Hemostatic Therapy Should Be Used for Acute Treatment of Anticoagulation-Related Intracerebral Hemorrhage
Not only does warfarin increase the risk of intracerebral hemorrhage (ICH), but it leads to more severe hemorrhages and worse outcome. This poor prognosis is primarily a function of ongoing bleeding from the warfarin-induced hemostatic defects. Use of warfarin is a strong and independent determinant of hematoma expansion1—a major risk factor for poor outcome in spontaneous ICH2—and prolongs the window during which expansion occurs.1
Warfarin-associated ICH therefore represents a true emergency requiring rapid and sustained reversal of anticoagulation to normal or near-normal values, a position endorsed by consensus guidelines from multiple organizations. This strategy makes intuitive sense; earlier international normalized ratio (INR) correction is associated with improved outcome in warfarin users with spontaneous3 and traumatic4 ICH.
If warfarin reversal is the goal how should it be accomplished? Vitamin K, even if given intravenously, is incapable of rapidly reversing warfarin-induced coagulopathy during the peak time for hematoma growth. Still, it should be administered to achieve sustained warfarin reversal because the other agents used have relatively short half-lives. Despite a common misperception, allergic and anaphylactic reactions to intravenous vitamin K are quite rare (approximately 3 per 10 000 doses).5
There are 3 options to achieve more rapid reversal: fresh-frozen plasma, prothrombin complex concentrate, and activated recombinant Factor VII. Based on their relative impact on blood levels of clotting factors, logistics of administration, and side effect profile, prothrombin complex concentrate (PCC) is the clear choice.
Fresh-frozen plasma (FFP) is appealing because it contains all the coagulation factors and restores blood levels of all clotting factors to effective levels, yet its use is fraught with logistical barriers and has potentially life-threatening side effects. Once the decision to administered FFP is made, several hurdles must be overcome before it can be administered. The patient's blood type must be confirmed and the FFP thawed, delaying administration for, at best, >1 hour. The recommended initial dose is 15 mL/kg.6 That is a lot of fluid (a colloid to boot) and can lead to circulatory overload. This is a particular concern in this setting because many patients are on warfarin because of atrial fibrillation. Frequently the initial dose is insufficient and additional plasma is required such that the time to normalize the INR usually exceeds 24 hours.7 Additionally, the actual content of the vitamin K-dependent coagulation factors is neither specified nor consistent, so FFP may not fully reverse warfarin effects.
Even more concerning about FFP is its propensity to induce transfusion-related acute lung injury, the leading cause of transfusion-related fatalities in the United States. Transfusion-related acute lung injury is characterized by the acute onset of noncardiogenic pulmonary edema after transfusion of blood products, of which FFP is the worst offender. Thought to be immune-mediated, transfusion-related acute lung injury is associated with pulmonary microvascular damage, often requires mechanical ventilation, and has a mortality approaching 10%. Other potential complications include bloodborne infection, citrate toxicity, and allergic reactions.
PCC offers a solution to all the limitations of FFP. It consists of a concentrated lyophilized form of unactivated clotting factors II, IX, and X and, in most preparations, factor VII. It does not require compatibility testing or thawing, can be reconstituted in 50 to 150 mL of fluid, and is administered over 10 to 15 minutes.8 This eliminates delay and avoids concerns of fluid overload and transfusion-related acute lung injury. The concentration of clotting factors is specified and consistent; the INR is normalized within 10 minutes. PCC has the potential to induce thrombosis and transmit infective agents, but only isolated cases have been reported in the setting of warfarin reversal.
Activated recombinant Factor VII has been touted as a rapid and effective means of reversing warfarin coagulopathy because of its ease of use and ability to rapidly correct the INR. For several reasons this is not a good idea and is potentially dangerous. First, it only replaces one of the vitamin K-dependent factors. Second, pharmacological doses of activated recombinant Factor VII interfere with the INR assay so that it always normalizes regardless of the levels of other coagulation factor or bleeding status. This not only creates a false sense of security, but also obfuscates the ability to monitor the effect of therapy with vitamin K, FFP, and PCC. Third, thromboembolic complications of activated recombinant Factor VII are more likely among patients with pre-existing cardiovascular disease9 such as those taking warfarin for atrial fibrillation.
So do the risks and benefits in the present case of a 65-year-old woman with prosthetic heart valve and acute ICH favor reversal of anticoagulation? Absolutely. She has cardiovascular disease and may be at risk of fluid overload with FFP administration and of thromboembolic events with activated recombinant Factor VII administration. Thus, the most appropriate treatment for this patient is urgent administration of 1000 to 2000 IU PCC to rapidly reverse anticoagulation (targeting an INR of <1.4) along with 10 mg intravenous vitamin K to achieve a sustained response over the next 24 to 48 hours. The INR should be monitored at regular intervals over this time and additional PCC and vitamin K administered as needed.
Dr. Diringer participated in an Advisory Board with CSL Behring after drafting this manuscript.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part 1 of a 3-part article. Parts 2 and 3 appear on pages 2537 and 2539, respectively.
A 65-year-old woman with a prosthetic aortic valve presents within 2 hours of onset of a spontaneous lobar intracerebral hemorrhage while taking warfarin. Her international normalized ratio is 2.3 and intracerebral hemorrhage volume is 25 mL (by the ABC/2 method).
Should the patient receive vitamin K and fresh-frozen plasma on evaluation in the emergency department to reverse international normalized ratio?
If so, what is the appropriate targeted international normalized ratio level?
Should other hemostatic agents such as prothrombin complex concentrates or NovoSeven be used instead of (or in combination with) fresh-frozen plasma?
Should hemostatic therapy (PCCs or NovoSeven) be used for acute treatment of anticoagulation-related intracerebral hemorrhage?
- Received November 7, 2011.
- Revision received January 26, 2012.
- Accepted January 27, 2012.
- © 2012 American Heart Association, Inc.
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