Management of Warfarin-Associated Bleeding or Supratherapeutic INR

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Management of warfarin-associated bleeding or supratherapeutic INR

Authors: Russell D Hull, MBBS, MSc, David A Garcia, MD
Section Editor: Lawrence LK Leung, MD
Deputy Editor: Jennifer S Tirnauer, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2022. | This topic last updated: Aug 23, 2022.
INTRODUCTION
Warfarin is associated with an increased risk of bleeding, as are a variety of other anticoagulants. The effect of warfarin has great inter-
and intra-individual variation based on a variety of genetic, dietary, and medication effects.
This topic discusses risk factors for warfarin-associated bleeding and poor international normalized ratio (INR) control and presents an
approach to the management of a patient with warfarin-associated bleeding or an INR above the therapeutic range (ie, a
supratherapeutic INR).
The following special populations are discussed in separate topic reviews:
● Intracerebral hemorrhage – (See "Reversal of anticoagulation in intracranial hemorrhage".)
● Surgery/invasive procedure – (See "Perioperative management of patients receiving anticoagulants".)
● Patient with a prosthetic heart valve – (See "Antithrombotic therapy for prosthetic heart valves: Management of bleeding and
invasive procedures".)
https://www.uptodate.com/contents/management-of-warfarin-associated-bleeding-or-supratherapeutic-inr/print 1/41
A discussion of factors that affect warfarin dosing and a review of warfarin administration and other complications are presented
separately. (See "Biology of warfarin and modulators of INR control" and "Warfarin and other VKAs: Dosing and adverse effects".)
MITIGATING BLEEDING RISK
The risk of major bleeding in patients treated with warfarin is related to the degree of anticoagulation as well as patient characteristics
and comorbidities [1-20]. Importantly, some of these risk factors are modifiable, and addressing modifiable risk factors may ultimately
reduce the risks of both bleeding and thrombosis. Even patients with a therapeutic INR can have an increased risk of bleeding, especially
those older than 70 years of age [21-23]. A comprehensive discussion of risk factors and risk reduction is presented separately. (See
"Risks and prevention of bleeding with oral anticoagulants".)
The INR above which bleeding risk increases further varies among studies. Studies in patients with atrial fibrillation indicate that the risk
of bleeding increases substantially at INR values ≥5 ( figure 1), although other studies including those with other patient populations
have shown an increased risk of bleeding when the INR is >3.0 or 3.5 ( figure 2) [24-26]. Isolated supratherapeutic INR values in
asymptomatic patients appear to be associated with a low risk of bleeding within 30 days, provided the warfarin dose is adjusted
promptly [22]. Factors that contribute to a supratherapeutic INR are discussed in detail separately. (See "Biology of warfarin and
modulators of INR control", section on 'Risk factors for supratherapeutic INR'.)
A number of bleeding risk scores have been developed and validated, mostly in patients receiving warfarin for atrial fibrillation.
However, these scores generally do not perform significantly better than clinician judgment based on close consideration of patient
characteristics. Further details are discussed separately. (See "Risks and prevention of bleeding with oral anticoagulants", section on
'Bleeding risk scores'.)
TREATMENT OF BLEEDING
As a general rule, patients with serious or life-threatening bleeding require rapid, full reversal of any warfarin effect, whereas those with
no bleeding or minor bleeding may be best served by holding warfarin without administration of a reversal agent, especially if the
underlying thrombotic risk is particularly high.
Serious/life-threatening bleeding — The following is appropriate for serious or life-threatening bleeding ( table 1) [27-31]:
● Discontinue warfarin
● Vitamin K – Administer 10 mg vitamin K by slow intravenous infusion (eg, over 20 to 60 minutes). For most patients receiving
warfarin who have severe, obvious bleeding, vitamin K can be administered without waiting for laboratory tests or imaging studies
because the risks associated with vitamin K are low, and if the patient requires reinitiation of anticoagulation while refractory to
warfarin, another agent such as heparin can be used. Vitamin K may be repeated at 12-hour intervals if the INR remains elevated.
(See 'Vitamin K dose, route, formulation' below.)
● PCC – For patients with serious bleeding and INR >2, we suggest using a 4-factor prothrombin complex concentrate (PCC,
unactivated) ( table 2) rather than a 3-factor PCC and/or Fresh Frozen Plasma (FFP) for rapid reversal, due to the similar efficacy
and lower risk of adverse events with 4-factor PCC.
PCC can be administered using a fixed dose, as illustrated in the table ( table 3), or using a regimen that calculates the dose
based on the patient's weight and the INR at presentation; a typical dose for INR >6 is 50 units/kg [32]. We generally suggest a fixed
dose for greater ease of use and faster treatment. Institutional protocols should be followed. (See 'Dosing' below.)
Constituents of PCC products, evidence for efficacy, and thrombotic risks are presented below. (See 'PCC products' below.)
● Monitoring – Recheck the prothrombin time (PT)/INR at approximately 30 minutes following PCC administration, and periodically
thereafter, with the frequency determined by the severity of bleeding. Repeat dosing of PCC is generally not needed for individuals
treated with a dose based on the patient's weight and INR; however, if bleeding is truly life-threatening and the INR remains
elevated, a second dose may be reasonable. Consultation with an expert in anticoagulant management may be helpful. If a fixed
dose regimen of 1000 or 2000 units was used and the INR remains elevated, a second dose may be required for full reversal. (See
'PCC products' below.)
● Other agents – Antifibrinolytic agents such as tranexamic acid or epsilon-aminocaproic acid may be used in some settings (eg,
oral/mucosal bleeding). Desmopressin (DDAVP) may be used for platelet dysfunction. (See "Management of bleeding in patients
receiving direct oral anticoagulants", section on 'Antifibrinolytics and other pro-hemostatic therapies'.)
Recombinant activated factor VII (rFVIIa) generally is not used to treat warfarin-associated bleeding, because it does not supply the
other vitamin K-dependent factors affected by warfarin, although there are reports of its use [33,34]. Thromboembolic events after
rFVIIa administration have been reported. (See "Recombinant factor VIIa: Administration and adverse effects", section on
'Thromboembolic complications'.)
● Transfusions
• Platelets – Platelet transfusion may be used if a patient is bleeding in the setting of thrombocytopenia. In the event of warfarin-
associated major bleeding, some experts use a target platelet count of >50,000/microL and others use a target platelet count of
>100,000/microL, especially for life-threatening bleeding. (See "Platelet transfusion: Indications, ordering, and associated risks",
section on 'Actively bleeding patient'.)
• RBCs – Transfusions of red blood cells (RBCs) are based on hemoglobin levels and/or estimated blood loss for rapid ongoing
bleeding. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Acute bleeding'.)
