Karen A Valentine, MD, PhD
Russell D Hull, MBBS, MSc
Lawrence LK Leung, MD
Stephen A Landaw, MD, PhD
INTRODUCTION — Warfarin has been the standard oral anticoagulant used in a variety of clinical settings; its clinical effect is monitored through a standardized prothrombin time, termed the International Normalized Ratio (INR). The optimal method for correcting excess anticoagulation after the use of warfarin (eg, returning an increased INR to the desired range) depends upon the degree of elevation and whether or not clinically significant bleeding is present [1-3], and will be discussed here.
Management of intracerebral hemorrhage as a complication of anticoagulation with warfarin is discussed separately. (See “Management of warfarin-associated intracerebral hemorrhage”.)
The clinical use of warfarin, including its biological properties, mechanism of action, laboratory monitoring, and complications is discussed in detail separately. (See “Therapeutic use of warfarin”.)
RISK FACTORS — Patients treated with warfarin frequently become excessively anticoagulated, even those who have been stable for many months. The most common causes are interactions between warfarin and other drugs and superimposed diseases (eg, liver disease, malabsorption) that may interfere with warfarin ingestion, absorption, or metabolism. (See “Therapeutic use of warfarin”, section on ‘Drug interactions’.)
The patient should also be questioned about the number and size of the pills he/she is taking, whether the prescription has been recently changed or renewed, and whether the color of the pills being prescribed is different from that usually taken, which may signify a difference in pill strength. When possible, the pills should be examined to make sure that the proper dose of warfarin was being taken.
Medical causes — Medical causes of excessive levels of anticoagulation were reviewed in a study of 17,000 outpatients treated with oral anticoagulants in a regional Red Cross anticoagulation clinic . An INR ≥6.0 was noted on 22.5 per 10,000 treatment days. Factors significantly associated with an INR ≥6.0 included:
- Diarrhea — relative risk (RR) 12.8
- Worsened heart failure — RR 3.0 
- Fever — RR 2.9
- Impaired liver function — RR 2.8
- Use of acenocoumarol rather than phenprocoumon — RR 1.9
- Stable heart failure — RR 1.6
Vitamin K deficiency — Patients who are vitamin K deficient are at risk for excessive degrees of anticoagulation following institution of treatment with warfarin . This may result from poor dietary intake (eg, starvation, fasting, anorexia following chemotherapy, total parenteral nutrition in the absence of vitamin K supplementation), vitamin K malabsorption (as in celiac disease) , or therapy with some antibiotics. (See “Therapeutic use of warfarin”, section on ‘Drug interactions’ and “Overview of the beta-lactam antibiotics”, section on ‘Hematologic reactions’ and “Overview of vitamin K”.)
If vitamin K deficiency is sufficiently severe, the INR may be prolonged even before warfarin is started . (See “Approach to the adult patient with a bleeding diathesis”, section on ‘Prolonged PT and normal aPTT’.)
Falsely elevated INRs — The most common cause of a falsely elevated INR is the presence of heparin in the blood sample. This can be avoided by obtaining the needed blood sample from a peripheral vein rather than from indwelling central venous catheters, which might be contaminated with heparin.
Another common cause of a falsely elevated INR is inadequate filling of pediatric collection tubes, resulting in a higher than normal ratio of citrate anticoagulant to patient plasma. (See “Clinical use of coagulation tests”, section on ‘Obtaining the sample’.)
TREATMENT — There are very few randomized studies comparing the various treatment options for patients with an elevated INR and/or bleeding following the use of warfarin. This discussion outlines the available literature for each of the following scenarios [1,8].
INR <5 without bleeding — If the INR is above the therapeutic range but <5.0 and no clinically significant bleeding is apparent, the next dose of warfarin should be omitted and/or the maintenance dose of warfarin reduced. There is no need to reduce the dose of warfarin if the INR is only minimally prolonged (table 1) .
