage of warfarin with regular check
up of INR is the cornerstone of treatment.
Once bleeding starts and INR is very high, Vit K, FFP, Factor
concentrate and PCC have shown to be very effective.
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