Reversal of Fortune: Supratherapeutic Warfarin Treatment

Reversal of Fortune: Supratherapeutic Warfarin Treatment

Authors: Grant S. Lipman, MD, Clinical Instructor of Surgery, Division of Emergency Medicine, Stanford University School of Medicine, Palo Alto, CA; Jamie Shandro, MD, MPH, Division of Emergency Medicine, Stanford University Medical Center, Palo Alto, CA

Peer Reviewer: Jonathan D. Lawrence, MD, JD, FACEP, Attending Emergency Physician, St. Mary Medical Center, Long Beach, CA; Assistant Professor of Medicine, Division of Emergency Medicine, Harbor/UCLA Medical Center, Torrance, CA.

Introduction

As our population ages, medical practitioners will see an increasing proportion of patients using oral anticoagulants. There are multiple indicators for prophylactic anticoagulation, with an annual risk of thrombotic complications in uncoagulated atrial fibrillation ranging from 1% to 10%, 10% to 23% with single valve prostheses, and up to 90% among patients with multiple valvular prostheses.¹ However, oral anticoagulation comes with an increased risk of bleeding complications. Acute health care providers often are faced with the dilemma of anticoagulated patients in the setting of symptomatic bleeding or with asymptomatic hypercoagulation. These potentially catastrophic situations require the medical practitioner to understand when anticoagulation should be reversed, and what therapeutic agents are at his/her disposal.

Well-established guidelines dictate therapeutic International Normalized Ratio (INR) goals for patients on warfarin. However, it has been shown that patients taking warfarin are within their goal therapeutic range only 50%-60% of the time.² Fluctuations in INR levels may result from numerous conditions, including medication interactions, changes in dietary vitamin K intake or absorption, or systemic health conditions that change warfarin metabolism. These conditions may lead to patients who are either under or over-anticoagulated. The risk of serious bleeding increases significantly with a supratherapeutic INR, with the risk of death and bleeding particularly increased with INR elevation over 4 or 5.^3-5 In addition, the risk of significant intracranial hemorrhage (ICH) from even minor trauma is elevated at baseline among patients taking warfarin.^{6, 7}

Means of warfarin reversal include withholding further warfarin doses or administering vitamin K, fresh frozen plasma (FFP), prothrombin complex concentrate (not widely available in the United States), and, more recently, recombinant factor VIIa (rFVIIa). Optimal dosing and preparations of these reversal agents continue to undergo scrutiny by researchers and clinicians.

Articles were selected for this review based upon their ability to present up-to-date information as well as provide answers to timely questions relevant to clinical practice. The objective of this article is to provide the reader with the latest information regarding indications for reversal of anticoagulation as well as the most efficacious and safest means of achieving reversal.

Risks and Benefits in the Aging

Source: Torn M, et al. Risks of oral anticoagulant therapy with increasing age. Arch Intern Med 2005;165(13): 1527-1532.

Torn and colleagues systematically reviewed 4202 patients seen in anticoagulation clinics in the Netherlands over 3 years. Grouping patients by age (< 60 years, 60-70 years, 71-80 years, and > 80 years), they analyzed INR values, hospitalizations, medical records, and autopsy results to determine rates of bleeding and/or thromboembolic events.

The incidence of all major bleeding events increased by age group, from 1.5 per 100 patient-years (95% CI, 1.0-2.2) in the younger than-60-years age group to 4.2 per 100 patient-years (95% CI, 3.1-5.5) in the group older than 80 years. The incidence of thromboembolic events (acute myocardial infarction, stroke, or pulmonary embolism) increased from 1.0 per 100 patient-years (95% CI, 0.6-1.6) to 2.4 per 100 patient-years (95% CI, 1.6-3.4) in the same age groups. The risk of any hemorrhage or thromboembolic event increased 2% per year of age increase.

Commentary

This paper highlights a fundamental challenge of oral anticoagulation, striking a balance between the preventive benefits and risks of bleeding. This sound study, while retrospective, shows that the most common indications for anticoagulation—atrial fibrillation, valve replacement, and post-thromboembolic event—are seen more commonly in an older population, as are the hemorrhagic sequelae. This study includes a broad population being treated with warfarin for routine indications, and the large number of enrolled patients avoids potential selection bias from the intense monitoring that often accompanies clinical trials. The data demonstrate the intuitive fact that the risk of both bleeding and thromboembolic phenomena increases with age among an anticoagulated population. Torn and colleagues provide support for the continued use of anticoagulation for established indications, but to retain a high clinical suspicion in the elderly anticoagulated population for both bleeding as well as for thromboembolic events.

