Treatment of warfarin-associated coagulopathy with vitamin K

Abstract

Warfarin is the most common form of oral anticoagulant therapy. Although it has indisputable benefit in the management of thromboembolic disease, warfarin-associated coagulopathy (WAC) is a well-documented complication of its use. As warfarin exerts its effect by impairing formation of the vitamin K-dependent clotting factors, a cornerstone of WAC management is vitamin K replacement. Daily vitamin K supplementation is an emerging approach to regulate international normalized ratios in difficult-to-control patients. Mild WAC without bleeding can often be managed with warfarin withdrawal alone. For excessive international normalized ratio elevation in the absence of bleeding, low-dose oral vitamin K (1–2.5 mg) is sufficient and achieves the same degree of international normalized ratio correction by 24 h as intravenous therapy. The stable patient with WAC and minor bleeding can also be given oral vitamin K, with correction of the underlying defect. Major bleeding should first be managed with factor replacement for immediate correction of the coagulopathy, using either a prothrombin complex concentrate or fresh-frozen plasma. High-dose vitamin K (10 mg) should be given concurrently via intravenous infusion to confer lasting correction. Warfarin resistance and vitamin K-associated anaphylaxis are rare. Despite development of new oral anticoagulant therapy compounds, warfarin will probably retain a prominent role in thromboembolism management for several years to come.

Keywords::

• anticoagulation
• bleeding
• coagulopathy
• coumarin
• INR
• prothrombin complex concentrates
• vitamin K
• vitamin K antagonists
• warfarin
• warfarin-associated coagulopathy

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Release date: November 11, 2011; Expiration date: November 11, 2012

Learning objectives

Upon completion of this activity, participants will be able to:

• • Evaluate the problem of warfarin-associated coagulopathy

• • Analyze the best treatments for warfarin-associated coagulopathy based on patients’ INR levels

• • Assess how to manage warfarin therapy and anticoagulation prior to major surgery

• • Develop a plan of care for warfarin-treated patients with major bleeding

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Christopher Patriquin

Division of Hematology & Thromboembolism, Department of Medicine, McMaster University, Hamilton, ON, Canada.

Disclosure: Christopher Patriquin has disclosed no relevant financial relationships.

Mark Crowther

Professor, Division of Hematology & Thromboembolism, Department of Medicine, McMaster University, Hamilton, ON, Canada.

Disclosure: M Crowther holds the Leo Pharma Chair in Thromboembolism Research at McMaster University and is a Career Investigator for the Heart & Stroke Foundation of Canada. He has attended advisory boards and/or produced educational materials for Octapharm, CSL Behring, Pfizer, Leo Pharma, Artisan, Bayer and BI. M Crowther’s institution has received research funding from Octapharm, Pfizer, Leo Pharma, Bayer and BI.

Oral anticoagulants have been available for clinical use for over half a century. The first class of drugs was the vitamin K antagonists (VKAs), including warfarin and the other coumarin derivatives. Warfarin (Coumadin^®) was licensed for human use in the USA in 1954, indicated for both primary and secondary prevention of thromboembolic disease [1]. It is the most common form of oral anticoagulant therapy (OAT) used in clinical practice today, with approximately 1–2% of adults in the developed world receiving it [2]. The most frequently cited use for VKAs is the treatment of atrial fibrillation; however, they are also extensively used in the management of venous thromboembolic events such as deep vein thromboses and pulmonary emboli, mechanical heart valves and cerebrovascular accidents [3]. There is also a role for warfarin in the secondary prevention of cardiac disease [4].

Coumarin derivatives such as warfarin exert their effect by antagonizing vitamin K, thereby inhibiting synthesis of the vitamin K-dependent clotting factors II, VII, IX and X, as well as the natural anticoagulants, protein C and protein S [5]. The effect of warfarin is quite unpredictable, however, and the dose–response characteristics can fluctuate significantly both between and within individuals. Accordingly, for safe and effective use of warfarin, the degree of anticoagulation must be monitored regularly using the prothrombin time, which is usually converted to the international normalized ratio (INR) prior to use [6]. Despite regular monitoring, most patients spend less than 55% of their time within the desired INR range [7–9].