• FFP – Fresh Frozen Plasma (FFP) may be given if no PCC is available (initial dose 15 to 30 mL/kg), or if the patient is receiving
massive transfusions for severe ongoing bleeding (see "Massive blood transfusion"). Doses of FFP required to replace
coagulation factors often involve multiple units of FFP, which must be thawed and may take hours to administer, with risks of
volume overload and transfusion reactions. (See "Approach to the patient with a suspected acute transfusion reaction", section
on 'Types of acute transfusion reactions'.)
Additional considerations in patients with prosthetic heart valves or intracerebral bleeding are presented separately. (See "Reversal of
anticoagulation in intracranial hemorrhage" and "Antithrombotic therapy for prosthetic heart valves: Management of bleeding and
invasive procedures", section on 'Management of overanticoagulation and bleeding'.)
Urgent surgery/procedure — On occasion, it is necessary to temporarily reverse anticoagulation for surgery or other invasive
procedure. Management in this setting depends on the urgency and bleeding risk of the procedure and the rapidity with which reversal
is required. The urgency of the procedure and necessity of reversing warfarin should be determined in consultation with the
surgeon/interventionist. (See "Perioperative management of patients receiving anticoagulants", section on 'Deciding whether to
interrupt anticoagulation'.)
● Urgent – For those requiring urgent (eg, same day) reversal, we suggest administration of a 4-factor PCC with vitamin K as
discussed in the preceding section. (See 'Serious/life-threatening bleeding' above.)
For patients who can wait 24 hours before going to surgery, vitamin K (dose 1 to 2 mg) will typically be sufficient to lower the INR;
in such cases, PCC and FFP can be avoided. This calculation regarding the urgency of the required procedure should involve close
consultation with the surgeon/interventionist.
The greater efficacy and lower risk of volume overload of 4-factor PCC versus FFP in the setting of urgent surgery was
demonstrated in an industry-funded trial that randomly assigned 181 patients who required an urgent procedure to receive either
4-factor PCC or FFP [35]. Doses were adjusted according to the INR; all patients received vitamin K. Adequate hemostasis was
achieved more frequently in those receiving 4-factor PCC (90 versus 75 percent), as was INR reduction within 30 minutes (55 versus
10 percent). Adverse events were similar in the two groups (56 versus 60 percent), thromboembolic complications were similar (7
versus 8 percent), and volume overload occurred less often with PCC (3 versus 13 percent). A post hoc analysis of data from this
trial confirmed that use of FFP was independently associated with a greater risk of volume overload compared with use of a 4-
factor PCC (odds ratio 2.74; 95% CI 1.21-6.19) [36].
● Elective – Management of warfarin around the time of elective surgery is discussed in detail separately. (See "Perioperative
management of patients receiving anticoagulants" and "Management of anticoagulants in patients undergoing endoscopic
procedures".)
Minimal bleeding — There is little guidance as to how patients with minimal bleeding in the setting of an elevated INR (eg, >5) should
be treated. Options include withholding warfarin, holding warfarin and giving vitamin K, or more aggressive reversal as outlined for
patients with more significant bleeding (see 'Serious/life-threatening bleeding' above). The choice among these approaches depends on
the perceived likelihood of progression to more severe bleeding. The approach is based largely on clinical judgment that considers the
extent and site of bleeding, previous bleeding, comorbidities such as renal insufficiency or hypertension, concomitant antiplatelet
therapy, INR level, and likelihood that the INR may be rising, based on the percent of time the INR has been supratherapeutic over the
previous few measurements [21]. As examples, a patient with a minor nosebleed in the setting of high thromboembolic risk may be
treated with local measures, whereas a patient with bleeding from a site not easily accessed who has a lower thromboembolic risk and
other comorbidities may require additional interventions.
TREATMENT OF SUPRATHERAPEUTIC INR WITHOUT BLEEDING
INR >10 without bleeding — If the INR is >10 and the patient does not have clinically significant bleeding, warfarin should be held until
the INR falls into the therapeutic range. Vitamin K can be administered as an oral dose of 2.5 to 5 mg, depending on the bleeding risk of
the patient [31,37]. Administration of vitamin K should produce a substantial reduction in the INR within 24 to 48 hours ( table 1)
[27,38]. The INR should be monitored closely (eg, daily, every other day), and oral vitamin K may be repeated as necessary.
In a retrospective series of 809 individuals with INR >10 and no bleeding, some of whom were treated with vitamin K and some not,
there was no statistically significant difference in the rate of bleeding or thrombosis at 30 days or in the time it took for the INR to drop
below 4 (on average, slightly over 2 days) [39]. Approximately 10 percent of the no vitamin K group received vitamin K more than a day
later, but exclusion of their data did not appreciably change the results.
A reduced maintenance dose of warfarin generally should be restarted when the INR falls into the therapeutic range.
Nonbleeding patients should not be given prothrombin complex concentrate (PCC) or FFP solely to correct a supratherapeutic INR as
these products have associated risks (eg, thrombosis, transfusion reactions) (see 'PCC products' below) and there is not clear evidence of
benefit. For nonbleeding patients, there is no clear benefit to giving larger doses of vitamin K or to giving vitamin K by the intravenous
route (unless the patient cannot take an oral medication). Patients who receive higher doses of vitamin K may have a prolonged period
in which the INR cannot be raised, and intravenous administration is associated with a small risk of anaphylaxis, especially when given
rapidly [40-43].
INR 4.5 to 10 without bleeding — If the INR is between 4.5 and 10 and the patient does not have clinically significant bleeding, warfarin
is held temporarily (eg, one or two doses), with or without administration of a small dose of oral vitamin K (1 to 2.5 mg) ( table 1). As
discussed below, evidence suggests that vitamin K does not reduce bleeding complications in this setting. The 2012 American College of
Chest Physicians and the 2018 American Society of Hematology (ASH) guidelines both have a suggestion not to use vitamin K in this
setting, although the 2012 ACCP guideline offers low dose oral vitamin K as an option [22,31,37]. (See 'ACCP and ASH guidelines' below.)
● We generally favor the administration of a low dose of oral vitamin K for individuals with a greater risk of bleeding (eg, older, prior
bleeding) and a lower risk of thromboembolism. We also have a low threshold for giving vitamin K to patients with conditions
known to slow the spontaneous lowering of a supratherapeutic INR such as decompensated heart failure or active malignancy.
These risk factors were identified in a retrospective record review of 633 patients with INR >6, in which the following predicted for a
supratherapeutic INR two days after stopping warfarin [44]:
• Older age (odds ratio [OR] 1.2 per decade of life)

