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Home , Antifibrinolytic, Antithrombotic

How to Reverse an Agent The authors review options and precautions to consider when you need to restore hemostasis in a patient receiving an , antiplatelet, or fibrinolytic agent who is getting into trouble with bleeding or an elevated INR.

By Maria Neuner, MD, and Jonathan Davis, MD

stable patient with a supratherapeutic mechanisms is fundamental to understanding anti- international normalized ratio (INR) thrombotic reversal. Hemostasis has level and a hemorrhaging patient on three key components: , the plasma coagu- both present the acute care lation cascade, and the vessel wall (endothe- Aprovider with the same difficult challenge: determin- lium). Primary hemostasis (Figure 1) involves the ing the most appropriate way to reverse an anti- formation of a “ plug” at the site of blood thrombotic medication. vessel injury. Platelets are activated and form a plug The ubiquity of antithrombotic agent use and the to initially halt bleeding. Platelet adhesion occurs range of serious health problems that call for it are through their binding to exposed subendothelial von sobering things to stop and think about. We have Willebrand factor. patients with atrial fibrillation or venous thrombo- Secondary hemostasis (Figure 2) stabilizes the ini- embolism taking such as tial platelet plug through fibrin deposition. Fibrin and enoxaparin, patients with a history of acute results from the plasma cascade. Throm- coronary syndromes (ACS) or cerebrovascular dis- bin converts soluble to insoluble fibrin, ease on antiplatelet agents which cements and stabilizes the plug. such as and clopido- The principal endogenous antithrombotic >>FAST TRACK<< grel, patients being treated mechanisms include III, , Hemostasis has three key with fibrinolytics for acute protein S, and the system. Antithrombin III components: platelets, myocardial infarction or neutralizes most of the enzymes in the coagulation the plasma coagulation (in carefully selected cases) cascade, particularly . Proteins C and S cascade, and the blood a cerebrovascular accident, work together to inactivate certain procoagulant vessel wall (endothelium). and more. Given the high- factors, and plasmin converts fibrin to its degrada- risk nature of many of these tion products. conditions, it is essential for us to have a solid un- derstanding of the actions of antithrombotic agents AND and of what is involved in reversing them. THEIR OPPONENTS Antithrombotic can be divided into COMPONENTS OF HEMOSTASIS three principal categories: anticoagulants, antiplate- Familiarity with the process of intrinsic hemostasis let agents, and fibrinolytics (Table 1). Antithrom- by endogenous prothrombotic and antithrombotic botic medications work by blocking endogenous prothrombotic pathways (warfarin, for example, an- Dr. Neuner is chief resident and Dr. Davis is associate tagonizes the carboxylation of K–dependent program director and associate professor in the department factors) or by accentuating endogenous antithrom- of emergency medicine at Georgetown University and the Washington Hospital Center Emergency Medicine Training botic pathways (, for example, accentuates Program in Washington, DC. the effects of antithrombin III).

8 EMERGENCY MEDICINE | JUNE 2009 www.emedmag.com The various available “reversal” agents share a common characteristic: they are prothrom- botic in nature. Prothrombotic agents include blood products and medications, either of which may exert their effects on primary or secondary hemostatic pathways (Table 2). The blood prod- ucts carry the potential for bloodborne pathogen transmission. Although more detailed informa- tion regarding transfusion medicine is beyond the scope of this article, it is important to rec- ognize that platelets, (FFP), prothrombin complex concentrate (PCC), and cryoprecipitate are all derived from donated hu- man blood. Factor VIIa, on the other hand, is a recombinant product, and thus classified as a medication for the purpose of this discussion. Extracellular Matrix

REVERSAL STRATEGIES FIGURE 1. Primary Hemostasis. The intrinsic hemostatic FOR SPECIFIC AGENTS response to blood vessel injury begins with the formation of a Management of antithrombotic medication plug as platelets bind to exposed subendothelial vWF. toxicity requires varying management strate- vWF = von Willebrand factor; GP IIb-IIIaR = glycoprotein receptor gies depending on several factors, including the mechanism of action of each antithrombotic medication involved.1,2 In the following sections, antithrombotic reversal will be discussed both generally and in terms of case-based scenarios. Anticoagulant reversal, specifically antagonists and , will be addressed first, followed by antiplatelet agent reversal, fibrino- lytic reversal, and reversal of the newer (alterna- tive) antithrombotic medications. Vitamin K antagonists. Warfarin is an agent that inhibits the activation of factors II, VII, IX, and X.3 Although there is a paucity of outcomes- based literature on this topic, the American Col- lege of Chest Physicians (ACCP) has published specific consensus recommendations regarding the reversal of vitamin K antagonists.4 The re- versal of warfarin coagulopathy involves three principal measures: discontinuing the warfarin, FIGURE 2. Secondary Hemostasis. As the hemostatic administering vitamin K, and consideration of response continues, the plasma coagulation cascade leads to the production of insoluble fibrin that cements and stabilizes factor replacement with FFP, PCC, or recom- the platelet plug. binant factor VIIa (rFVIIa). The underlying indication for the patient’s antithrombotic therapy must be reviewed prior to any decision about warfarin reversal. For instance, warfarin is to help maintain a mechanical heart valve. reversal would increase a patient’s risk of throm- If atrial fibrillation is the indication, warfarin reversal boembolic complications if the purpose of the will raise the risk of mural and consequent