Patients with subtherapeutic INRs are predisposed to OAT failure, with progression of their thromboembolic disease [10–12]. At the opposite end of the clinical spectrum is warfarin-associated coagulopathy (WAC), in which the INR exceeds the therapeutic range (INR 2.0–3.0 for the majority of indications). High INR values can occur for several reasons, including inappropriate drug dosing, low dietary vitamin K intake, drug–drug and drug–food interactions, alcohol consumption and other causes of acquired hepatic impairment [13,14]. Patients with supratherapeutic INRs are at increased risk of hemorrhagic complications, including life-threatening gastrointestinal, intracerebral and other major bleeding [2,15]. Rates of hemorrhagic events increase significantly once the INR is greater than 4.5 [16,17]. Indeed, a supratherapeutic INR is recognized as an independent predictor of major bleeding, with an approximate doubling of the hemorrhagic risk for every one-point increase above an INR of 3.0 [18,19].

INR variability

Genetic polymorphisms, such as VKORC1 and CYP2C9, are involved in various steps in warfarin metabolism, and are emerging as a recognized cause of poor INR control [20]; however, clinical knowledge of these polymorphisms has not been shown to reduce the potential for thrombotic or hemorrhagic complications of such INR variability [20–22]. The aforementioned issues of dietary intake, drug–drug and drug–food interactions, liver disease, as well as other environmental factors, are still considered to play a large role in the complications of OAT.

One potentially important cause of INR variability is inconsistency of vitamin K intake. Despite technical difficulty in accurately assessing overall vitamin K status [20], Sconce et al. demonstrated inferior INR control in patients with poorer dietary vitamin K intake [23]. Regular low-dose vitamin K has since been studied in an effort to improve anticoagulation control. Several groups have shown an improvement in overall INR regulation and time in therapeutic range (TTR) with the manipulation of vitamin K intake, either by dietary modification or exogenous supplementation. A randomized, controlled trial by de Assis et al. demonstrated improved TTR (74 vs 58%) in the group who had dietary modification of vitamin K-containing foods and their warfarin doses held constant, compared with the group assigned to a conventional management strategy [24]. In another study, Sconce et al. randomized patients to receive low-dose vitamin K supplementation (150 µg) or placebo for 6 months and found significantly tighter control and improved TTR (28 ± 20% vs 15 ± 20%) in the treatment arm [25]. By contrast, Rombouts et al. compared daily supplementation of 100 µg vitamin K versus placebo in patients taking phenprocoumon for any indication, and did not observe a statistically significant improvement in INR control in those receiving the supplement; however, this study was complicated by impeccably tight control in both arms [26]. A recent literature review on this topic by Ford and Moll highlights both the lack of dose standardization of supplemental vitamin K, and also the inconsistency in therapeutic effect [27]. It has therefore been suggested that larger, multicentred studies be conducted for validation, and that vitamin K supplementation be used only if other reasons for INR variability have been identified and corrected [6,27,28].

Elevated INR in the nonbleeding patient

The rationale for intervening in patients with elevated INRs without bleeding is to minimize the risk of developing hemorrhagic complications. Care must also be taken not to overcorrect the INR. Choice of treatment in this patient population depends on the degree of coagulopathy, and on the clinical impact of potential blood loss should bleeding occur. One option is to simply hold the warfarin until the INR again is within therapeutic range. Alternatively, vitamin K may be given as a more active management strategy. Vitamin K safely and effectively corrects the INR but does not necessarily reduce bleeding events compared with warfarin withdrawal alone [29]. If used, intravenous (iv.) and oral (p.o.) vitamin K are preferred over subcutaneous administration [30–32]. Choice of therapeutic strategy in these clinical scenarios is often further guided by the degree of INR elevation above the therapeutic target [28].

INR between 3.0 & 4.5

Spontaneous bleeding events with minimal INR elevation are uncommon. A review by Oake et al. in 2008 calculated the relative risk of bleeding events to be 2.7 with INR values between 3.0 and 5.0, compared with a relative risk of 21.8 if the INR was greater than 5.0 [10]. However, as there is only a slightly increased risk of bleeding when the INR is between 3.0 and 4.5, the published literature and most guidelines support withholding warfarin until the INR is again within therapeutic range and/or lowering the daily dose, without treating with vitamin K [6,30].