Consensus Guidelines

Source: Ansell J, et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest Sep 2004;126(3 Suppl):204S-233S.

This article summarizes the guidelines of the American College of Chest Physicians (ACCP) regarding antithrombotic therapy including initiation, dosing, and monitoring. The vitamin K antagonist (warfarin) reversal guidelines were chosen for purposes of this review. These guidelines were developed after systematic review of the best available evidence to guide clinical practice. Guidelines for managing elevated INR or active bleeding in patients on warfarin are noted in Table 1.

Commentary

This review provides evidence-based guidelines toward approaching asymptomatic elevation of INR as well as active bleeding with any INR. There is room for provider discretion under each set of circumstances, leaving room for assessment of the risks and benefits of each action for individual patients. These guidelines rely on prothrombin complex concentrate, which is not as readily available across the United States, as is FFP. Acute care providers will need to take into account available resources when utilizing these guidelines. The "best evidence" is more robust for critical patients requiring emergent anticoagulation reversal. The evidence is not quite as strong for the other groups in whom the consensus opinion is based more on the panel's "gut feelings". This is probably because those other anticoagulated groups had no evidence of bleeding, thus no way of knowing whether the intervention was of any clinical use.

Anticoagulation and Trauma

Source: Cohen DB, et al. Traumatic brain injury in anticoagulated patients. J Trauma 2006;60(3):553-557.

There is widespread acceptance that anticoagulation increases the risk and severity of bleeding, but a paucity of data evaluating the extent of this risk. This article offers descriptive data on the severity of traumatic brain injury (TBI) among anticoagulated patients. The authors reviewed two large independent trauma center databases from 1999-2002 to identify 515 patients diagnosed with TBI who were concurrently taking warfarin. They divided the cases into severe TBI, with Glasgow Coma Scale (GCS) score less than 8, and minor TBI, with GCS score of 13-15.

Outcomes for severe TBI and warfarin therapy were very poor, with 88% mortality, 10% vegetative state, and 2% severe disability. The average INR was 6.5, as compared with the minor TBI victims – the half tested had an average INR of 4.4. Among those cases with anticoagulated minor TBI, mortality was also high (80%), but recovery was improved (4%-22%). Of interest, the authors identified 20 patients who were seen in an ED and sent home, one-third of them after having normal head CT results. These 20 patients eventually developed significant intracranial hemorrhage (ICH), with a mortality rate of 88%. They also identified 45 patients who were admitted after minor TBI (70% with CT on admission), who subsequently developed neurologic deterioration and significant ICH, with a deterioration time of 8 to 18 hours and 84% mortality.

Commentary

This review article highlights the significant risk of poor outcome among patients on oral anticoagulation who sustain a TBI. Limitations to this study include the retrospective format without a control group, as well as the selection bias of only including patients who met criteria for trauma database inclusion. Also, many patients received CT imaging at the time of deterioration, meaning they may have harbored asymptomatic ICH that subsequently enlarged. These factors likely affect the higher mortality rates than those for all patients on warfarin who present acutely with head injury.

The take-home message from this database review is that patients on warfarin can present with normal or near-normal neurologic and CT findings, and then subsequently develop significant ICH with devastating deterioration. Providers should have very low threshold for initial and repeat CT scanning of TBI, as well as admission and observation of anticoagulated patients with TBI.

Reversal Protocol in TBI

Source: Ivascu FA, et al. Rapid warfarin reversal in anticoagulated patients with traumatic intracranial hemorrhage reduces hemorrhage progression and mortality. J Trauma 2005;59(5):1131-1139.

Anticoagulated patients who develop traumatic ICH experience a mortality rate four to five times greater than nonanticoagulated controls, and many present with normal initial neurologic status.⁸ Ivascu and colleagues developed a protocol for the rapid evaluation, diagnosis, and reversal of anticoagulated trauma patients. This article describes the prospective implementation and initial outcomes of this protocol, which included rapid identification of all anticoagulated TBI victims, universal FFP (2 Units) preparation, expedited head CT study, and immediate reversal of anticoagulation with FFP and vitamin K for any patients found to have ICH. Protocol patients were compared with a group of historical control patients and a group of patients treated during a previous protocol that included immediate triage but not expedited anticoagulation reversal.

