Emergency physicians routinely encounter patients who are receiving some form of anticoagulant therapy. This population becomes increasingly challenging to treat in the face of major bleeding complications or prior to emergency surgery.

Management of anticoagulant therapy is multifaceted because of the significant individual variations in dosage requirements that make over-anticoagulation very common in this population. Additionally, because of the narrow therapeutic window for many anticoagulants such as warfarin and heparin, treatment frequently results in bleeding that can be life-threatening.

Major bleeding involving the gastrointestinal or urinary tract or the soft tissue occurs in up to 6.5% of patients on anticoagulant therapy. The incidence of fatal bleeding, such as intracranial hemorrhage, is approximately 1% annually.¹ As over-anticoagulation is commonly seen and its effects are potentially harmful to the patient, emergency physicians should know the major anticoagulants routinely used in patients presenting to the emergency department, as well as the current indications, agents used, and recommendations for reversal.

Indications for Reversal

The clear risk of anticoagulation is the possibility of bleeding, which can cause death or serious morbidity.

Emergency physicians should consider reversal of anticoagulation if patients experience bleeding in the brain, the gastrointestinal tract, the deep muscles, the retro-ocular region, or the joint spaces. Emergency physicians should also consider the severity of the hemorrhage seen, reversing in cases of shock or if the patient requires blood transfusions as a result of the bleeding.

Finally, patients should undergo reversal of anticoagulation if urgent or emergent surgery is indicated, such as for ischemic surgical events, septic shock, and treatment of open fractures.²

Anticoagulants and Recommendations for Reversal

Warfarin is a commonly used oral anticoagulant used to prevent and treat many thromboembolic conditions, such as acute deep venous thrombosis, pulmonary emboli, and ischemic strokes from clots formed on mechanical valves. Warfarin blocks the activation of Vitamin K and interferes with the carboxylation of Vitamin K–dependent coagulation factors I, VII, IX, and X, which in turn blocks the extrinsic coagulation pathway. Warfarin also blocks synthesis of antithrombotic proteins C and S, which serve to inhibit the function of factors V and VII in the coagulation cascade.

For most medical conditions requiring anticoagulation, the target international normalized ratio (INR) is 2.0 to 3.0. Two notable exceptions to this general rule are patients with mechanical heart valves and antiphospholipid antibody syndrome, who require more intense anticoagulation, with a goal INR of 2.5 to 3.5. A prolonged INR without clinically evident bleeding necessitates cessation of warfarin administration, observation, and serial INR measurements.

Patients on warfarin who experience clinically significant bleeding are eligible for reversal of their anticoagulation with three approaches: (1) stop warfarin therapy, (2) administer vitamin K, and (3) administer fresh frozen plasma (FFP) or prothrombin complex concentrates (PCCs).³

Vitamin K is often included in first-line therapy for the reversal of anticoagulation. However, normalization of INR values with only vitamin K is often slow because of the time needed for hepatic synthesis of vitamin K dependent coagulation factors. While the increase in factor VII following intravenous vitamin K administration causes the INR to fall within 4 hours, the more important increase in factor II requires 24 hours to affect the INR. This correction of coagulation factor levels takes even longer with administration of oral vitamin K.

Because of this delay to optimal reversal, it is recommended to combine vitamin K therapy with fresh frozen plasma or prothrombin complex concentrates.

Fresh frozen plasma contains all vitamin K–dependent factors and is often used in conjunction with vitamin K and prothrombin complex concentrates. However, one significant side effect remains the volume-associated sequelae from fluid overload suffered as a result of infusion. Additionally, FFP is the most commonly blamed blood product in transfusion-related acute lung injury (TRALI), and the risks and benefits of transfusion must be carefully weighed in each patient. ²

Prothrombin complex concentrates (PCCs) provide an extremely rapid and effective method to replace deficient clotting factors and correct INR. PCCs are pooled plasma products that contain factors I, IX, and X with variable amounts of factor VII and proteins C and S. When compared with Vitamin K administration, PCC injection obtained maximum correction of INR after 30 minutes compared to 24 hours after IV vitamin K administration.¹

Other studies have found that PCCs achieved a significantly more rapid and complete INR reversal and correction than FFP, due to intrinsic properties as well as faster preparation because there is no need for thawing and quicker infusion rates. PCCs also have been shown to have fewer complications related to fluid overload.

The volume of PCC needed to reverse anticoagulation is far less than the volume of FFP that is needed (typically only about 5%), which decreases the risk of fluid overload. Furthermore, infusion of FFP has been known to increase the risk of TRALI, a major cause of mortality associated with transfusion. No incidents of TRALI following administration of PCCs have been reported. While some clinicians continue to use FFP because of the lower cost per unit, larger volumes of FFP are needed for effective anticoagulant reversal, resulting in an overall cost of FFP administration that is similar to that of PCCs.²

Suggested dosing schemes include using a dose of 500 U or 8.8 U/kg may be optimal for emergent warfarin reversal in patients with an INR less than 5, with adjustment of this dose for those with higher INR values.

Recombinant activated factor VII has been proposed as an alternative agent for warfarin reversal. Bolus infusions of this agent in doses ranging from 10 to 90 mcg/kg rapidly reversed warfarin toxicity accompanied by significant bleeding.