Mild coagulopathy is more likely to be an issue around the time of surgery and other invasive procedures. Current guidelines suggest discontinuing warfarin 5 days before surgery, or longer if the INR is above 3.5 [17]. This recommendation is based on a study by White et al. that documented INR normalization to below 1.2 after four omitted warfarin doses, as long as the baseline INR was between 2.0 and 3.0 [33]. A more recent retrospective cohort study identified the baseline INR as the only factor that correlated with the rate of normalization following warfarin discontinuation [34]. Furthermore, Woods et al. recently performed a retrospective analysis of the utility of vitamin K given the day before surgery. Patients whose INRs the day before surgery were between 1.4 and 1.9 were included in the study. In those given 1 mg oral vitamin K preoperatively (mean INR = 1.6), 76.6% had a normal INR (≤1.3) the day of surgery, and 90.7% had INR values in the ‘near normal’ range (i.e., ≤1.4) [35]. Compared with patients requiring higher warfarin dosing, those who are more warfarin-sensitive (i.e., maintained in therapeutic range with lower weekly doses) may also require longer periods of warfarin discontinuation before their INRs approach near normal range. INR monitoring the day before surgery/invasive procedures would identify these patients and allow for intervention. In this setting, low-dose vitamin K may prophylactically minimize complications of WAC and decrease rates of last-minute procedure cancellation due to elevated INRs, without causing postoperative warfarin resistance.

INR between 4.5 & 10.0

Rates of spontaneous and procedure-based bleeding events increase once the INR exceeds therapeutic targets more significantly. A prospective cohort study found a 14-day major bleeding rate of approximately 5% in patients presenting with INR values over 6.0 [18]. Other groups have documented bleedings rates lower than this. A prospective cohort study by Garcia et al. reported an overall rate of major hemorrhage of 1.3% in patients with INR values above 5.0, and 0.96% in those with INRs between 5.0 and 9.0. These lower rates could be partially explained, however, by the overall lower mean INRs, as 80% of the subjects had values below 7.0 [36]. The increased risk of bleeding with higher INRs argues for the active management of WAC with vitamin K over OAT withdrawal alone. A meta-analysis on the treatment of excess anticoagulation with vitamin K found that most patients receiving p.o. (82%) and iv. (77%) preparations achieved an INR in the target range (1.8–4.0), compared with 31% receiving subcutaneous formulations and only 20% with placebo. This same study also noted that although iv. vitamin K led to more rapid correction, the rates of INR normalization at 24 h were roughly equivalent between iv. and p.o. therapy [32]. Dentali et al. conducted a systematic review of the treatment of coagulopathy associated with VKA therapy and concluded that iv. vitamin K at a dose of 0.5 mg was sufficient to return the INR to therapeutic range, and without increased rates of warfarin resistance or significant anaphylaxis [30,37].

The correction of supratherapeutic INRs in patients with mechanical heart valves is an important subgroup to consider. Ageno et al. randomized a group of 59 such patients with INRs ranging from 6.0 to 12.0 to receive either 1 mg p.o. vitamin K or no treatment. No major bleeding events were recorded in either group, but the vitamin K cohort did achieve more rapid INR correction. One other important finding, however, is that three of the patients given vitamin K overcorrected to INRs of less than 1.8, potentially increasing their risk of thromboembolic complications [38]. More recently, we conducted a randomized controlled trial of low-dose (1.25 mg) oral vitamin K versus placebo in nonbleeding patients with INRs ranging from 4.5 to 10. Although treatment with vitamin K led to a more rapid and robust correction of the INR, we found no accompanying reduction in bleeding rates, questioning the added benefit of vitamin K over just withholding the warfarin [29].