Eighty-two patients were entered into the protocol, with 19 (23%) demonstrating CT evidence of ICH. Demographic variables, including initial GCS score and INR among those with ICH, were not different from those without ICH (INR 2.7 vs 2.5). None of the 63 patients admitted for observation developed subsequent ICH.

Compared with either control group, protocol patients were diagnosed with ICH more quickly (40 minutes vs >2 hours), reversed with FFP more quickly (< 2 hours vs > 4 hours), showed less progression of ICH (11% vs 40%), and had lower mortality (10% vs 50%).

Commentary

The authors demonstrated that rapid identification of TBI and an aggressive treatment protocol for ICH among anticoagulated patients significantly affected morbidity and mortality among patients at their trauma center. Their previous protocol, which focused only on rapid triage and identification of ICH, did not demonstrate the decrease in mortality seen with this more comprehensive system-wide protocol that incorporated expedited FFP reversal. A multi-center validation study of this protocol would be useful, especially with the small number of patients entered into the protocol, to determine the applicability of this approach in a variety of institutions and patient populations. In the meantime, these outcomes pointed out the importance of rapid recognition and expedited management of anticoagulation-associated ICH to obtain more favorable outcomes for these patients. In contrast with the previous paper, that had a subset of patients sent home with a normal CT that developed subsequent bleeds, none of the patients admitted for observation had any subsequent bleeding. This poses the question if a protocol reversing all anticoagulated patients with TBI may be beneficial.

Rapid Timing of Reversal in ICH

Source: Goldstein JN, et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 2006;37(1):151-155.

This article focuses on the importance of the timing of reversal of anticoagulation in the setting of nontraumatic ICH. Goldstein and colleagues undertook a retrospective review of all ED patients presenting to an urban tertiary care hospital from 1998-2004 with warfarin-related ICH; examining the timing of administration of FFP and vitamin K. After exclusion criteria, 69 patients were available for analysis. The primary outcome measure was a repeat INR of 1.4 or less within 24 hours. They found that patients with successful reversal of INR had a shorter time from diagnosis to first dose of FFP (90 minutes vs 210 minutes). Multivariate analysis predicted that shorter time to vitamin K as well as FFP predicted successful reversal of INR within 24 hours. Other interventions—such as dose or route of reversal agents, intubation, or time to CT scan—did not affect INR reversal rate at 24 hours.

When the authors evaluated time to treatment and outcomes, they found that early administration of reversal agents and reversal of INR was not associated with improved outcomes at 90 days.

Commentary

This study shows the importance of rapid and aggressive administration of reversal agents to reverse anticoagulation in patients who are actively bleeding. Researchers found that among emergency interventions in warfarin-associated ICH, rapid timing is the most important reversal intervention. This study carries the limitations of a retrospective chart review, without any control group or randomization. Despite this, the consistency of intra-institution treatment allows for valid comparison. No patient received recombinant factor VIIa or prothrombin complex concentrate, but all received both vitamin K and FFP.

Unfortunately, the authors were not able to demonstrate any clinical improvement in 90-day outcomes between groups with rapid reversal of anticoagulation versus those patients with more delayed reversal. A larger prospective trial of a rapid reversal protocol for nontraumatic anticoagulation-associated ICH may change this result. In the meantime, the laboratory benefits of rapid reversal should encourage practitioners to expedite reversal agents to their patients with warfarin-related ICH.

Asymptomatic Supratherapeutic INR

Source: Yiu KH, et al. Comparison of the efficacy and safety profiles of intravenous vitamin K and fresh frozen plasma as treatment of warfarin-related over-anticoagulation in patients with mechanical heart valves. Am J Cardiol Feb 1 2006;97(3):409-411.