While optimal dosing has yet to be established, the short (3-hour) half-life of recombinant activated factor VII may require multiple doses if longer hemostasis is indicated, which could increase the risk of thrombosis.¹

Unfractionated heparin binds to antithrombin III to inhibit multiple steps in the extrinsic and common coagulation pathways. Unfractionated heparin must be given parenterally and its anticoagulation effect can be monitored using the activated partial thromboplastin time, which for most purposes is 1.5 to 2.5 times the “normal” value. Unfractionated heparin administration should be stopped immediately if bleeding develops.

The anticoagulant effect of heparin can last up to 3 hours. Observation is appropriate in less severe cases with serial aPTT levels used to determine when to resume heparin therapy.

Protamine can reverse the anticoagulant effect of heparin in major bleeding complications; 1 mg intravenous protamine will neutralize 100 units of heparin administered in the previous 4 hours.

However, great care should be given with protamine administration, as 0.2% of patients receiving protamine develop anaphylaxis, which has a mortality rate of 30%.3 The risk of severe adverse reactions to protamine can be minimized by administering this reversal agent slowly.

Patients who have previously received protamine sulfate–containing insulin, who have undergone vasectomy, or who have a known allergy to fish are at increased risk of having preformed antibodies against protamine and suffering allergic reactions; these patients can be pretreated with corticosteroids and antihistamines.⁵

Low molecular weight heparin, like unfractionated heparin, anticoagulates by activating the antithrombin III complex, which in turn inactivates factor Xa. Low molecular weight heparin, however, has a plasma half-life that is 2 to 4 times as long as unfractionated heparin, which allows for dosing once or twice a day. Enoxaparin, dalteparin, and ardeparin are the most widely available of the low molecular weight heparin products. These preparations cause less bleeding than unfractionated heparin.

Protamine will neutralize the antithrombin effect of low molecular weight heparin but incompletely reverses factor Xa inhibition. In the event of clinically significant bleeding, 1 mg of protamine will neutralize 1 mg of enoxaparin and 100 units of dalteparin,³ given within 8 hours of low molecular weight heparin administration.

A second dose of 0.5 mg protamine sulfate per 1 mg of enoxaparin should be administered if the bleeding continues. Smaller doses of protamine sulfate can be given if the time since low molecular weight heparin administration exceeds 8 hours.⁵

Aspirin irreversibly blocks cyclooxygenase, a platelet enzyme that catalyzes the conversion of arachidonic acid to thromboxane A2 and promotes prostacyclin synthesis, which results in vasodilation and the inhibition of platelet aggregation. Aspirin’s antiplatelet effect lasts for the life span of the platelet, about 10 days. Upper gastrointestinal irritation is the most commonly seen side effect of aspirin therapy, while life-threatening gastrointestinal bleeding is uncommon.

Management of acute aspirin-induced hemorrhage requires the transfusion of enough normal platelets to increase the platelet count by 50,000/mcL. Because of the irreversible effect of aspirin on platelets, the coagulopathy might last for 4 to 5 days following discontinuation of aspirin therapy, and platelet transfusions may have to be repeated daily.

Other nonsteroidal anti-inflammatory agents (NSAIDs) reversibly inhibit patelet cyclooxygenase. This inhibition of platelet aggregation typically lasts less than 24 hours, with the exception of piroxicam, which has a half-life of 2 days. Because of the relatively short half-life, platelet dysfunction caused by NSAID use will usually resolve within 1 day of stopping use.

Clopidogrel and ticlopidine selectively inhibit platelet aggregation induced by ADP. Both agents carry a rare risk of TTP, even after as little as 2 weeks of therapy. Should quick reversal of these agents be required, the physician should consider platelet transfusion.³

Summary

Supratherapeutic INRs and overanticoagulation leading to clinically significant bleeding are problems commonly encountered by the emergency physician. In order to effectively diagnose and manage these problems, the emergency physician must be well versed in anticoagulants frequently used and the antidotes used to treat their overuse.

While vitamin K, FFP, and protamine have been the mainstay of anticoagulant correction to date, many new therapies such as prothrombin complex concentrates and recombinant activated factor VII hold promise in improving the outcomes of patients who require emergent reversal of their anticoagulant therapy.

References

1. Leissinger CA, Blatt PM, Hoots WK, et al. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: A review of the literature. Am J Hematol. 2008;83:137-43.
2. Vigue B. Bench-to-bedside review: Optimising emergency reversal of vitamin K antagonists in severe haemorrhage—from theory to practice. Crit Care. 2009;13:209.
3. Weber JE, Jaggi FM, Pollack, CV. Anticoagulants, antiplatelet agents, and fibrinolytics. In: Tintinalli JE, Kelen GD, Stapczynski JS, eds. Emergengy Medicine: A Comprehensive Study Guide. 6th ed. McGraw-Hill; 2004: 1354-60.
4. Hirsh J, Guyatt G, Albers GW, et al. Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2008;133:72S-3S.
5. Hirsh J, Bauer KA, Donati MB, et al. Parenteral Anticoagulants. Chest 2008;133:147S-50S.