INR values above 10.0

Vitamin K may again be used alone in the situation of highly excessive INR values, but its action is not immediate, requiring 6–24 h before an effect is seen [39]. Larger doses can also lead to difficulty achieving therapeutic targets once warfarin is restarted [40], particularly if more than one dose is required for correction. However, at lower doses, such warfarin resistance is uncommon [29,30,41,42], although trials directly exploring this issue are few in number and further limited by inconsistent definitions of the phenomenon [32].

Guidelines have historically recommended that higher doses (e.g., 2.5–5 mg) of vitamin K be used in excessively elevated INRs [6]; however, several studies have now demonstrated effectiveness of lower doses. Gunther et al. reported on 75 patients assessed with INRs over 10.0 and, of those 51 episodes treated with low-dose (2 mg) p.o. vitamin K, no significant major bleeding events occurred, compared with three clinically significant bleeds in the 24 episodes treated with only warfarin discontinuation [43]. Similarly, results from a recent international prospective cohort study found that low-dose (2.5 mg) oral vitamin K was a reasonable therapeutic option for patients with INR values exceeding 10.0 in the absence of active bleeding, with major bleeding event rates as low as 0.9 and 3.9% at 7 and 90 days, respectively. Furthermore, the authors concluded that patients in this category do not necessarily need hospital admission for observation, providing they can be monitored closely as outpatients [44].

Elevated INR in the bleeding patient

Management of minor bleeding

Management of the bleeding anticoagulated patient depends on the severity and location of the bleed. Patients with supratherapeutic INRs and non-life-threatening bleeding can usually be treated with local measures, close monitoring and either warfarin interruption alone or in conjunction with low-dose vitamin K [30]. Correcting the underlying defect is also required whenever bleeding is an issue, as WAC predisposes but does not directly cause bleeding [28]. For example, minor cutaneous bleeding or epistaxis can usually be managed with external compression or packing. Oral cavity bleeds can often be controlled with topical antifibrinolytics (e.g., tranexamic acid mouth rinse) in addition to warfarin withdrawal [45]. However, there is little in the way of guidelines or evidence for the standardization of treating minor bleeds, and clinical judgement must be used [46].

Management of major bleeding

When urgent reversal of anticoagulation is needed, such as with active severe bleeding or imminent surgery, more immediate measures are required. The aim should be to correct the INR to normal or near-normal (<1.5) levels regardless of the initial INR, including supratherapeutic, therapeutic or even slightly subtherapeutic values. INR correction in this setting is accomplished with intravenous factor replacement. Current options available include fresh-frozen plasma (FFP), recombinant activated factor VII (rFVIIa) and prothrombin complex concentrates (PCCs) [2,46]. Regardless of the chosen therapy, the current consensus recommendations are to target a post-treatment INR below 1.5 [6]. FFP is used frequently for reversal of WAC, and contains all of the vitamin K-dependent clotting factors; however, there are several disadvantages to its use, including longer time to achieve INR targets, incomplete correction, high rates of inappropriate transfusions and potential circulatory overload from the significant volumes infused. It is also the blood product most frequently linked to occurrences of transfusion-related acute lung injury [46–48]. Rapid reversal of anticoagulation with rFVIIa remains controversial, with no definitive evidence to suggest improved clinical outcomes [49]. The emerging standard of care, if available, is the use of PCCs, which have been shown to reverse WAC within minutes, can be delivered in significantly less volume (80 ml of PCC is equivalent to 2 l of FFP) [50], are virally inactivated, have long shelf-lives, do not require cross-matching, and are associated with far fewer complications [13,51,52]. The most common adverse events associated with use of PCCs are thromboembolic, at an estimated rate of approximately 2%, and are more often associated with the use of first-generation products. Development of the second-generation PCCs focused on reducing levels of activated clotting factors (e.g., factor VIIa), increasing concentrations of natural anticoagulants (e.g., protein C and protein S), as well as other purification steps [53]. A recent review of the published literature found no evidence of disseminated intravascular coagulopathy, transfusion-related or other complications [2,54].