INR 5 to 9 without bleeding — If the INR is between 5.0 and 9.0 and no clinically significant bleeding is present, the risk of a major hemorrhage within the next 30 days is estimated to be approximately 1 percent . Two options are available for the correction of this degree of INR elevation: stopping warfarin temporarily, or stopping warfarin temporarily plus adding a small dose of ORAL vitamin K (table 1). However, even after correction of the INR, patients with a history of an INR >4.5 , >5.0 , or >6.0  were found to be at increased risk for future hemorrhage, especially those with an INR >8 and/or age >70. (See ‘Stopping warfarin plus oral vitamin K1’ below.)
Stopping warfarin — The next one to two doses of warfarin should be withheld, the INR should be monitored more frequently, and a lower maintenance dose of warfarin should be reinstituted when the INR falls into the therapeutic range.
A retrospective study reviewed the records of 633 patients with an index INR >6.0, 80 percent of whom had been taking warfarin for at least one year . In all cases, warfarin was withheld for two days, and a repeat INR was performed on the second day. Of the 562 patients with an index INR of 6 to 10, 34 percent were still excessively anticoagulated (INR >4.0), while 12 percent of a group of 525 patients with an INR of 6 to 9 had a subtherapeutic INR (ie, INR <2) on day two.
A multiple logistic regression model indicated the following risk factors for having an INR >4.0 on the second day:
- Older age
- Higher index INR
- Lower maintenance dose of warfarin
- Active cancer and/or heart failure
As an example, in patients with an index INR of 6 to 8, the risk of having an INR >4 on day two was 14 percent for patients <60 years old without heart failure or cancer, who were taking ≥57.5 mg of warfarin/week. The risk was 80 percent for patients ≥80 years old with cancer or decompensated heart failure who were taking ≥30 mg/week.
In a second study, 114 patients taking warfarin for at least one month with an INR >6.0 and no clinical bleeding were managed conservatively with temporary discontinuation of warfarin . Repeat INR was <4.0 in 33, 55, 73, and 90 percent of patients after an interval of <24, 48, 72, or 96 hours, respectively. Subsequent bleeding was noted in 10 of these patients (9 percent), with a major bleeding episode noted in 5 (4 percent), 2 of which were fatal.
A similar study showed the safety of this approach in 26 children who were taking warfarin and had an INR ≥5.0 (mean INR 5.9) without bleeding . The mean INR one day after withholding one dose of warfarin was 3.3 (range 1.2 to 6.8), with 89 percent of the INR values falling below 5.0. There were no overt bleeding or symptomatic thrombotic events in the following month.
Stopping warfarin plus oral vitamin K1 — An alternative approach in patients with an INR between 5 and 9 and no bleeding, especially in those at increased risk for bleeding, consists of withholding the next dose of warfarin and administering 1 to 2.5 mg of oral vitamin K1, which corrects the excessive degree of anticoagulation more rapidly than the simple withholding of warfarin [11,17].
Such small doses are effective for reducing the INR quickly into the therapeutic range, while larger doses tend to lower a moderately elevated INR into the normal range and render the patient temporarily resistant (eg, days to weeks) to further therapy with warfarin [17-20]. A lower maintenance dose of warfarin should be reinstituted when the INR falls into the therapeutic range (see ‘Stopping warfarin’ above).
The safety and efficacy of this approach were confirmed in a randomized, double-blind trial, in which 724 asymptomatic patients with an INR between 4.5 and 10 had their warfarin dose withheld and were randomly assigned to receive either 1.5 mg of oral vitamin K or matching placebo. The following results were obtained :
- An INR in the range of 2.0 to 3.0 on the day after treatment was significantly less common in the placebo group (10 versus 42 percent).
- At 90 days after intervention, the cumulative incidences of thromboembolism, major bleeding, or any bleeding were 1.0, 1.8 and 16 percent, respectively, with no significant difference between the two treatment arms.
- Of the 13 major bleeding events reported in the study, 10 (77 percent) occurred in subjects >70 years of age.