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TABLE 1. Commonly Used Antithrombotic Agents

Drug class Acts on Examples

Anticoagulants

vitamin K antagonists II, VII, IX, X warfarin

heparins Xa, others UFH, LMWH

pentasaccharides Xa , indraparinux

direct thrombin inhibitors II , ,

Antiplatelet agents

NSAIDs prostaglandin aspirin

ADP clopidogrel, ticlodipine

pyrimido-pyrimidine cAMP

glycoprotein IIb/IIIa receptor , , antagonists

Fibrinolytics

plasminogen activators , ,

UFH = unfractionated heparin; LMWH = low-molecular-weight heparin; NSAIDs = nonsteroidal anti-inflammatory ; ADP = adenosine diphosphate; cAMP = cyclic adenosine monophosphate

ischemic . A careful risk-benefit analysis must vitamin K, differ depending on the degree of devia- be undertaken on a case-by-case basis. In certain tion from the therapeutic target range for INR. If instances the decision is made easier due to one of the patient’s INR is between 3 and 5, a single dose of two relatively firm indications for warfarin reversal: warfarin should be withheld; between 5 and 9, one serious or life-threatening hemorrhage or the need or two doses should be withheld and 1 to 5 mg of for invasive procedures. A softer indication is cor- oral vitamin K should be considered; and if the INR rection of a supratherapeutic INR level in a mildly is above 9, warfarin should be stopped and 2.5 to 5 symptomatic (limited to nuisance-level bleeding) or mg of oral vitamin K considered.4 Oral vitamin K entirely asymptomatic patient. given according to these guidelines will significantly Scenario 1: An asymp- reduce INR within 24 to 48 hours. >>FAST TRACK<< tomatic elderly female pa- Scenario 2: A patient with a supratherapeutic INR tient with a supratherapeutic on warfarin (INR = 4.6) with an active lower GI bleed The underlying indication for the patient’s INR level (INR = 12) who is and associated vital sign abnormalities (mild tachycardia, antithrombotic therapy referred by her primary care borderline hypotension). must be reviewed prior provider for evaluation. Patients with serious or life-threatening bleeding to any decision about Mildly symptomatic or need more aggressive reversal of their coagulopathy. warfarin reversal. asymptomatic patients with Recommendations include withholding warfarin ther- elevated INR need frequent apy, giving intravenous vitamin K (up to 10 mg slow in the short term, followed by an adjust- infusion), and supplementing these interventions ment in warfarin dosage. The ACCP’s management with FFP, PCC, or rFVIIa, depending on the urgency recommendations, including those on the dosing of of the situation.5 In patients with life-threatening

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bleeding (such as intracranial hemorrhage), there doses. The effects of vitamin K can overcorrect the may not be enough time to wait for FFP to be INR or last for a longer period than desired (war- thawed and delivered from the blood bank. In ad- farin “resistance”), particularly with higher doses, dition, the amount of FFP required to fully correct and may last up to 7 days. the INR is considerable and may take hours to in- Intravenous vitamin K has long been shunned by fuse. Therefore, guidelines recommend bypassing health care providers because of its association with FFP for other alternatives, such as rFVIIa or PCC. anaphylactic reactions. Although controlled data are It is important to note, however, that both rFVIIa lacking, a large case series demonstrated a lower and PCC have been associated with an increased rate of serious allergic reactions—approximately 3 risk of thromboembolic events, which must be per 10,000 doses—than is generally appreciated.6 weighed in the overall risk-benefit equation when Interestingly, reactions may in fact be related to the contemplating their use. pharmaceutical vehicle and not to the vitamin itself. The delayed and unpredictable response to both Emergency medicine textbooks typically advocate subcutaneous and intramuscular administration of a conservative approach to the use of intravenous vitamin K makes those routes inappropriate for anti- vitamin K, recommending it for use only in patients coagulant reversal. Adequate effects are typically with life-threatening bleeding, suicidal vitamin K achieved within 24 hours when the vitamin is ad- antagonist ingestion, or “super-warfarin” poisoning, ministered orally, or within 12 hours when it is given as in rodenticide ingestion. intravenously. For asymptomatic (or mildly symp- Overall, the risks associated with intravenous tomatic) patients, it is best to start with lower oral vitamin K have been exaggerated. With this said,