The duration of action of PCCs and FFP are predictably dependent on the half-life of the factors infused [55]. The half-life of factor VII is approximately 6 h and the increase in its activity acutely affects the INR more than changes in the other factors [6,56]. To avoid ‘rebound’ over-anticoagulation, vitamin K should be administered with FFP or PCC to provide an enduring correction of the INR. Intravenous vitamin K is the preferred formulation when treating the bleeding patient due to its faster onset of action, with a first effect on the INR noted within 2 h and a maximum effect within 6–12 h, compared with 12–24 h for oral preparations [6,41]. The systematic review by Dentali et al. concluded that all patients with major bleeding should receive iv. vitamin K over other preparations owing to its rapidity of action and predictable delivery [30]. These conclusions are echoed in the 2008 American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines by Ansell et al., in which a dose of 10 mg of iv. vitamin K is recommended for any patients with major or life-threatening bleeds [6]. The ACCP suggest that iv. vitamin K be administered by slow infusion if at all possible, and with the lowest required dose to minimize the risk of anaphylaxis, though this does not completely eliminate the risk. However, the frequency of anaphylaxis associated with iv. vitamin K seems to be quite low, estimated at approximately three events per 10,000 doses, and may be more associated with the preservatives used and the speed at which it is given [30,57].

Expert commentary

The use of vitamin K is a cornerstone in the management of WAC and its complications (Table 1). Daily supplementation of vitamin K is increasingly being recognized as a simple method to stabilize dietary stores and thereby improve TTR. However, not all studies conducted thus far have noted a benefit, and larger trials are needed for validation of this approach. For that reason, such a strategy should currently be reserved for patients whose INRs are difficult to control, and after ruling out other causes of variability such as medication compliance, interactions and alcohol consumption.

In cases of mild WAC (INR 3.0–4.5) and in the absence of bleeding, there is a questionable role for vitamin K. For patients in the perioperative setting, low-dose oral vitamin K given the day before the procedure may provide a safe and effective option for lowering the INR to an appropriate level in patients for whom VKA withdrawal alone was incompletely effective. The effect of this vitamin K should be monitored with a repeat INR on the day of surgery.

Warfarin withdrawal alone is an option in patients with INR values above 4.5, but runs the risk of prolonging the period of WAC and associated bleeding risk. This is particularly true for patients with higher baseline INRs, older age, decompensated congestive heart failure and active malignancy, in whom INR correction is prolonged [58]. Again, in this population there is more convincing evidence for the use of vitamin K. In the nonbleeding patient, the evidence has shown that iv. and p.o. preparations are essentially equivalent. Intravenous administration does more rapidly lead to INR normalization, but the overall magnitude of correction is similar at 24 h. In addition, at least in patients with INR values between 4.5 and 10.0, there may not be any clinical reduction in bleeding events despite expediting the return to appropriate INR values [29]. Assuming there is no urgent correction required in the nonbleeding patient, we would recommend the use of oral over iv. vitamin K. Subcutaneous formulations should not be used in any clinical scenario due to their unpredictable and suboptimal effect. Based on the reviewed literature, we would recommend using a single oral dose of 1 mg in the nonbleeding patient with INR values between 4.5 and 10.0, and 2–2.5 mg if the INR is over 10.0. If the INR lowering effect is incomplete, a repeat dose after 24 h can be considered. Vitamin K doses not easily obtained from available oral formulations can be prepared by mixing the desired quantity of an iv. preparation in a flavored beverage (e.g., orange juice) to mask its unsavory astringency. If iv. vitamin K must be used, a starting dose of 0.5–1 mg is suggested with close INR follow-up and possible repeat administration if the coagulopathy persists.

The stable patient with minor bleeding can also be managed with oral vitamin K, but at a higher dose (e.g., 2.5–5 mg), in combination with correction of the bleeding source. More serious and life-threatening bleeding necessitates high-dose iv. vitamin K. The 2008 ACCP guidelines recommend a 10 mg vitamin K infusion, in conjunction with factor replacement therapy (e.g., PCC, FFP or rFVIIa) for more rapid, but short-lived reversal. The higher vitamin K dose in such scenarios predictably returns the INR to a safe range, while the slow infusion minimizes the risk, rare though it may be, of anaphylaxis. Again, most reports in the literature attribute anaphylactic events to the dose of vitamin K, the speed in which it is given, and the associated excipients.