Yiu and colleagues conducted a randomized controlled trial comparing fresh frozen plasma (FFP) and low-dose intravenous (IV) vitamin K as reversal agents for mild to moderate over-anticoagulation among patients with mechanical heart valves. During a 24-month period, 102 patients seen at an outpatient clinic were enrolled. Participants, who did not have active bleeding, presented with supratherapeutic INR levels (INR 4-7) and were randomized to receive either 1 unit FFP or 1mg IV vitamin K, with repeat INR levels drawn at 6 hours and at 1 week. The goal was to determine safety profile (bleeding, thromboembolic events, or anaphylaxis), and INR outcomes after these reversal agents were administered.

At 6 hours post intervention, all patients demonstrated decreasing INR values, with a larger decrease (from 4.61 to 2.75 +/- 0.06) in the FFP group than in the IV vitamin K group (from 4.78 to 3.44 +/- 0.10). At 1 week after treatment, the rates of therapeutic, supratherapeutic, and subtherapeutic INR were not different between the FFP and IV vitamin K group. There were no major bleeding, thromboembolic, or anaphylactic events in either group during the study.

The authors concluded that while FFP results in a more rapid initial decrease in INR, the lack of long-term INR differences or clinical sequelae show low-dose IV vitamin K as a safe alternative to FFP.

Commentary

The population studied in this article was limited to patients who were anticoagulated for prosthetic heart valves; it was a relatively small study population limited to mild-to-moderate over-anticoagulation. A strength of this study is that it is a randomized controlled trial directly comparing FFP versus IV vitamin K for reduction of supratherapeutic anticoagulation reversal. The presence of a control group would have raised a valid question: Is there a clinical necessity to reverse asymptomatic supratherapeutic INR?

Vitamin K is usually portrayed as a therapeutic agent that should be utilized only when there is urgent need for reversal. In reality, low-dose IV vitamin K offers an alternative that does not require the volume infusion of FFP, nor does it carry the small but potential risks of infection or hematologic reaction of a blood product transfusion. This study did not address oral vitamin K as a third option, but did demonstrate the equal safety and efficacy of FFP and low-dose IV vitamin K in reducing supratherapeutic INR values.

Anaphylaxis: Debunking the Myth

Source: Riegert-Johnson DL, et al. The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5-year retrospective review. Ann Allergy Asthma Immunol 2002;89(4): 400-406.

There is much concern regarding the safety of IV vitamin K administration, with many practitioners avoiding IV administration due to a perceived risk of adverse reactions. This retrospective review shows the actual incidence of anaphylaxis after intravenous phytonadione (vitamin K1) administration. Riegert-Johnson and colleagues found that during 5 years, a total of 6572 doses of IV vitamin K were administered. Two cases of anaphylaxis occurred, with a rate of 3 per 10,000 doses (95% CI, 0.04 to 11 per 10,000 cases).

The rate of anaphylaxis to IV vitamin K found is comparable to rates of anaphylaxis with more common medications and substances. Penicillin causes anaphylaxis in 2.75 per 10,000 cases, and high-osmolarity radio contrast media causes anaphylaxis in 9 per 10,000 cases.^9,10

Commentary

This is an important study because it debunks a commonly believed myth of the danger of IV vitamin K administration. The reported rate of anaphylaxis with IV vitamin K is comparable to other frequently used medications and substances known to cause anaphylaxis. This fact provides some basis upon which to weigh the actual risks and benefits of the need for IV vitamin K versus other routes or reversal options.

One weakness of this study is its retrospective nature, which could lead to an underestimation of the true risk of anaphylaxis due to reporting bias and low rates of reported episodes of anaphylaxis or allergic reactions to IV vitamin K. Thus, the true rate of anaphylaxis to IV vitamin K may be slightly higher

Practitioners may be aware that while there is a risk of anaphylaxis with IV vitamin K, that risk is low. If IV vitamin K is chosen as a reversal agent, the safest approach is with a low dose and slow rate of infusion with close monitoring for adverse reactions.

Vitamin K: The Optimum Route

Source: Dezee KJ, et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med Feb 27 2006; 166(4):391-397.

Vitamin K administration is efficacious in reversing warfarin anticoagulation, and the optimal route of administration remains controversial. Previous studies show that IV vitamin K reverses an INR more quickly at 4 hours than oral vitamin K, but that both have equivalent reversal potential at 24 hours after administration.¹¹ DeZee and colleagues conducted a meta-analysis to evaluate the effectiveness of vitamin K by various dosing routes including subcutaneous (SC) in reversing excessive anticoagulation. They reviewed 21 randomized controlled trials and prospective trials using vitamin K for treatment of INR greater than 4 secondary to warfarin, in the absence of major hemorrhage, with a primary outcome of INR level at 24 hours after vitamin K administration.