Route of vitamin K — A meta-analysis of 10 randomized and 11 prospective trials was performed to determine the relative effectiveness of the various routes of vitamin K administration for improving the INR in patients overanticoagulated with warfarin to an INR of 4.0 to 10.0 without bleeding. The percentages of patients with an INR in the range of 1.8 to 4.0 twenty-four hours after stopping warfarin and the administration of vitamin K by various routes were, as follows :
- 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. Since the oral and intravenous routes were equally effective, and there is a risk of anaphylaxis with the intravenous route, the oral route is to be preferred.
This analysis was unable to determine the optimal dose of vitamin K; effective doses ranged from 1.0 to 2.5 and 0.5 to 3.0 mg for the oral and intravenous routes, respectively. Given the size of vitamin K tablets available in the United States (5.0 mg, scored to allow administration of 2.5 mg), it has been suggested that a 1.0 mg oral dose is most reliably given by administering 1.0 mg of the intravenous preparation (2.0 mg/mL) by mouth .
Acenocoumarol — Addition of vitamin K to stopping anticoagulation may not be necessary in patients overanticoagulated (ie, INR 4 to 10 without bleeding) with acenocoumarol, a coumarin derivative widely used in Europe and other countries, which has a shorter half-life than warfarin [3,23,24].
INR >9 without bleeding — If the INR is >9.0 and the patient is without clinically significant bleeding, warfarin should be stopped and 2.5 to 5 mg of oral vitamin K1 administered, which should produce a substantial reduction in the INR within 24 to 48 hours (table 1) [1,25]. The INR should be monitored closely, and repeat treatment with oral vitamin K1 should be undertaken as necessary. A reduced maintenance dose of warfarin should be restarted when the INR falls into the therapeutic range.
As noted above, it has been suggested that these oral doses of vitamin K may be reliably given by administering the intravenous preparation (2.0 mg/mL) by mouth [22,26,27].
Elevated INR with minimal bleeding — There is little in the way of guidance as to how patients with an elevated INR (eg, >5) with only minimal bleeding should be treated. Such patients can be treated as outlined above (ie, INR >9 without bleeding), or as outlined below for those with significant bleeding. The choice of approach is based largely on clinical judgment, the current level of the INR, the percent of time the patient has been supra-therapeutic over the past month or so, the current extent of bleeding, and the risk of worsening of the bleeding . (See “Therapeutic use of warfarin”, section on ‘Other causes for bleeding’.)
Significant or life-threatening bleeding — Rapid reversal of excessive anticoagulation should be undertaken in patients with serious bleeding at any degree of anticoagulation (table 1) [1,28,29]. General measures that should be taken in any patient with anticoagulant-associated severe bleeding are presented separately. (See “Anticoagulants other than heparin and warfarin”, section on ‘Emergency treatment of bleeding’.)
If serious or life-threatening bleeding is present, or if rapid reversal of anticoagulation is required (eg, in preparation for emergency surgery), warfarin should be stopped and 10 mg of vitamin K1 administered by a slow intravenous infusion (eg, over 20 to 60 minutes), supplemented by transfusions of fresh frozen plasma (FFP, initial dose: 2 to 3 units; more as clinically indicated) for less urgent situations. For more urgent situations, recombinant human factor VIIa or prothrombin complex concentrate (PCC) may be employed. Suggested doses of recombinant factor VIIa to use in this setting are unclear, but have been in the range of 10 to 80 microg/kg. (See “Management of warfarin-associated intracerebral hemorrhage”, section on ‘Recombinant factor VIIa’.)