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TABLE 2. Prothrombotic Agents

Reversal agent Mechanism of action Typical adult dosage*

Medications

1° hemostasis dDAVP releases vWF 0.3 μg/kg IV

2° hemostasis vitamin K rejuvenates factors varies II, VII, IX, X

protamine reverses heparin 50 mg IV maximum

rFVIIa activates coagulation 30 μg/kg IV (range cascade 15-90 μg/kg)

/ variable

Blood products

1° hemostasis platelets supplies platelets 1 unit (apheresis) or “6 pack” IV

2° hemostasis FFP supplies clotting factors 5-15 mL/kg IV

PCC supplies factors II, 20-50 IU/kg IV VII, IX, X

cryoprecipitate supplies factor VIII, 10 units IV vWF, and fibrinogen

* These are general guidelines, as dosing for antithrombotic agent reversal has not been firmly established. dDAVP = deamino-D-arginine vasopressin (desmopressin); vWF = von Willebrand factor; IV = intravenously; rFVIIa = recombinant factor VIIa; FFP = fresh frozen plasma; PCC = prothrombin complex concentrate

practitioners experienced in administering intra- cases of persistent coagulopathy despite initial inter- venous vitamin K recommend a very slow, dilute, ventions aimed at reversal. controlled infusion (1 mg per hour), despite the The use of PCC can be considered for the treat- maximum infusion rate of 1 mg per minute recom- ment of hemophilia in patients who have developed mended in the medication inhibitors to single-factor concentrates. The concen- >>FAST TRACK<< package insert, because the tration of vitamin K–dependent factors is 25 times risks, although very rare, higher in PCC than in FFP (and therefore the volume Intravenous vitamin K are real. needed for effect is much less). This is not always a has long been shunned by health care providers In patients with serious practical option, however, because PCC is not uni- because of its association bleeding, 5 to 15 mg/kg formly available “on demand” in the United States. with anaphylactic IV FFP should be admin- When there is not enough time for the thawing of reactions. istered.7,8 In the average FFP to treat life-threatening hemorrhage and PCC is adult, this amounts to ap- unavailable, the use of rFVIIa should be considered as proximately 3 to 4 units of its effects are immediate.9 The typical recommended FFP. There is no additional benefit to be gained dose of rFVIIa in this setting is anywhere from 15 to 90 from exceeding this recommended dose. Rather, in- μg/kg IV. Administration leads to a burst of thrombin fusing more FFP increases the potential for volume generation at sites of vessel injury. The use of rFVIIa overload. The treatment may need to be repeated in is associated with theoretical and anecdotal benefits,

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but since outcomes-based data are lacking, a trial of Scenario 3: A patient who receives UFH for treatment more “traditional” therapies (vitamin K, FFP) is typi- of a recurrent deep venous thrombosis and develops coffee- cally indicated first.10 As a general rule, rFVIIa should ground emesis following heparin bolus. be reserved for use as a rescue agent in patients with Directed treatment of the bleeding source and serious or life-threatening bleeding complications of waiting for the effects of heparin to simply dissi- antithrombotics for whom conventional therapies have pate on its own represent the most straightforward failed or are unavailable. approach to this problem. Alternatively, protamine Heparin. Heparins bind and activate antithrom- sulfate may be given. Protamine is a basic protein bin III, which in turn inactivates factors Xa and IIa. that binds to heparins, forming a stable salt. It should The half-life of unfractionated heparin (UFH) is 30 be administered cautiously, with a maximum intra- to 150 minutes, and the level of anticoagulation can venous dose of 50 mg over 10 minutes. Protamine is be followed with the activated partial thromboplas- dosed in direct proportion to the amount of heparin tin time (aPTT). Low-molecular-weight heparins received (1 mg protamine for every 100 U of heparin (LMWH) inactivate factor Xa primarily. Reversing administered in the preceding few hours). The risks anticoagulant effects of heparins involves two prin- of protamine include allergic phenomena, as well as cipal strategies: allowing the anticoagulant effect to the potential for platelet aggregation, which may dissipate over time or protamine administration. cause either bleeding (reduced number of functional Low-molecular-weight heparins present a special platelets) or thrombosis. circumstance, as there is no proven, reliable method There is currently no reliable available for their reversal. for LMWH. Given its comparatively long half-life,