• Higher index INR (OR 1.25 per unit of elevation)
• Lower warfarin maintenance dose (OR 0.87 per 10 mg increase in total weekly dose)
• Decompensated heart failure (OR 2.79; 95% CI 1.30-5.98)
• Active cancer (OR 2.48; 95% CI 1.11-5.57)
Other factors such as lack of rapid access to medical care may also contribute to the decision regarding vitamin K administration.
Patients should be instructed to report and/or seek prompt medical attention for any signs of bleeding (eg, headache, melena,
cardiovascular symptoms) or thromboembolism.
It has been suggested that small oral doses of vitamin K may be given by administering the intravenous preparation (2 mg/mL)
orally, because pills may be difficult to cut [45-47]. (See 'Vitamin K dose, route, formulation' below.)
● We generally favor holding the vitamin K antagonist without giving vitamin K for individuals with a low risk of bleeding and those
who may have a more rapid return of the INR to the therapeutic range, such as the following:
• Children – Children metabolize warfarin more rapidly than adults. In a series of 89 children with supratherapeutic INR (mean
INR, 5.9) who did not receive vitamin K, the next day repeat was below 5 in 89 percent (mean INR, 3.3) [48].
• Acenocoumarol – Acenocoumarol has a shorter half-life than warfarin. Two small trials that randomly assigned a total of 169
acenocoumarol-treated patients with a supratherapeutic INR to receive vitamin K versus placebo along with omitting the
acenocoumarol dose both found that omitting the dose without giving supplemental vitamin K was associated with similar time
to return of the INR to the therapeutic range and less risk of a subtherapeutic INR [49-51].
The INR should be monitored more frequently during the period of observation and warfarin reinitiation (eg, every 24 to 72 hours until
warfarin is resumed). When warfarin is restarted, a lower maintenance dose is likely to be appropriate unless a transient cause of the
supratherapeutic INR has been identified and corrected. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Initial
dosing'.)
The similar efficacy and safety of holding warfarin with or without giving vitamin K for this degree of INR elevation was documented in a
2019 meta-analysis [52]. Examples of illustrative trials include the following:
● In a multicenter trial that randomly assigned 724 patients with INR between 4.5 and 10 without bleeding to receive vitamin K (1.25
mg orally) or placebo, outcomes were similar in both arms [22]. All patients had their warfarin dose held.
• Bleeding was seen with equal frequency in both the vitamin K and placebo groups (16 versus 16 percent cumulative rates at 90
days), although the INR decreased more rapidly in the vitamin K group (mean decrease on the day after treatment, 2.8 versus
1.4; decrease into the therapeutic range on the day after treatment, 42 versus 10 percent).
• There were no significant differences in mortality (2 percent in both groups), bleeding at one month (12 versus 13 percent), and
thromboembolic events (1 percent in both groups). There was a trend towards more major bleeding events in the vitamin K
group that did not reach statistical significance (9 versus 4 patients; 2.5 versus 1.1 percent; respectively). Outcomes were
unaffected by patient age or INR, although most of the major bleeding (10 of 13 events) occurred in patients older than 70 years
of age.
● In a smaller trial that randomly assigned 92 patients with INR between 4.5 and 10 without bleeding to receive vitamin K (1 mg
orally) or placebo, a therapeutic INR on the day after treatment was more likely in the vitamin K group (56 versus 20 percent) [40].
Bleeding at 30 days was less frequent in the vitamin K group (two versus eight events). However, the likelihood of overcorrection
(subtherapeutic INR on the day after treatment) was also greater with vitamin K (16 versus 0 percent), although subsequent INRs
were similar (ie, there was no delay in re-anticoagulation). There was one thrombotic event in each group.
● In another trial, investigators randomly assigned 59 patients with a prosthetic heart valve and INR between 6 and 12 to receive
vitamin K (1 mg orally) or no treatment [53]. There were no major bleeding events; INR correction was more rapid with vitamin K
(mean INR on the day after treatment: 3 versus 5).
Patients who receive higher doses of vitamin K may have a prolonged period in which the INR cannot be raised, and intravenous
administration is associated with a small risk of anaphylaxis, especially when given rapidly [40-43].
Nonbleeding patients also should not be given FFP or other PCCs solely to correct a supratherapeutic INR, as these products have risks
(eg, transfusion reactions, thromboembolic events) and no clear benefit from their administration has been demonstrated in this setting
[54].
INR <4.5 without bleeding — If the INR is above the therapeutic range but <4.5 and no clinically significant bleeding is apparent, the
next dose of warfarin should be omitted and/or the maintenance dose of warfarin reduced slightly ( table 1) [31,37]. Often, the
maintenance dose does not need to be reduced at all, especially if the INR elevation is minimal and/or expected to be transient [55].
Additional therapies such as vitamin K are not indicated in this setting. Increased monitoring (eg, INR testing once or twice a week)
during the period of dose adjustment is appropriate.
SUPERWARFARIN POISONING
The "superwarfarins" (eg, brodifacoum, bromadiolone, coumafuryl, difenacoum) are used as rat poisons (rodenticides); these lipophilic,
long-acting agents are up to 100 times as potent as warfarin. They have half-lives within the body of weeks to months compared with
hours to days for clinically used vitamin K antagonists [56-58].
Poisoning with superwarfarins has been due to accidental exposure, suicide attempts, or occupational exposure. Individuals may also be
exposed when drugs of abuse (eg, marijuana, synthetic cannabinoids, crack cocaine) are combined ("laced") with superwarfarins,
presumably to potentiate their effect [59-61]. The diagnosis is confirmed when specific assays for the superwarfarin molecule are
performed [62]. However, this testing may involve significant delays, and management must be made based on the clinical history and
results of coagulation testing pending results of superwarfarin testing. Additional details of the evaluation for superwarfarin poisoning
are discussed separately. (See "Anticoagulant rodenticide poisoning: Clinical manifestations and diagnosis" and "Synthetic cannabinoids:
Acute intoxication", section on 'Life-threatening coagulopathy (brodifacoum adulteration)'.)
Individuals poisoned with one of the superwarfarins can develop a severe, long-lasting coagulopathy and may have bleeding associated
with a prolonged PT, activated partial thromboplastin time (aPTT), and INR; these individuals usually require massive doses of vitamin K
(eg, 50 to 800 mg per day) given orally over extended periods of time up to months to years [56-58,62,63]. Repeated assays for the
superwarfarin and/or coagulation testing may be helpful in determining the duration of vitamin K treatment required [57,63].
PCC PRODUCTS
All centers that treat patients with warfarin-associated bleeding should stock a prothrombin complex concentrate (PCC) for rapid
reversal when needed. When available, a 4-factor PCC is the preferred agent for the acute reversal of warfarin anticoagulation.
However, PCC products may be unavailable in some institutions, and their high cost poses a serious barrier to their use [64]. If a 4-factor
PCC is unavailable, a 3-factor PCC can be given; this is often supplemented with a plasma product such as Fresh Frozen Plasma (FFP) to
provide a source of factor VII, which is present in low/insufficient amounts in 3-factor PCC products [65].
Dosing — Dosing units are based on units of factor IX activity. Dosing can be by fixed dose ( table 3) or calculated based on the
patient's weight and INR at presentation.
We generally suggest a fixed dosing regimen, since it is easier to use and may result in faster treatment. Additional doses can be
provided if needed for individuals with higher-than average weight or if the INR does not decrease sufficiently. Institutions should
determine their own protocols and make these available to clinicians for maximum ease of use. An institutional set of reversal guidelines
that specify dosing and monitoring based on locally available products can be of great value in guiding the clinician in treating patients
with significant bleeding. Such institutional plans can be updated iteratively based on local experience and can incorporate simplified
dosing based on patient weight and INR when appropriate [28].
Evidence to support fixed versus weight-based dosing is limited. A randomized trial in 199 adults who presented with major extracranial
bleeding associated with a vitamin K antagonist compared fixed dose 4-factor PCC (1000 units) versus weight-based dosing (calculated
from weight and INR) [66]. Effective hemostasis (determined by blinded clinicians) was seen in 74 of 84 fixed dose patients (88 percent)
and 76 of 85 weight-based dose patients (89 percent). Effective INR lowering and other outcomes were also similar between groups.
Door to needle times were shorter in the fixed dose arm (median time 109 versus 142 minutes; difference, 33 minutes; 95% CI 56 to 4
minutes), and initial PCC dose was lower in the fixed dose arm (1000 units, versus 1750 units with weight-based dosing). To avoid delays,