Suggestions for how this should be accomplished with FFP or PCC include the following :
- Determine the desired target INR, as follows:
- Moderate bleeding and high thrombotic risk: target INR 2.0 to 2.1
- Serious bleeding and moderate thrombotic risk: target INR 1.5
- Serious or life-threatening bleeding and low thrombotic risk: target INR 1.0
- Determine the approximate prothrombin complex percentage according to the INR:
- INR ≥4.0: 5 to 10 percent of normal activity
- INR 1.9 to 3.2: 15 to 25 percent of normal activity
- INR 1.4 to 1.8: 30 to 40 percent of normal activity
- INR 1.0: 100 percent of normal activity
- Determine the dose of FFP or PCC from the following formula:
- Dose = (target INR level [as %] – present INR level [as %]) x body weight (kg)
- This is the mL of FFP or the International Units of PCC needed
- As an example, in a 70 kg patient with a pulmonary embolus 3 months prior who now has major intestinal bleeding and an INR of 7.5 (5 percent of normal activity), the target INR would be 1.5 (40 percent of normal activity), and the dose would be: (40 – 5) x 70 = 2450 mL of FFP or 2450 International Units of PCC.
The INR should be monitored frequently. Vitamin K1 may be repeated at 12-hour intervals. Fresh frozen plasma (FFP), PCC, or recombinant human factor VIIa can be repeated if necessary, depending upon the INR response .
The effectiveness of this combined approach was illustrated in a report of 10 patients with major bleeding and an INR ≥8.0 (range 8.9 to >20) . Patients were treated with a single intravenous dose of 5 mg of vitamin K and 30 U/kg of PCC (Beriplex P/N) infused over a 10 to 15 minute period. The median INR 30 minutes post-treatment was 1.1 (range: 1.0 to 1.3). Once treatment was given there was no further evidence of fresh bleeding, no thromboembolic complications, and no adverse events.
Similar efficacy was seen two other studies in a total of 86 patients requiring immediate reversal of warfarin for any cause (eg, severe bleeding or preparation for emergency surgery or interventional procedures) who had somewhat lower initial INR levels [32,33].
In two separate studies involving a total of 17 patients, doses of recombinant factor VIIa (NovoSeven) as low as 15 to 20 microg/kg IV were successfully and safely used in patients in whom excessive warfarin-associated bleeding was present and/or rapid reduction of anticoagulation was required [34,35]. Use of this agent avoids the need for large volumes of fresh-frozen plasma in patients at risk for volume overload.
Both PCC products and recombinant factor VIIa may be unavailable for acute reversal of overanticoagulation in some medical centers in the United States and Europe and their high expense (and off-label status of the latter) pose serious constraints on their use . In addition, the PCC products available in the United States (but not those available in Canada and Europe), the so-called “three-factor” PCCs, may have low concentrations of factor VII, requiring additional use of FFP to effectively lower an elevated INR . (See “Therapeutic uses of recombinant coagulation factor VIIa”, section on ‘Regulatory concerns and costs’.)
Management of intracerebral hemorrhage as a complication of anticoagulation with warfarin is discussed separately. (See “Management of warfarin-associated intracerebral hemorrhage”.)
Superwarfarin poisoning — The “superwarfarins” (brodifacoum, bromadiolone, coumafuryl, difenacoum) are lipophilic, long-acting rat poisons (rodenticides), which are up to 100 times as potent as warfarin. They have half-lives within the body on the order of weeks to months, as compared with 40 hours for warfarin [38-40].
Poisoning with superwarfarins has been due to accidental exposure and suicide attempts, as well as occupational exposure. Subjects may also be exposed when drugs of abuse (eg, marijuana, crack cocaine) are laced with superwarfarins, presumably to potentiate their effect [41,42].
Subjects poisoned with one of the superwarfarins may present with bleeding and prolonged PT, aPTT, and INR, and usually require massive doses of vitamin K (eg, 50 to 800 mg/day PO) given over extended periods of time (eg, months) in order to control their coagulopathy [38-40,43]. The diagnosis is confirmed when specific assays for the superwarfarin molecule are performed. Repeated assays may be helpful in determining the duration of vitamin K treatment required in a particular individual [39,43].