There still exists a concern in clinical practice regarding over-correction of the INR. Despite this, warfarin resistance is a rare occurrence in the published literature. Current rates, as reported by Dezee et al., range from 0 to 3% of cases [32]. Clinicians should still avoid the use of traditional larger doses (e.g., 10 mg daily for 3 days), as this clearly causes warfarin resistance and confers no additional efficacy. The optimal dose of vitamin K will most likely continue to have to be gleaned from observational studies, as it has been estimated that a randomized controlled trial of vitamin K, intended to show a reduction in major bleeding events from 4 to 1%, would need at least 1000 subjects [32], which would definitely require multicenter and likely international collaboration.

Five-year view

Warfarin and the coumarin derivatives are no longer the only class of OAT available. Several newer agents, such as dabigatran (a direct thrombin inhibitor) and rivaroxaban and apixaban (factor Xa inhibitors), are approved for use in some of the same clinical contexts as warfarin. Many other compounds, the majority being Xa inhibitors, are in Phase III trials [59]. The new agents have been lauded for easier administration and control (no monitoring required), significantly fewer drug interactions, and equivalent or lower bleeding rates compared with the VKAs.

Despite these obvious benefits, dabigatran and the Xa inhibitors have some disadvantages. First, they are renally excreted so their use in patients with acute or chronic kidney disease must be monitored with extreme caution or, more likely, completely avoided. As these are novel agents, there is also significantly less long-term safety data available, compared with warfarin’s nearly 60 years of use in North America. The shorter half-lives could also prove troublesome in patients anticoagulated for mechanical heart valves; warfarin’s long half-life provides a therapeutic buffer that allows the clinician time to readjust the anticoagulant effect in patients with poor or variable medication compliance [59,60]. Perhaps the most concerning issue with the new oral agents is that there does not exist a specific, targeted antidote for reversal of their anticoagulant effects. A review by Brenner and Hoffman outlines several experimental approaches, such as a recombinant form of factor Xa, or use of high doses of PCCs or rFVIIa, but these have for the most part only been trialed in animal models or in vitro with human plasma [60]. By contrast, we are able to rapidly reverse WAC with PCCs or FFP, in conjunction with vitamin K.

Existence of the new OAT agents will most certainly lead to lower rates of warfarin use in the next few years, particularly with increased clinical experience and collection of longer-term safety data. However, as highlighted above, there will be patient populations whose clinical contexts still require the use of warfarin, such as in patients with kidney disease and mechanical heart valves, and, at least in the near future, for those patients unable to afford the new drugs. Therefore, clinicians must still be proficient in the management of WAC. The advent and wider availability of PCCs will lead to their establishment as the new gold standard in factor replacement therapy. The clinical role of vitamin K will also expand to patients taking it regularly to control their TTR, and it will indeed continue to be central in the management of WAC.

Table 1. Suggested management strategy for various clinical scenarios in patients with warfarin-associated coagulopathy.

Event	Management strategy	Ref.
Difficult-to-control INR	1. Question and control for common causes of INR variability 2. Consider low-dose daily vitamin K supplementation	[24,25]
The nonbleeding patient
INR 3.0–4.5	1. Warfarin withdrawal ± dose adjustment 2. Consider preoperative vitamin K 1 mg p.o. if INR elevated the day before surgery, and recheck INR on day of operation	[35]
INR 4.5–10	1. Warfarin withdrawal ± dose adjustment 2. Consider vitamin K 1 mg p.o. (or 0.5 mg iv.) 3. Close monitoring for INR and signs of bleeding	[29]
INR above 10	1. Warfarin withdrawal ± dose adjustment 2. Vitamin K 2.0–2.5 mg p.o. (or 0.5–1 mg iv.) 3. Close monitoring for INR and signs of bleeding	[6,43,44]
The bleeding patient
Minor bleeding	1. Warfarin withdrawal ± dose adjustment 2. Correction of the underlying defect (e.g., compression, packing, topical antifibrinolytics) 3. Vitamin K 2.5–5 mg p.o., with possible repeat dose after 24 h if incomplete correction	[28,46]
Major bleeding	1. Warfarin withdrawal ± dose adjustment 2. Correction of the underlying defect (e.g., compression, packing, topical antifibrinolytics) 3. Factor replacement with PCC or FFP 4. Vitamin K 10 mg iv. via slow infusion	[28,30,54]

FFP: Fresh-frozen plasma; INR: International normalized ratio; iv.: Intravenous; PCC: Prothrombin complex concentrate; p.o.: Oral (per os).