treating clinicians were not blinded, and the trial was closed early due to low accrual; however, these results are reassuring that fixed
dosing is a reasonable approach.
Repeat dosing may be required if a fixed dose regimen of 1000 or 2000 units was used and the INR remains elevated. If a regimen
titrated to patient weight and INR is used, a second dose is rarely needed but might be used if the INR remains elevated and life-
threatening (eg, intracranial) bleeding is being treated. (See 'Serious/life-threatening bleeding' above.)
It is important to be aware of which PCC products are locally available and recommended by institution-specific protocols ( table 2):
● 4-factor PCC – 4-factor PCCs (eg, Beriplex [available as Kcentra in the United States], Octaplex, Cofact Proplex [available in Europe
and Canada]) contain all of the vitamin K-dependent coagulation factors (ie, factors II, VII, IX, and X) in an unactivated form [67].
● 3-factor PCC – 3-factor PCC (eg, Profilnine) contains only factors II, IX, and X, in an unactivated form.
● Activated PCC – Activated PCC (aPCC) contains factors II, VII, IX, and X; factor VII is mostly present in the activated form, which is
potentially more prothrombotic. The only aPCC available in the United States is Factor Eight Inhibitor Bypassing Activity (FEIBA).
FEIBA generally is not used for reversing warfarin anticoagulation, based on theoretical concerns that the activated factor VII in
FEIBA is potentially more prothrombotic than the unactivated factors in unactivated PCC. For warfarin, an activated factor is not
needed to "bypass" any inhibitory activity in the patient's coagulation system (as occurs with some other anticoagulants).
Differences between various PCC products are discussed separately. (See "Plasma derivatives and recombinant DNA-produced
coagulation factors", section on 'PCCs'.)
Evidence for efficacy — Advantages of PCC over FFP include the rapidity of administration and INR reversal, and the small volume in
which factors can be administered. PCC are preferred over FFP because they raise the activity levels of the depleted factors very quickly
without risks associated with FFP such as volume overload and transfusion-related acute lung injury (TRALI).
● PCC versus FFP – Evidence that 4-factor PCCs are at least as effective as FFP comes from a trial that randomly assigned 216
patients with major warfarin-associated bleeding to receive a 4-factor PCC or FFP; all were given intravenous vitamin K [68]. PCC
and FFP provided similar hemostasis (72 versus 65 percent) and similar length of hospital stay (median 4.5 versus 4.2 days). There
were more deaths in the PCC group (mortality in 10 versus 5 percent); however, when only deaths considered to be related to the
therapy were compared, mortality was seen in only 1 versus 0 percent (according to the Safety Adjudication Board) or 0 versus 0
percent (according to the investigators). Adverse events related to the study drug were seen in 2 versus 4 percent with PCC versus
FFP; fluid overload was more common in those given FFP. A 2022 network meta-analysis of randomized trials (594 participants in
total) found that PCCs had a higher rate of INR reversal and in some comparisons a higher rate of bleed cessation [69].
Similar results were seen in patients requiring urgent surgery, for whom 4-factor PCC resulted in faster INR correction and fewer
episodes of volume overload compared with FFP. (See 'Urgent surgery/procedure' above.)
● 4-factor versus 3-factor PCC – A 4-factor product has not been compared with a 3-factor product in a randomized controlled trial.
In a retrospective cohort study involving 195 individuals with life-threatening warfarin-associated bleeding, those treated with a 4-
factor PCC had better outcomes than those treated with a 3-factor PCC plus recombinant activated factor VII (rFVIIa), including
improved survival, shorter stays in the intensive care unit, and fewer thrombotic complications (7 versus 28 percent; p <0.01) [70].
There were no deaths in the 4-factor PCC group, versus three deaths in the 3-factor PCC plus rFVIIa group. It is difficult to draw
strong conclusions based on observational data in which administration was noncontemporaneous. Contributing factors to the
better outcomes in those treated with 4-factor PCC may have included avoidance of rFVIIa, which has known prothrombotic risks;
lower doses of the 4-factor product than the 3-factor product in some cases (25 units/kg versus 50 units/kg for INRs between 2 and
4); and general advances in care during the period of time when the 4-factor product became available.
● 4-factor PCC versus FEIBA – FEIBA is generally not used for warfarin-associated bleeding due to a greater thrombotic risk and no
need to bypass a factor inhibitor. There is a lack of high-quality data on the safety of FEIBA for warfarin-associated bleeding, and no
randomized trials have directly compared FEIBA with unactivated PCC in this setting. In a retrospective observational study
involving 342 individuals with warfarin-associated intracerebral hemorrhage who were treated with a 4-factor PCC or FEIBA, those
receiving 4-factor PCC were more likely to have improvement in the PT/INR to ≤1.5 [71].
Several smaller earlier series also reported administration of 4-factor PCC for vitamin K antagonist reversal and found rapid
normalization of the INR (eg, within 30 minutes) without thromboembolic complications or additional bleeding [72-74].
Evidence for fixed versus weight-based dosing is discussed above. (See 'Dosing' above.)
PCC risks — As noted above, PCC carries a small but real prothrombotic risk. This risk was estimated from a 2011 meta-analysis of 27
observational studies that included 1032 patients treated with PCCs for bleeding or urgent surgery in the setting of a vitamin K
antagonist [75]. Twelve patients had a thromboembolic complication (1.4 percent), two of which were fatal. A single institution
observational study of persons with warfarin-associated ICH suggests the short-term risk of venous thromboembolism after PCC
administration may be particularly high in patients with a prior history of venous thrombosis [76]. Thus, PCC should only be used for
individuals who require rapid warfarin reversal.
Another series published in 2016 (after the meta-analysis) included 113 consecutive patients who received 4-factor PCC for vitamin K
antagonist reversal in the setting of bleeding or emergency surgery [77]. Approximately one-third of the patients in this series were at a
higher risk of thrombosis due to conditions such as sepsis or antiphospholipid syndrome (APS). There were seven thromboembolic
complications (6 percent), two of which (1.8 percent) occurred within three days of PCC administration and thus were deemed potentially
related to the PCC (one ischemic stroke in a patient on a left ventricular assist device [LVAD] and one abdominal ischemic event in a
patient with APS and sepsis). There were 17 deaths, including the two patients with PCC-related events (from hemorrhagic
transformation and sepsis, respectively).
Some PCC products contain heparin, and these should not be used in individuals with a history of heparin-induced thrombocytopenia
(HIT).
VITAMIN K DOSE, ROUTE, FORMULATION
Vitamin K is appropriate for warfarin-treated individuals with serious/life-threatening bleeding and for some individuals with a
supratherapeutic INR, as discussed above. (See 'Treatment of bleeding' above.)
Vitamin K administration should occur promptly when indicated. However, reversal of the warfarin effect may take several hours to fully
occur because it depends on new synthesis of coagulation factors in the liver. Thus, for serious/life-threatening bleeding, administration
of clotting factors (either as prothrombin complex concentrates [PCCs] or Fresh Frozen Plasma [FFP]) is paramount; PCCs can correct a
supratherapeutic INR within 30 minutes.
Vitamin K can be administered intravenously or orally for patients receiving warfarin; intramuscular and subcutaneous routes of
administration are not appropriate for reversing anticoagulation. The dose and route of vitamin K depends on the severity of bleeding
[42].
● Individuals with major bleeding generally are given 10 mg of vitamin K by slow intravenous infusion (eg, over 20 to 60 minutes).
(See 'Serious/life-threatening bleeding' above.)
● Individuals with a supratherapeutic INR without bleeding for whom vitamin K is clinically appropriate generally are given lower
doses of oral vitamin K because oral administration is effective within one to two days and eliminates the small risk of anaphylaxis
with intravenous use. Use of excessive doses of vitamin K should be avoided, especially for individuals who do not have bleeding,
because the effect can last for several days (or even weeks). (See 'INR >10 without bleeding' above and 'INR 4.5 to 10 without
bleeding' above.)
Vitamin K dosing can be repeated at approximately 12-hour intervals if needed based on the criteria outlined above (see 'Treatment of
bleeding' above). A requirement for more than one or two days should raise the possibility of superwarfarin poisoning or impaired
absorption of an oral preparation. (See 'Superwarfarin poisoning' above.)
A meta-analysis of 10 randomized and 11 prospective trials evaluated the relative effectiveness of the various routes of vitamin K
administration in patients with an INR of 4 to 10 without bleeding. At 24 hours after stopping warfarin, the percentages of patients with
an INR in the range of 1.8 to 4.0 were as follows [78]:
● Placebo – 20 percent (95% CI 0-47)