INTRACRANIAL INJURY AFTER HEAD TRAUMA — It has been recommended that patients with mild head injury (low-risk group: those who are asymptomatic or who have one or more of the following: headache, dizziness, scalp hematoma, laceration, contusion, or abrasion) are unlikely to have associated intracranial injury, and that CT scanning is not required in this population . Whether this is true for low-risk patients who are anticoagulated is unclear [45,46]. Two retrospective studies shed some light on this issue:
- A retrospective study evaluated patients receiving anticoagulation who presented to two different accident and emergency departments . Patients were included if they would otherwise have been judged as low-risk and had a CT scan performed. A total of 144 patients met inclusion criteria; most were elderly women taking warfarin for atrial fibrillation who had suffered a fall. The incidence of significant CT findings (ie, one resulting in a change in the patient’s care) was 7 percent (95 percent confidence limits: 3 to 11 percent), similar to that in non-anticoagulated patients with moderate-risk trauma (ie, those presenting with post-traumatic amnesia, seizures, vomiting, unreliable histories, or multiple trauma) .
- A retrospective review determined the incidence of intracranial hemorrhage (ICH) in 141 patients with minor head trauma who were taking anticoagulant or antiplatelet medication, had a Glasgow Coma Scale of 15 (the best possible score, consistent with mild brain injury (table 2)), and underwent head CT . In this study, 41 (29 percent) were diagnosed with ICH, 5 required surgical evacuation of an ICH, and 4 died. Loss of consciousness predicted for a positive CT result, while the type of medication (eg, warfarin, aspirin, clopidogrel) did not reach statistical significance as a predictor of a positive result.
Taken together, these studies suggest that intracranial imaging should be performed during emergency assessment of head trauma in all patients receiving anticoagulants.
TEMPORARY REVERSAL OF WARFARIN — On occasion, it is necessary to temporarily reverse chronic anticoagulation in order to prepare the patient for an invasive procedure. In these cases, a small dose of vitamin K1 administered slowly by intravenous infusion may be most appropriate. Two studies have evaluated the appropriate dose of vitamin K to be used in this setting:
- In one retrospective study of 105 chronically anticoagulated patients being prepared for surgery or an invasive procedure, most subjects stopped warfarin and received a single 0.5 to 1.0 mg dose of intravenous vitamin K1 . This resulted in an INR of 1.4 or less in 57 percent of the patients at a median elapsed time of 27 hours. There were no episodes of thromboembolism, while procedure-associated major bleeding was noted in 2.4 percent of patients. Warfarin was reinstituted on the day following the procedure or surgery, with a median elapsed time from procedure completion to an INR ≥2.0 of 4.1 days.
- In a prospective single-arm study, 178 patients on long-term warfarin therapy stopped this treatment and received 3 mg of intravenous vitamin K1 12 to 18 hours prior to elective surgery . An INR ≤1.7 or ≤1.4 was achieved in 100 and 94 percent of the subjects on the day of surgery. Warfarin was re-started within 12 to 24 hours post-procedure at the previous therapeutic dose. Four patients (2.2 percent) had procedure-related major bleeding, although all four had an INR <1.5 and vitamin K-dependent factor levels >0.30 International Units/mL at the time of the bleeding episode. No patient had an adverse reaction to the vitamin K infusion or a symptomatic thromboembolism during a six-week follow-up period. A therapeutic INR was re-established at a median time of four days post-procedure (range: 2 to 11 days).
Given that the 3 mg dose achieved preoperative INR goals better than the 0.5 to 1 mg dose, with no more in the way of side effects, bleeding, thromboembolism, or time to reestablish a therapeutic INR, we prefer the 3 mg dose for this purpose.
Management of anticoagulation before and after elective surgery, gastroenterologic procedures, or in patients with prosthetic valves is discussed separately. (See “Management of anticoagulation before and after elective surgery” and “Management of anticoagulants in patients undergoing endoscopic procedures” and “Antithrombotic therapy in patients with prosthetic heart valves” and “Management of pregnant women with prosthetic heart valves” and “Cataract in adults” and “Anticoagulant, antiplatelet, and fibrinolytic (thrombolytic) therapy in patients at high risk for ocular hemorrhage”.)
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.)