The authors found the target INR at 24 hours was achieved in 82% with oral vitamin K (95% CI, 70-93%), 77% with intravenous vitamin K (95% CI, 60-95%), 31% of the time with SC vitamin K (95% CI, 7-55%), and 20% of the time by withholding therapy alone (95% CI, 0-47%). Bleeding or thromboembolic complications were not evaluated.

Commentary

Among these trials, oral and IV vitamin K demonstrated very similar rates of target INR levels at 24 hours, and SC vitamin K demonstrated much less success than oral or IV vitamin K, as well as no significant benefit over simply withholding warfarin. The authors were unable to determine optimal dosing of vitamin K through their meta-analysis, but the commonly used doses were 1 to 2.5 mg orally and 0.5 to 3 mg intravenously.

This systematic review gives practitioners grounds to use oral and IV vitamin K preferentially over SC vitamin K to reach target INR levels. IV vitamin K has been shown to reduce INR levels more quickly than oral vitamin K, but in the absence of significant or active bleeding, oral vitamin K has a better safety profile and is equally efficacious at 24 hours.

Recombinant Factor VIIa – The New Deal

Source: Deveras RA, et al. Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med 2002; Dec 3;137(11):884-888.

Recombinant factor VIIa is an engineered concentrate of factor VIIa, initially developed as an adjunctive therapy in hemophilia, which since has been shown to induce a procoagulant "burst" and is the topic of many studies looking into potential uses. The goal of this article was to evaluate the safety and efficacy of rFVIIa in patients requiring rapid reversal of warfarin-related anticoagulation.

In 13 patients with INR greater than 10, significant hemorrhage with any INR on warfarin, or in need of urgent procedure while on warfarin, rFVIIa was administered and INR assessed within 1 hour pre and post-administration. All subjects demonstrated significant and rapid decrease in INR after a single dose of rFVIIa, and none of the subjects suffered adverse consequences.

The study began with a higher dose of rFVIIa (90 mcg/kg), but subsequent patients received progressively decreasing doses to the 15-20 mcg/kg range, when it became apparent that even the lower doses provided adequate homeostasis. There were no adverse outcomes (i.e., pro-thrombotic events) among this case series, and in all cases of active bleeding the active bleeding ceased shortly after administration of rFVIIa.

Commentary

This uncontrolled case series demonstrated that rFVIIa immediately reversed INR values among 13 patients requiring rapid reversal of warfarin anticoagulation without adverse effects. The authors pointed out that there are limitations to traditional methods of warfarin reversal, such as significant volume administration with FFP that would make an alternative and faster reversal agent clinically appealing for patient care. The potential for a low-volume, safe, and rapid reversal agent for warfarin anticoagulation is appealing.

Although this study supports the role of rFVIIa as a potential warfarin reversal agent, the small sample size mandates further studies comparing this agent versus traditional reversal agents; cost-effectiveness analyses, safety analyses and optimal dose-defining studies are needed before we can change practice.

RFVIIa in ICH

Source: Freeman WD, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc Dec 2004;79(12):1495-1500.

The authors reviewed case series of patients treated with rFVIIa for acute nontraumatic ICH in the setting of warfarin anticoagulation. The authors assessed the effect of rFVIIa on INR, hemorrhage volume, and functional outcomes in 7 subjects. The mean INR decreased from 2.7 to 1.08 after administration of 15-90 mcg/kg rFVIIa. Subjects also were treated initially with vitamin K and/or FFP. Similar to other studies, the authors found that INR values were normalized within 2-3 hours of rFVIIa administration in nearly all patients.^{12, 13}

This small series had a 30-day mortality rate of 28.5%, which is lower than that observed in larger studies. However, functional outcomes of the 5 surviving patients were all "severely impaired."

Commentary

A rapid warfarin reversal agent is desirable in the setting of warfarin-associated nontraumatic ICH, which has a 30-day mortality of more than 50%. Because traditional warfarin reversal methods, such as FFP and vitamin K administration, are limited by volume considerations and time of onset, the authors chose to assess the therapeutic efficacy of rFVIIa. However, the retrospective nature of this study makes it difficult to tease out the effects of rFVIIa alone, given that all of the patients also were treated with FFP and/or vitamin K. While the authors reported no adverse thrombotic complications among this series, patients were not followed for long-term outcomes.