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discontinuation is a less attractive reversal option inhibitors (DTIs). Fondaparinux, a factor Xa inhibi- for LMWH. Similarly, protamine is less reliable tor, has begun to take on a role in the management for LMWH as compared with UFH. Fortunately, of ACS. In addition, argatroban and bivalirudin however, bleeding complications related to LMWH are DTIs being used in ACS patients undergoing are infrequent. One important exception is patients interventional procedures. Currently there are no with underlying renal disease, who are more prone specific for bleeding in patients receiving to LMWH-related bleeding complications than are these medications. There is some literature to sup- those with normal renal function. port the use of rFVIIa in patients with complications Antiplatelet agents. There are no formal guide- while on these medications, but further investigation lines and limited data regarding optimal strategies is needed. for reversing antiplatelet agents. Available options include discontinuing the antiplatelet medication, KNOW YOUR ARSENAL administering desmopressin (deamino-D-arginine Antithrombotic agents are ubiquitous and are uti- vasopressin [dDAVP]), and transfusing platelets. In lized in the treatment of many high-risk conditions. addition, there is a potential role for rFVIIa in this Anticoagulants, antiplatelet agents, and fibrinolytics setting. If you have time and the patient does not all carry the potential for bleeding complications. have life-threatening bleeding, discontinue the an- With knowledge regarding the arsenal of available tiplatelet medication and consider dDAVP at a dose reversal agents and strategies, the emergency prac- of 0.3 μg/kg IV (approximately 20 μg for an adult titioner is armed with the essential tools to safely patient). In the case of serious or life-threatening and effectively manage bleeding complications of bleeding, administer dDAVP, transfuse platelets, and antithrombotic medications. Q if all else fails, consider the use of rFVIIa as a rescue agent in the direst situations. REFERENCES Fibrinolytic agents. In patients with massive 1. Cruickshank J, Ragg M, Eddey D. Warfarin toxicity in the emer- gency department: recommendations for management. Emerg bleeding, hemodynamic compromise, or intracra- Med (Fremantle). 2001;13(1):91-97. nial hemorrhage following fibrinolytic administra- 2. Kessler CM. Urgent reversal of warfarin with prothrombin com- plex concentrate: where are the evidence based data? J Thromb tion, all anticoagulant, antiplatelet, and fibrinolytic Haemost. 2006;4(5):963-966. medications should be immediately discontinued. 3. Hirsh J, Fuster V, Ansell J, Halperin JL; American Heart Associa- In addition, give medication-specific reversal agents tion/American College of Cardiology. American Heart Associa- tion/American College of Cardiology Foundation guide to warfa- based on the antithrombotics that are “on-board” at rin therapy. J Am Coll Cardiol. 2003;41(9):1633-1652. the time. The central strategy for reversal of fibrino- 4. Ansell J, Hirsch J, Hylek E, et al. and manage- ment of the vitamin K antagonists: American College of Chest lytic agent–related bleeding involves preservation of Physicians. Evidence-Based Clinical Practice Guidelines (8th fibrin. Cryoprecipitate may be utilized to replenish Edition). Chest. 2008;133:6(suppl):160S-198S. 5. Schulman S, Bijsterveld NR. Anticoagulants and their reversal. fibrinogen stores (particularly when fibrinogen lev- Transfus Med Rev. 2007;21(1):37-48. els are less than 100 mg/dL), and FFP may be ad- 6. Riegert-Johnson DL, Volcheck GW. The incidence of anaphylaxis ministered to replete all coagulation factors (which following intravenous phytonadione (vitamin K1): a 5-year retro- spective review. Ann Allergy Asthma Immunol. 2002;89(4):400- fuels the conversion of 406. fibrinogen to fibrin). An- 7. American Society of Anesthesiologists Task Force on Periopera- >>FAST TRACK<< tive Blood Transfusion and Adjuvant Therapies. Practice guide- tifibrinolytic agents such lines for perioperative blood transfusion and adjuvant therapies: The central strategy for as aminocaproic acid serve an updated report by the American Society of Anethesiologists reversal of fibrinolytic Task Force on Perioperative Blood Transfusion and Adjuvant as an additional option Therapies. Anesthesiology. 2006;105(1):198-208. agent–related bleeding but are rarely utilized in involves preservation of 8. O’Shaughnessy DF, Atterbury C, Bolton Maggs P, et al. Guide- this setting. lines for the use of fresh-frozen plasma, cryoprecipitate and fibrin. cryosupernatant. Br J Haematol. 2004;126(1):11-28. Alternative antithrom- 9. Ingerslev J, Vanek T, Culic S. Use of recombinant factor VIIa botic agents. The search for for emergency reversal of anticoagulation. J Postgrad Med. novel antithrombotic agents has made great strides in 2007;53(1):17-22. 10. O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thrombo- recent years. Two new antithrombotic classes include embolic adverse events after use of recombinant human coagu- the factor Xa inhibitors and the direct thrombin lation Factor VIIa. JAMA. 2006;295(3):293-298.

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