- Beyond the Basics topics (see “Patient information: Warfarin (Coumadin®)”)
SUMMARY AND RECOMMENDATIONS
Diagnosis — Overanticoagulation with warfarin, requiring action on the part of the clinician, is present when one or both of the following occur:
- The patient has a standardized prothrombin time test result (the International Normalized Ratio, INR) which is greater than the upper limit of the targeted INR range (eg, an INR >3.0 in a non-bleeding patient whose INR target range is 2.0 to 3.0).
- The patient develops clinically significant bleeding, irrespective of the degree of elevation of the INR (eg, an episode of massive retroperitoneal bleeding in a warfarin-treated patient with an INR of 2.9).
Cause of excess anticoagulation — The cause for the increased INR should be sought in all cases. The most common causes include interaction with another medication, wrong dosage of warfarin, vitamin K deficiency, impaired liver function, heart failure, or diarrhea. (See ‘Risk factors’ above.)
Occasionally, a patient will have a variable and unstable response to warfarin over a period of time, which cannot be attributed to one or more of the above causes. This subject, and its management, is discussed separately. (See “Outpatient management of oral anticoagulation”, section on ‘Importance of strict INR control’.)
Treatment principles — Appropriate treatment of the patient with an excessive elevation of the INR and/or warfarin-associated bleeding depends upon the following:
- Degree of elevation of the INR. Minor degrees of INR elevation can be managed simply by omitting one or more doses of warfarin.
- Whether or not it is necessary or desired to continue the patient on warfarin anticoagulation after the episode has been resolved. Treatment of the episode with high doses of vitamin K may make it difficult to resume effective anticoagulation with warfarin for days to weeks after the episode has been controlled. (See ‘Stopping warfarin plus oral vitamin K1’ above.)
- Seriousness of the degree of bleeding. Major bleeding constitutes a medical emergency, and requires the use of high doses of vitamin K given intravenously along with fresh frozen plasma, prothrombin complex, and/or recombinant human factor VIIa.
Treatment guidelines — Our recommendations, consistent with the 2008 American College of Chest Physician clinical practice guidelines , are outlined below (table 1). (See ‘Treatment’ above.)
- INR <5 and no bleeding — For patients with an INR <5 and no bleeding, we recommend either lowering the subsequent dose of warfarin or omitting one or more doses of warfarin. The INR should then be monitored more frequently, and therapy resumed at an adjusted dose when the INR is again within the desired target range (Grade 1C).
If the INR elevation is minimal and/or expected to be transient, no dose reduction may be necessary.
- INR 5 to 9 without bleeding — For patients with an INR in the range of 5 to 9 without bleeding, we recommend omitting a dose of warfarin and administering a low dose of vitamin K (eg, 1 to 2.5 mg), given orally (rather than by the subcutaneous or intravenous route) (Grade 1A). The INR should then be monitored more frequently, and therapy resumed at a reduced dose once the INR is again in the therapeutic range. (See ‘Route of vitamin K’ above.)
If more rapid reversal is required because of the need for urgent surgery, we suggest stopping warfarin and administering one or more oral doses of vitamin K (≤5 mg/dose) (Grade 2C). (See ‘Temporary reversal of warfarin’ above.)
- INR ≥9 without bleeding — For patients with an INR ≥9 without bleeding, we recommend holding warfarin therapy, administering one or more 2.5 to 5 mg doses of vitamin K orally, monitoring the INR more frequently, and resuming therapy at a reduced dose once the INR is again in the therapeutic range, rather than more aggressive treatment (Grade 1B).
- Serious or life-threatening bleeding and elevated INR — We recommend holding warfarin and giving vitamin K (10 mg) by slow IV infusion, supplemented with fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa (Grade 1C). Vitamin K administration can be repeated every 12 hours for persistently elevated INR. (See ‘Significant or life-threatening bleeding’ above.)
- Intracerebral hemorrhage — Management of intracerebral hemorrhage in a warfarin-treated patient is discussed separately. (See “Management of warfarin-associated intracerebral hemorrhage”, section on ‘Reversing the coagulation defect’.)
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