Further randomized studies with larger populations are needed to show a clinical benefit of rFVIIa that justifies the significant expense of this treatment. Although initial case series data are promising, full clinical benefit of this therapy remains to be proven. Changing clinical practice to include routine use of rFVIIa will have to wait for trials comparing reversal methods and clinical outcomes.

Conclusion/Recommendations

When and how to reverse warfarin anticoagulation are questions that health care providers confront regularly. As Torn and colleagues illustrated, the issue is increasingly relevant as acute care providers confront an aging population. Given the best available evidence, following ACCP guidelines generally will provide optimal care for our patients.

Acute care providers in trauma centers should be aware of the dismal outcome of patients who are on anticoagulation and sustain a TBI. Cohen and colleagues emphasize the importance of a low threshold for observing these patients post accident – as well as having a high index of suspicion for early and repeated CT studies. Ivascu and colleagues research demonstrated impressive improvements in mortality with an established protocol for the rapid reversal of supratherapeutic INR in brain injury patients.

Vitamin K is a therapeutic option that is effective, fast, and safe. Dezee and colleagues support dosing of vitamin K by either an oral or intravenous route, but not subcutaneously. The myths regarding the high risks of anaphylaxis due to IV vitamin K are dispersed by Riegert-Johnson and colleagues. The risk of anaphylaxis with IV Vitamin K is present, but small and comparable to rates of other anaphylaxis-producing medications regularly used. Thus, it seems prudent to use oral Vitamin K in non-urgent situations, such as the patient with asymptomatically elevated INR. In emergent situations, such as active hemorrhage or ICH, IV vitamin K should be used to more rapidly reverse the effect of warfarin, with close monitoring for the rare but serious side effect of anaphylaxis.

The morbidity and mortality of warfarin-associated ICH is high enough to support aggressive and early reversal of anticoagulation. The studies show that there is benefit in prompt and aggressive reversal, using FFP, vitamin K, and potentially, rFVIIa, whether any of these treatment modalities results in improved clinical outcome has yet to be determined.

New therapeutic options and an awareness of the available evidence will assist practitioners in optimal reversal therapies for warfarin anticoagulation. As we see increasing numbers of anticoagulated patients and the inevitable side effects, acute care providers need to be prepared to effectively evaluate the risks and benefit of diagnostic and therapeutic interventions.

References

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2. Poller L, et al. Multicentre randomised study of computerised anticoagulant dosage. European Concerted Action on Anticoagulation. Lancet Nov 7 1998;352 (9139):1505-9.

3. Hylek EM, et al. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med Jun 12 2000;160(11): 1612-7.

4. Oden A, et al. Optimal INR for prevention of stroke and death in atrial fibrillation: a critical appraisal. Thromb Res 2006;117(5):493-9.

5. Cannegieter SC, et al. Oral anticoagulant treatment in patients with mechanical heart valves: how to reduce the risk of thromboembolic and bleeding complications. J Intern Med Apr 1999; 245(4):369-74.

6. Karni A, et al. Traumatic head injury in the anticoagulated elderly patient: a lethal combination. Am Surg Nov 2001;67(11): 1098-100.

7. Lavoie A, et al. Pre-injury warfarin use among elderly patients with closed head injuries in a trauma center. J Trauma Apr 2004;56(4):802-7.

8. Mina AA, et al. Intracranial complications of preinjury anticoagulation in trauma patients with head injury. J Trauma Oct 2002;53(4):668-72.

9. Idsoe O, et al. Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull World Health Organ 1968;38(2): 159-88.

10. Caro JJ, et al. The risks of death and of severe nonfatal reactions with high- vs low-osmolality contrast media: a meta-analysis. AJR Am J Roentgenol Apr 1991;156(4):825-32.

11. Watson HG, et al. A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol 2001;115(1):145-9.

12. Sorensen B, et al. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis 2003;14(5):469-77.

13. Lin J, et al. The use of recombinant activated factor VII to reverse warfarin-induced anticoagulation in patients with hemorrhages in the central nervous system: preliminary findings. J Neurosurg 2003;98(4):737-40.