Key issues

• • Warfarin is the most common oral anticoagulant in use today, and its effect must be monitored regularly via the international normalized ratio (INR).

• • INR variability may be managed, in the difficult-to-control patient, with supplementary low-dose daily vitamin K once other causes of variability have been controlled for.

• • The nonbleeding patient whose INR is minimally elevated can be managed by omission of one or two warfarin doses, and/or reducing the daily warfarin prescription.

• • The nonbleeding patient whose INR does not correct appropriately before a planned surgery or procedure may be given low-dose vitamin K the day before to correct it.

• • The nonbleeding patient whose INR is elevated (i.e., >4.5) should be given low-dose (1–2.5 mg) oral vitamin K and monitored closely. Hospital admission is not necessarily required for observation.

• • Patients with elevated INRs but minimal bleeding can be managed with oral vitamin K, temporary warfarin withdrawal and proper control of the bleeding source, such as compression, packing or topical antifibrinolytics.

• • Major or life-threatening bleeding in the context of an elevated INR should be managed first by factor replacement with prothrombin complex concentrates or fresh-frozen plasma, and intravenous high-dose (10 mg) vitamin K.

• • Warfarin resistance is rare with most current vitamin K dosing strategies; however, repetitive administration of high-dose vitamin K may lead to difficulty returning to therapeutic targets.

• • Anaphylaxis with intravenous vitamin K is rare, and more likely associated with the rate of infusion and/or associated excipients.

• • Patients with renal dysfunction and/or mechanical heart valves will continue to require warfarin instead of the currently available novel oral anticoagulant therapy agents.

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Treatment of warfarin-associated coagulopathy with vitamin K

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
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1. Your patient is a 68-year-old woman who recently initiated treatment with warfarin after being diagnosed with atrial fibrillation.

What should you consider in general regarding treatment with warfarin and its associated risk for bleeding?

• □ A Time in therapeutic range (TTR) generally exceeds 80% among patients receiving warfarin

• □ B The risk for hemorrhage approximately doubles with every 1-point increase in INR above 3.0

• □ C The current standard of care is to test for genetic polymorphisms affecting the efficacy of warfarin

• □ D The current standard of care is routine supplementation with vitamin K to increase TTR

2. The patient’s laboratory work demonstrates that she is very sensitive to treatment with warfarin. Three months later, the patient returns to your clinic and has an INR of 4.3. She has no symptoms or signs of bleeding. What is the best next step in her care at this time?

• □ A Withhold warfarin only

• □ B Subcutaneous vitamin K 1 mg now

• □ C Intravenous vitamin K 1 mg now

• □ D High-dose oral vitamin K 5 mg now

3. The patient’s INR corrects to 1.9. Two weeks later, she tells you that she is going to undergo total abdominal hysterectomy with bilateral salpingo-oophorectomy next month. What should you consider regarding reversal of anticoagulation with warfarin in the setting of major surgery?

• □ A Halting warfarin 2 days prior to surgery should bring her INR to near normal levels

• □ B Her history of an elevated INR means that her INR will decline more rapidly after withholding warfarin

• □ C Vitamin K 1 mg orally on the day prior to surgery should reduce her INR to near normal levels

• □ D A repeat INR on the day of surgery is unnecessary if she receives vitamin K preoperatively

4. The patient undergoes surgery successfully. Six months later, she is admitted to the hospital for a major gastrointestinal bleed with hypotension and syncope. Her INR level is 3.4. Which of the following is the best acute treatment for her now?

• □ A High-dose oral vitamin K 5 mg

• □ B Fresh frozen plasma

• □ C Prothrombin complex concentrates

• □ D Recombinant activated factor VII