● Subcutaneous vitamin K – 31 percent (95% CI 7-55)
● Intravenous vitamin K – 77 percent (95% CI 60-95)
● Oral vitamin K – 82 percent (95% CI 70-93)
The authors concluded that the subcutaneous route for vitamin K was no better for this purpose than placebo and should not be
employed. This analysis was unable to determine the optimal dose of vitamin K; effective doses ranged from 1 to 2.5 and 0.5 to 3 mg for
the oral and intravenous routes, respectively. Given the size of vitamin K tablets available in the United States (5 mg, scored to allow
administration of 2.5 mg), it has been suggested that a 1 mg oral dose is most reliably given by administering 1 mg of the intravenous
preparation (2 mg/mL) by mouth [45].
Vitamin K represents a family of structurally similar compounds required for the synthesis of vitamin K-dependent clotting factors.
Commercially available preparations include vitamin K1 (phytonadione, the form produced by plants), K2 (menaquinone, the form
synthesized by bacteria and mitochondria, and the main storage form in humans), and other synthetic forms [79,80].
● Vitamin K1 – Most of the clinical trials that have studied vitamin K administration for warfarin reversal have used vitamin K1. This is
the most commonly available formulation in the United States.
● Vitamin K2 – Vitamin K2 is commonly used in Japan [81].
Since both vitamin K1 and K2 are effective in reversing coagulopathy, we favor whichever formulation is most readily available. (See
"Vitamin K and the synthesis and function of gamma-carboxyglutamic acid" and "Overview of vitamin K".)
ADDITIONAL EVALUATIONS
Other explanations for bleeding or high INR — Not all bleeding (or bleeding risk) is due to warfarin. In some cases, an anatomic lesion
(eg, tumor, arteriovenous malformation) may contribute to bleeding or may be revealed in the setting of anticoagulant administration,
especially gastrointestinal bleeding or hematuria [80]. Many patients will require additional evaluation for such lesions in the setting of
warfarin anticoagulation and/or warfarin-associated bleeding as discussed in the sections below.
In addition, individuals with a supratherapeutic INR should also be evaluated for possible medication errors or other factors that might
lead to excessive anticoagulation.
● Correct dosing – The patient should be asked about the number of pills and their physical description (eg, color) and whether the
prescription has been recently changed or renewed. When possible, the pills should be examined to make sure that the proper
dose of warfarin was being taken. Factors that may interfere with medication adherence are discussed in more detail separately.
(See "Biology of warfarin and modulators of INR control", section on 'Medication adherence'.)
● Metabolic changes – The patient should be asked about new medications, over the counter remedies, symptoms that may affect
absorption (decreased intake, diarrhea), and recent dietary changes. (See "Biology of warfarin and modulators of INR control",
section on 'Overview of INR control'.)
Additional interventions for labile INRs that cannot be explained by these factors (eg, low-dose vitamin K supplementation, changing to
another anticoagulant) are presented separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Establishing a
maintenance dose'.)
Mild head trauma — Intracerebral bleeding in an anticoagulated patient, either spontaneous or trauma-induced, is a medical
emergency that requires immediate treatment (see "Reversal of anticoagulation in intracranial hemorrhage"). However, some
anticoagulated patients with intracerebral bleeding do not have focal neurologic symptoms, and some patients with neurologic
symptoms may have an ischemic event (eg, thromboembolic stroke related to atrial fibrillation). Thus, it is important to evaluate
individuals with potential central nervous system bleeding using imaging studies.
For any individual receiving warfarin (or any anticoagulant) who presents to the emergency department with head trauma,
neuroimaging should be performed during the emergency assessment regardless of the presence of neurologic symptoms or the
severity of the trauma. Non-contrast computed tomography (CT) or magnetic resonance imaging (MRI) can be used, as long as there is
not a substantial delay. This practice is supported by the following studies:
● A retrospective review of 215,785 patients seen in two emergency departments identified 144 individuals who were taking warfarin,
experienced head trauma, lacked new neurologic defects or other risk factors, and were evaluated with a CT scan [82]. Most were
elderly women taking warfarin for atrial fibrillation who had fallen. Of these, 10 had clinically important injuries (7 percent)
including parenchymal, subdural, and subarachnoid hemorrhages. One had an acute ischemic stroke.
● A retrospective review at a trauma center identified 105 patients receiving warfarin who experienced mild head trauma and had a
normal neurologic examination [83]. Of these, 26 (25 percent) had evidence of intracranial bleeding. No clinical finding could
reliably predict the findings on neuroimaging, including mechanism of injury, fracture, loss of consciousness, or INR.
A discussion of typical clinical and radiographic findings in patients with anticoagulant-associated intracerebral hemorrhage is presented
separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".)
Management of patients with head trauma and negative neuroimaging should be individualized. The intensities of monitoring and
reversal of anticoagulation depend upon the degree of anticoagulation, the underlying indication, and the clinical findings. As examples,
for a patient with atrial fibrillation and a low thromboembolic risk (eg, CHA2DS2-VASc score of 2 (calculator 1)) who fell a large distance
and has an INR of 4, the risk-benefit analysis may favor vitamin K administration. In contrast, for a patient with a recent pulmonary
embolism (<1 month), a minor fall, and an INR of 2, the risk-benefit analysis may favor close observation without warfarin reversal, with
rapid access to reversal should it be needed.
Gastrointestinal bleeding — For a patient receiving warfarin who has gastrointestinal bleeding, endoscopy can be both diagnostic and
therapeutic. Bleeding should not be attributed solely to anticoagulation, and the source of bleeding should be pursued as done for
patients not receiving an anticoagulant. Details of the evaluation are presented separately according to the age of the patient and the
acuity of bleeding:
● Child, acute bleeding – (See "Approach to upper gastrointestinal bleeding in children" and "Lower gastrointestinal bleeding in
children: Causes and diagnostic approach".)
● Adult, acute bleeding – (See "Approach to acute upper gastrointestinal bleeding in adults" and "Approach to acute lower
gastrointestinal bleeding in adults".)
● Occult bleeding (eg, positive fecal occult blood test or iron deficiency anemia without visible blood loss) – (See "Evaluation of occult
gastrointestinal bleeding".)
● Suspected small bowel bleeding (eg, bleeding despite an obvious etiology from upper endoscopy and colonoscopy) – (See
"Evaluation of suspected small bowel bleeding (formerly obscure gastrointestinal bleeding)".)
Hematuria — Hematuria in an anticoagulated patient is likely to be due to factors other than the anticoagulation (eg, anatomic lesion,
infection) and it is important to evaluate the underlying cause of hematuria rather than to ascribe it merely to anticoagulation.
This was demonstrated in a prospective study of 243 patients treated with warfarin who were followed for two years with serial
urinalysis [84]. Microscopic hematuria (≥5 red blood cells) was seen at least once in 69 of these individuals (28 percent); the majority of
episodes were associated with a urinary tract infection that responded to antibiotic therapy. Of the 32 who had at least two episodes of
hematuria without an obvious infection, an anatomic or infectious source was found in 27 (84 percent), including bladder cancer,
nephrolithiasis, a cyst, or infection. Of interest, the incidence of hematuria and likelihood of finding a genitourinary source was similar to
a control group not receiving anticoagulation. Other studies have reported similar findings and noted a greater increase in the
prevalence of hematuria when the anticoagulant is combined with an antiplatelet agent [85].
In some cases, hematuria may be accompanied by a decline in renal function (referred to as "warfarin-related nephropathy" or
"anticoagulant-related nephropathy"). This subject is discussed in detail separately. (See "Anticoagulant-related nephropathy".)
Details of the evaluation of hematuria (eg, urine culture, renal imaging) are also presented separately. (See "Evaluation of microscopic
hematuria in children" and "Evaluation of gross hematuria in children" and "Etiology and evaluation of hematuria in adults".)
Unknown bleeding source — For patients who have evidence of bleeding (eg, acute decline in hemoglobin level) but for whom the site
of bleeding is not obvious, it may be appropriate to evaluate the possibility of bleeding into a retroperitoneal or deep muscle site, as
these may not always be apparent on the initial physical examination.
RESUMPTION OF ANTICOAGULATION AFTER BLEEDING
The decision regarding whether to resume anticoagulation depends on the patient's underlying thromboembolic risk and the estimated
risk of rebleeding. As an example, a clearly reversible cause that is not likely to recur (eg, trauma) may favor resumption of warfarin. In
contrast, an unexplained INR variability in a patient taking warfarin appropriately may favor changing to another oral anticoagulant, and
a new comorbidity or inability to take an oral anticoagulant appropriately may favor permanent discontinuation.
The risk of thrombosis and need for ongoing anticoagulation depends on the underlying condition, as discussed in separate topic
reviews. (See "Antithrombotic therapy for mechanical heart valves" and "Selecting adult patients with lower extremity deep venous
thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'High recurrence risk'.)
A significant number of patients are able to resume warfarin safely, and the risk-benefit calculation may favor this practice as illustrated
by the following series:
● Intracerebral – A retrospective cohort study compared outcomes in 719 patients who experienced an intracerebral hemorrhage
(ICH) and survived the acute hospitalization; 172 (24 percent) resumed a vitamin K antagonist (median, 30 days after bleeding), and
547 did not [86]. The median age was 74 years, and three-quarters had atrial fibrillation (mean CHADS2 score, 2.6). Compared with
individuals who did not resume anticoagulation, those who resumed anticoagulation had a decreased risk of ischemic stroke at
one year (3.9 versus 12.7 per 100 patient-years) and no increase in recurrent ICH (3.9 per 100 patient-years for both groups).
Survival was also better in those who resumed anticoagulation (92 versus 62 percent); however, patients who restarted their
anticoagulant were younger and had better functional status at hospital discharge.
A discussion of anticoagulant resumption following ICH is presented separately. (See "Spontaneous intracerebral hemorrhage:
Acute treatment and prognosis" and "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis",
section on 'Anticoagulation'.)
● Gastrointestinal – A retrospective cohort study compared outcomes in 442 patients who experienced a gastrointestinal bleed
while on warfarin; 260 (59 percent) resumed warfarin (median, four days after bleeding) or never stopped it (41 patients; 9 percent),
and 182 did not [87]. The median age was 74, and half of patients had used aspirin in the 90 days preceding the bleed. Compared
with individuals who did not resume warfarin, those who resumed warfarin had a decreased risk of thromboembolic complications
during 90 days of observation (0.4 versus 5.5 percent, which included three fatal ischemic strokes; hazard ratio [HR] 0.05; 95% CI
0.0-0.6). There was a trend toward increased bleeding that was not statistically significant (10 versus 5.5 percent; HR 1.32; 95% CI
0.5-3.6). Although five of the index bleeds were fatal, none of the recurrent bleeds were fatal. Warfarin resumption was associated
with better survival (HR 0.31; 95% CI 0.2-0.6); however, this may reflect overall better clinical status despite the use of multivariable
analysis adjusted for comorbidities.
The optimal timing for anticoagulant resumption following gastrointestinal bleeding is discussed separately. (See "Management of
anticoagulants in patients undergoing endoscopic procedures", section on 'Resuming anticoagulants after hemostasis'.)
Additional factors may influence the decision to reinitiate anticoagulation with an agent other than warfarin (eg, a direct oral
anticoagulant [DOAC] such as dabigatran, apixaban, edoxaban, or rivaroxaban). Overall, DOACs are reported to confer a lower risk of
major bleeding than warfarin, including ICH. Although all DOACs appear to cause less intracranial bleeding than warfarin, some DOACs
cause more gastrointestinal bleeding than warfarin. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting
anticoagulants: Dosing and adverse effects", section on 'Comparison with heparin and warfarin'.)
Additional evidence from series that include individuals receiving DOACs further supports the potential benefits of anticoagulant re-
initiation. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Resumption of anticoagulation'.)
Bleeding risk with these agents and differences that may affect choice of anticoagulant are presented separately. (See "Risks and
prevention of bleeding with oral anticoagulants".)
ACCP AND ASH GUIDELINES
Recommendations presented here are consistent with the 2018 American Society of Hematology (ASH) Guidelines and 2012 American
College of Chest Physicians (ACCP) clinical practice guidelines ( table 1) [27,31,37].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately.
(See "Society guideline links: Anticoagulation".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about
a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade
reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients.
(You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Choosing a medicine for blood clots (The Basics)" and "Patient education: Taking medicines
for blood clots (The Basics)")
● Beyond the Basics topics (see "Patient education: Warfarin (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● Risk reduction – The greatest risk of bleeding generally occurs during initial treatment and with international normalized ratio
(INR) instability. Bleeding risk is increased by liver disease, kidney disease, heart failure, older age, prior hemorrhage, and
concomitant nonsteroidal anti-inflammatory drug [NSAID] use). Major bleeding rates in randomized trials are 1 to 3 percent per
person-year. (See 'Mitigating bleeding risk' above and "Risks and prevention of bleeding with oral anticoagulants".)
● Treatment – The optimal approach depends on bleeding, degree of INR elevation, and underlying thrombotic risk ( table 1).
• Serious bleeding, INR >2.0 – Warfarin should be withheld, vitamin K (10 mg) given by slow intravenous infusion, and a rapid
reversal agent given. We suggest 4-factor prothrombin complex concentrate (PCC) ( table 2) rather than a 3-factor PCC or
Fresh Frozen Plasma (FFP) (Grade 2B). If 4-factor PCC is not available, a 3-factor PCC supplemented with FFP or FFP alone is
appropriate. For most cases, we suggest a fixed dosing regimen rather than dosing calculated based on weight or INR (Grade
2C); this facilitates ease of use and faster treatment. Institution-specific guidelines should be followed, and additional doses of
PCC may be given if needed.
Vitamin K can be repeated every 12 hours if needed. (See 'Serious/life-threatening bleeding' above and 'PCC products' above.)
Reversal in intracerebral hemorrhage is discussed separately. (See "Reversal of anticoagulation in intracranial hemorrhage".)
• Surgery, INR >2.0 – Bleeding risk, need to reverse anticoagulation, and urgency of the procedure should be determined in
consultation with the interventionist. (See 'Urgent surgery/procedure' above and "Perioperative management of patients
receiving anticoagulants", section on 'Deciding whether to interrupt anticoagulation'.)
- Same day surgery required – Warfarin should be held, vitamin K given, and a rapid reversal agent given. We suggest a 4-
factor PCC rather than FFP (Grade 2B).
- Can wait 24 hours – Warfarin may be held and vitamin K given without a PCC.
- Elective – (See "Perioperative management of patients receiving anticoagulants".)
• Minimal bleeding – Minimal bleeding can be treated as serious bleeding (with a PCC) or as supratherapeutic INR without
bleeding, depending on the perceived likelihood of more severe bleeding. (See 'Minimal bleeding' above.)
• Without bleeding – Nonbleeding patients should not be given a PCC or FFP to correct a supratherapeutic INR.
- INR >10 – Warfarin should be held. Oral vitamin K (2.5 to 5 mg) can be administered, depending on bleeding risk. INR is
monitored daily or every other day, and warfarin is resumed at a lower dose once the INR is therapeutic. (See 'INR >10
without bleeding' above and 'Vitamin K dose, route, formulation' above.)
- INR 4.5 to 10 – Warfarin is held for one or two doses, with or without 1 to 2.5 mg of oral vitamin K. Warfarin is resumed at a
lower dose once the INR is therapeutic. (See 'INR 4.5 to 10 without bleeding' above and 'Vitamin K dose, route, formulation'
above.)
- INR <4.5 – One or more doses of warfarin may be omitted or the dose reduced slightly. If the INR elevation is minimal or
expected to be transient, dose reduction may not be necessary. Vitamin K is not indicated. (See 'INR <4.5 without bleeding'
above.)
● Poisoning – Superwarfarins can cause severe, prolonged coagulopathy. Massive vitamin K doses may be needed over months to
years. (See 'Superwarfarin poisoning' above.)
● Post-treatment evaluation – Individuals with a supratherapeutic INR should be evaluated for medication errors or metabolic
changes that might have contributed. Those with gastrointestinal bleeding or hematuria will require evaluation for the bleeding
source. Any individual who presents with head trauma while on warfarin should be considered for neuroimaging regardless of
neurologic symptoms or severity of trauma. (See 'Additional evaluations' above.)
● Resuming warfarin – Anticoagulant resumption depends on thrombotic risk, bleeding site, and other risk factors for bleeding.
Many patients are able to resume warfarin safely. Some may be good candidates to resume anticoagulation with a direct oral
anticoagulant (DOAC). (See 'Resumption of anticoagulation after bleeding' above and "Risks and prevention of bleeding with oral
anticoagulants", section on 'Prognosis and reinitiation of anticoagulation'.)
● Prosthetic heart valves – (See "Antithrombotic therapy for prosthetic heart valves: Management of bleeding and invasive
procedures", section on 'Management of overanticoagulation and bleeding'.)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Karen A Valentine, MD, PhD, who contributed to earlier versions of this topic review.
Use of UpToDate is subject to the Terms of Use.
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60. Spahr JE, Maul JS, Rodgers GM. Superwarfarin poisoning: a report of two cases and review of the literature. Am J Hematol 2007;
82:656.
61. Outbreak alert: Potential life-threatening vitamin K-dependent antagonist coagulopathy associated with synthetic cannabinoids use.
Centers for Disease Control and Prevention. April 5, 2018. https://content.govdelivery.com/accounts/USCDC/bulletins/1e6dac3.
62. Schulman S, Furie B. How I treat poisoning with vitamin K antagonists. Blood 2015; 125:438.
63. Hollinger BR, Pastoor TP. Case management and plasma half-life in a case of brodifacoum poisoning. Arch Intern Med 1993;
153:1925.
64. Evans SJ, Biss TT, Wells RH, Hanley JP. Emergency warfarin reversal with prothrombin complex concentrates: UK wide study. Br J
Haematol 2008; 141:268.
65. Holland L, Warkentin TE, Refaai M, et al. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in
correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion 2009; 49:1171.
66. Abdoellakhan RA, Khorsand N, Ter Avest E, et al. Fixed Versus Variable Dosing of Prothrombin Complex Concentrate for Bleeding
Complications of Vitamin K Antagonists-The PROPER3 Randomized Clinical Trial. Ann Emerg Med 2022; 79:20.
67. http://www.kcentra.com/docs/Kcentra_Prescribing_Information.pdf (Accessed on May 09, 2013).

68. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K
antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128:1234.
69. Pagano MB, Foroutan F, Goel R, et al. Vitamin K antagonist reversal strategies: Systematic review and network meta-analysis from
the AABB. Transfusion 2022; 62:1652.
70. Barton CA, Hom M, Johnson NB, et al. Protocolized warfarin reversal with 4-factor prothrombin complex concentrate versus 3-factor
prothrombin complex concentrate with recombinant factor VIIa. Am J Surg 2018; 215:775.
71. Peksa GD, Mokszycki RK, Rech MA, et al. Reversal of Warfarin-Associated Major Hemorrhage: Activated Prothrombin Complex
Concentrate versus 4-Factor Prothrombin Complex Concentrate. Thromb Haemost 2020; 120:207.
72. Evans G, Luddington R, Baglin T. Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in
patients presenting with major bleeding. Br J Haematol 2001; 115:998.
73. Preston FE, Laidlaw ST, Sampson B, Kitchen S. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex
concentrate (Beriplex): efficacy and safety in 42 patients. Br J Haematol 2002; 116:619.
74. Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a
prospective multinational clinical trial. J Thromb Haemost 2008; 6:622.
75. Dentali F, Marchesi C, Giorgi Pierfranceschi M, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal
of vitamin K antagonists. A meta-analysis. Thromb Haemost 2011; 106:429.
76. Felton D, Foley EM, Traub SJ, et al. Risk of Venous Thromboembolism After Receiving Prothrombin Complex Concentrate for
Warfarin-associated Intracranial Hemorrhage. J Emerg Med 2016; 50:1.
77. Joseph R, Burner J, Yates S, et al. Thromboembolic outcomes after use of a four-factor prothrombin complex concentrate for vitamin
K antagonist reversal in a real-world setting. Transfusion 2016; 56:799.
78. Dezee KJ, Shimeall WT, Douglas KM, et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis.
Arch Intern Med 2006; 166:391.
79. Nakagawa K, Hirota Y, Sawada N, et al. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature
2010; 468:117.
80. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e44S.
81. Hifumi T, Takada H, Ogawa D, et al. Vitamin K2 for the reversal of warfarin-related coagulopathy. Am J Emerg Med 2015; 33:1108.e1.
82. Li J, Brown J, Levine M. Mild head injury, anticoagulants, and risk of intracranial injury. Lancet 2001; 357:771.
83. Brewer ES, Reznikov B, Liberman RF, et al. Incidence and predictors of intracranial hemorrhage after minor head trauma in patients
taking anticoagulant and antiplatelet medication. J Trauma 2011; 70:E1.
84. Culclasure TF, Bray VJ, Hasbargen JA. The significance of hematuria in the anticoagulated patient. Arch Intern Med 1994; 154:649.
85. Wallis CJD, Juvet T, Lee Y, et al. Association Between Use of Antithrombotic Medication and Hematuria-Related Complications. JAMA
2017; 318:1260.
86. Kuramatsu JB, Gerner ST, Schellinger PD, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in
patients with anticoagulation-related intracerebral hemorrhage. JAMA 2015; 313:824.
87. Witt DM, Delate T, Garcia DA, et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption
for gastrointestinal tract bleeding. Arch Intern Med 2012; 172:1484.
Topic 1324 Version 72.0
GRAPHICS
Optimal INR to minimize both bleeding and thromboembo
lism in patients with atrial fibrillation
(A) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by
INR level in adults with nonvalvular AF, with 8 INR categories using INR 2.0 to
2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and
controls for each INR category are given below the figure.
(B) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by
INR level in adults with nonvalvular AF, with 6 INR categories using INR 2.0 to
2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and
controls for each INR category are given below the figure.
AF: atrial fibrillation; INR: international normalized ratio; OR: odds ratio; TE:
thromboembolism; ICH: intracranial hemorrhage; CI: confidence interval.
Reproduced with permission from: Singer DE, Chang Y, Fang MC, et al. Should patient
characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular
atrial fibrillation? The ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. Copyright ©
2009 Lippincott Williams & Wilkins.
Graphic 65373 Version 13.0
Optimal INR for minimizing bleeding and

thromboembolism when using oral anticoagulation
This figure shows the relative risks and their 95 percent confidence
intervals for the occurrence of thromboembolism (closed circles,
confidence intervals in yellow) and hemorrhage (open circles,
confidence intervals in blue) as a function of the INR range in patients
prescribed oral anticoagulant therapy. The comparator for both end-
points is the INR range of 2.0 to 3.0 (ie, relative risk of 1.0). Note that
hemorrhagic risk becomes dominant at an INR >3, while

thromboembolic risk is dominant at an INR <2.
Data from: Oake N, et al. Anticoagulation intensity and outcomes among patients
prescribed oral anticoagulant therapy: a systematic review and meta-analysis. CMAJ
2008; 179:235.
Guideline recommendations for management of warfarin-associated bleeding and/or high INR
Clinical setting 2018 ASH guideline 2012 ACCP guideline
Serious or life-threatening bleeding 4-factor PCC 4-factor PCC*

Any INR Vitamin K (intravenous) Vitamin K (intravenous)
Hold warfarin Hold warfarin
No bleeding (No recommendations given) Vitamin K (oral)

INR >10 Hold warfarin
No bleeding Hold warfarin Hold warfarin

INR 4.5 to 10 No vitamin K Vitamin K (low dose, oral) is optional
Clinical judgment is required to assess the severity of bleeding, urgency of warfarin reversal, and need for other interventions. Refer to UpToDate
for details and additional advice such as the duration of warfarin interruption and repeat INR testing.
INR: international normalized ratio; ASH: American Society of Hematology; ACCP: American College of Chest Physicians; PCC: prothrombin
complex concentrate; FFP: fresh frozen plasma.
* A plasma product such as thawed plasma or FFP (approximately 10 mL/kg, depending on INR) can be used as an alternative if PCC is not
available.
References:
1. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of
anticoagulation therapy. Blood Adv 2018; 2:3257.
2. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e152S.
PCC products available in the United States*
Unactivated prothrombin complex concentrates (PCCs)

4 factor:
Contains inactive forms of 4 factors: Factors II, VII, IX, and X
Kcentra Also contains heparin
3 factor: Contains inactive forms of 3 factors: Factors II, IX, and X

Profilnine Contains little or no factor VII
Does not contain heparin
Activated prothrombin complex concentrate (aPCC)

4 factor:
Contains 4 factors: Factors II, VII, IX, and X. Of these, only factor VII is mostly the activated form¶
FEIBA Does not contain heparin
The table lists 4-factor and 3-factor PCC products available in the United States. Kcentra is available as Beriplex in Canada. Bebulin (a 3-factor
PCC) was discontinued in 2018 due to decreased demand for the product. Potency is determined differently for different products; refer to
product information. All PCCs are plasma derived and contain other proteins, including anticoagulant proteins (proteins C and S). Unactivated
factors are proenzymes (inactive precursor proteins). Activated factors have higher enzymatic activity. Refer to UpToDate topics for use of these
products.
US: United States; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity.
* Other 4-factor PCCs available outside the US include Octaplex and Cofact Proplex.
¶ Single-factor recombinant activated factor VII (rFVIIa) products are also available.
Emergency reversal of anticoagulation from warfarin for life-threatening hemorrhage in adults: Suggested
approaches based upon available resources
A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach):
1. Give 4F PCC* 1500 to 2000 units¶ IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not ≤1.5, give additional
4F PCC (refer to topic or drug reference for details).
2. Give vitamin K 10 mg IV over 10 to 20 minutes.
B. If 3-factor prothrombin complex concentrate (3F PCC) is available but 4F PCC is not available:
1. Give 3F PCC* 1500 to 2000 units¶ IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not ≤1.5, give additional
3F PCC (refer to topic or drug reference for details).
2. Give Factor VIIa 20 mcg/kg IV OR give FFP 2 units IV by rapid infusion. Factor VIIa may be preferred if volume overload is a concern.
C. If neither 3F PCC nor 4F PCC is available:
1. Give FFP 2 units IV by rapid infusion. Check INR 15 minutes after completion of infusion. If INR ≥1.5, administer 2 additional units of FFP IV
rapid infusion. Repeat process until INR ≤1.5. May wish to administer loop diuretic between FFP infusions if volume overload is a concern.
These products and doses are for use in life-threatening bleeding only. Evidence of life-threatening bleeding and over-anticoagulation with a
vitamin K antagonist (eg, warfarin) are required. Anaphylaxis and transfusion reactions can occur.
It may be reasonable to thaw 4 units of FFP while awaiting the PT/INR. The transfusion service may substitute other plasma products for FFP (eg,
Plasma Frozen Within 24 Hours After Phlebotomy [PF24]); these products are considered clinically interchangeable. PCC will reverse
anticoagulation within minutes of administration; FFP administration can take hours due to the volume required; vitamin K effect takes 12 to 24
hours, but administration of vitamin K is needed to counteract the long half-life of warfarin. Subsequent monitoring of the PT/INR is needed to
guide further therapy. Refer to topics on warfarin reversal in individual situations for further management.
PCC: unactivated prothrombin complex concentrate; 4F PCC: PCC containing coagulation factors II, VII, IX, X, protein S and protein C; 3F PCC: PCC
containing factors II, IX, and X and only trace factor VII; FFP: fresh frozen plasma; PT: prothrombin time; INR: international normalized ratio;
FEIBA: factor eight inhibitor bypassing agent.
* Before use, check product label to confirm factor types (3 versus 4 factor) and concentration. Activated complexes and single-factor IX products
(ie, FEIBA, AlphaNine, Mononine, Immunine, BeneFix) are NOT used for warfarin reversal.
¶ PCC doses shown are those suggested for initial treatment of emergency conditions. Subsequent treatment is based on INR and patient weight
if available. Refer to topic and Lexicomp drug reference included with UpToDate for INR-based dosing.
Contributor Disclosures
Russell D Hull, MBBS, MSc Grant/Research/Clinical Trial Support: Bayer [VTE];LEO Pharma [VTE];Portola [VTE];Sanofi [VTE].
All of the relevant financial
relationships listed have been mitigated. David A Garcia, MD Other Financial Interest: Abbott [Stroke prevention in atrial fibrillation].
All of the relevant
financial relationships listed have been mitigated. Lawrence LK Leung, MD No relevant financial relationship(s) with ineligible companies to
disclose. Jennifer S Tirnauer, MD No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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28/08/22, 16:45 Management of warfarin-associated bleeding or supratherapeutic INR - UpToDate

Official reprint from UpToDate®

The following special populations are discussed in separate topic reviews:

● Intracerebral hemorrhage – (See "Reversal of anticoagulation in intracranial hemorrhage".)

● Surgery/invasive procedure – (See "Perioperative management of patients receiving anticoagulants".)

MITIGATING BLEEDING RISK

underlying thrombotic risk is particularly high.

TREATMENT OF SUPRATHERAPEUTIC INR WITHOUT BLEEDING

• Older age (odds ratio [OR] 1.2 per decade of life)

VITAMIN K DOSE, ROUTE, FORMULATION

an INR in the range of 1.8 to 4.0 were as follows [78]:

● Placebo – 20 percent (95% CI 0-47)

● Vitamin K2 – Vitamin K2 is commonly used in Japan [81].

RESUMPTION OF ANTICOAGULATION AFTER BLEEDING

ACCP AND ASH GUIDELINES

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

- Elective – (See "Perioperative management of patients receiving anticoagulants".)

Use of UpToDate is subject to the Terms of Use.

67. http://www.kcentra.com/docs/Kcentra_Prescribing_Information.pdf (Accessed on May 09, 2013).

Graphic 65373 Version 13.0

Optimal INR for minimizing bleeding and

hemorrhagic risk becomes dominant at an INR >3, while

Graphic 78252 Version 3.0

Guideline recommendations for management of warfarin-associated bleeding and/or high INR

Clinical setting 2018 ASH guideline 2012 ACCP guideline

Serious or life-threatening bleeding 4-factor PCC 4-factor PCC*

No bleeding (No recommendations given) Vitamin K (oral)

No bleeding Hold warfarin Hold warfarin

Graphic 119954 Version 2.0

PCC products available in the United States*

Unactivated prothrombin complex concentrates (PCCs)

3 factor: Contains inactive forms of 3 factors: Factors II, IX, and X

Does not contain heparin

Activated prothrombin complex concentrate (aPCC)

* Other 4-factor PCCs available outside the US include Octaplex and Cofact Proplex.

¶ Single-factor recombinant activated factor VII (rFVIIa) products are also available.

Graphic 94210 Version 8.0

A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach):

2. Give vitamin K 10 mg IV over 10 to 20 minutes.

3. Give vitamin K 10 mg IV over 10 to 20 minutes.

C. If neither 3F PCC nor 4F PCC is available:

2. Give vitamin K 10 mg IV over 10 to 20 minutes.

FEIBA: factor eight inhibitor bypassing agent.

Graphic 89478 Version 10.0

Conflict of interest policy

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