|Year : 2015 | Volume
| Issue : 1 | Page : 5-9
Rapid reversal of anticoagulants in trauma patients
Dalia M El-Fawy MD
Department of Anesthesiology, Intensive Care, and Pain Management, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
|Date of Submission||19-Jan-2015|
|Date of Acceptance||08-Feb-2015|
|Date of Web Publication||25-Mar-2015|
Dalia M El-Fawy
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain-Shams University, Abbasia, Cairo 11566
Source of Support: None, Conflict of Interest: None
Anticoagulation therapies are one of the most commonly encountered therapies by healthcare professionals each day. One of the most important adverse effects of anticoagulation therapy is life-threatening hemorrhage, and it may result in visits to the emergency department. Some of the common reversal agents include vitamin K, protamine sulfate, desmopressin, recombinant factor VIIa, and prothrombin complex concentrates. Each of these agents has the potential to reverse specific anticoagulation therapies, but each agent has a unique administration procedure and monitoring parameters. However, these agents are not without a risk of adverse effects.
Keywords: anticoagulation, reversal, trauma
|How to cite this article:|
El-Fawy DM. Rapid reversal of anticoagulants in trauma patients. Ain-Shams J Anaesthesiol 2015;8:5-9
| Introduction|| |
With advanced understanding of hemostasis in recent years, it became apparent that fibrinogen is in a central position  . During primary hemostasis, platelets become activated  , resulting in an inside-out activation of platelet glycoprotein IIb/IIIa complex receptors that enable interplatelet linking by fibrinogen  . In addition, these activated platelets present highly efficacious surfaces for plasma coagulation to occur according to the cell-based model , , resulting in a thrombin burst  ([Figure 1]). This thrombin burst results in the conversion of fibrinogen into soluble fibrin and in the activation of factor XIII to cross-link the soluble fibrin into solid fibrin strands  . In many bleeding situations, including trauma and cardiac surgery, fibrinogen is the first coagulation element that may become critically low. This is because the fibrinogen concentration is relatively low to start with in these situations , and because there is no fibrinogen stored in the human body that might be mobilized  .
|Figure 1: Activated platelets present highly effi cacious surfaces for plasma coagulation, according to the cell-based model, resulting in the thrombin burst. As a result of the thrombin burst, fi brinogen is converted into fi brin and factor XIII (FXIII) is activated. The activated FXIII (FXIIIa) crosslinks the initially soluble fi brin monomers into an insoluble fi brin strand.|
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Excessive anticoagulation may require treatment with a pharmacologic reversal agent. The emergency department is often the first location where a patient experiencing bleeding associated with anticoagulation will present for treatment. With the evolution of newer anticoagulants now targeting more specific sites of the coagulation cascade, reversal therapies and their use must also evolve. The choice of which reversal agent to initiate must be considered carefully to promote safe and effective treatment. Knowledge of the unique aspects of each reversal agent and the anticoagulant that was administered must be reflected upon when selecting or recommending pharmacologic anticoagulation reversal.
| Products and administration|| |
Vitamin K, also known as phytomenadione or Aquamephyton, is a common reversal agent for patients with a supratherapeutic international normalized ratio (INR) and/or bleeding associated with vitamin K antagonist (VKA) therapy. In the USA, warfarin is the most commonly used VKA. Warfarin inhibits activation of the vitamin K-dependent clotting factors II, VII, IX, and X by inhibition of the vitamin K epoxide reductase enzyme  . Inhibition of this enzyme results in a deficiency of reduced vitamin K, which is necessary for clotting factor activation. Administration of vitamin K, orally or intravenously, reverses this effect of warfarin.
A common consideration associated with the use of vitamin K is the preferred route of administration. The CHEST guidelines provide a grade 1A recommendation for oral vitamin K use being preferred over subcutaneous administration for mild to moderately increased INRs without major bleeding  . Vitamin K is considered a fat-soluble vitamin. These lipophilic properties result in erratic absorption and extended durations of action when administered by a subcutaneous injection. Intramuscular administration should be avoided because of the increased risk of hematoma. As described previously, intravenous administration is preferred in emergent situations of serious or life-threatening bleeding. However, a concern with the intravenous use of vitamin K is the increased risk of hypersensitivity reactions. Anaphylactoid reactions with intravenous vitamin K are relatively uncommon. However, anaphylactoid reactions can exert serious adverse effects when they do occur. Because of these concerns, in nonsignificant bleeding situations, administration of oral vitamin K is preferred.
Recommendations for vitamin K use are described in the American College of Chest Physician (CHEST) guidelines, which were last updated in 2008  . The CHEST guidelines base their vitamin K administration recommendations on the patient's current INR and the presence of any significant bleeding ([Table 1]). Vitamin K may be repeated in 12 h depending on the INR. Patients with life-threatening bleeding should receive 10 mg vitamin K by a slow intravenous infusion, with the administration rate not exceeding 1 mg/min  .
|Table 1 Recommendations for the management of supratherapeutic international normalized ratio with|
vitamin K pharmacotherapy
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Protamines are a mixture of polypeptides that occur naturally and are isolated from the sperm of certain fish species such as salmon  . These proteins are rich in arginine, strongly basic, and have a low molecular weight. Protamine sulfate is indicated for the reversal of heparin overdosage. Protamine sulfate, itself, exerts an anticoagulant effect; however, when administered with heparin, a stable salt forms, resulting in a loss of anticoagulant effects of both agents. This stable salt forms as a result of an interaction of the strongly basic protamine and the strongly acidic heparin. The onset of action of protamine sulfate is ~5 min after intravenous administration  . Intravenous protamine sulfate is beneficial for patients experiencing bleeding associated with un-fractionated heparin (UFH). Intravenous protamine sulfate completely neutralizes the effects of UFH rapidly. The half-life of intravenous heparin is ~60-90 min. Because of this short half-life, only intravenous heparin administered during the few hours before the indication for reversal needs to be considered when calculating a protamine sulfate dose  . Protamine dosages should be adjusted, depending on the duration of time since administration of heparin, to account for rapid decreases in serum concentrations. If intravenous heparin was administered within the past few minutes, 1-1.5 mg of protamine should be used to reverse each 100 U of heparin administered. If 30-60 min have elapsed since the administration of heparin, the protamine dose should be reduced by 50% to 0.5-0.75 mg for each 100 U of heparin. If greater than 2 h have elapsed since the administration of heparin, the protamine dose should be reduced by 75% to 0.25-0.375 mg for every 100 U of heparin. Intravenous protamine sulfate may have beneficial effects for patients who require reversal associated with low molecular weight heparin (LMWH); however, the reversal of the anti-Xa activity associated with LMWH is incomplete. Because of the differences in the effects of protamine sulfate on UFH and LMWH, dosing strategies differ on the basis of agents being reversed. One milligram of protamine sulfate will neutralize ~100 U of UFH. For LMWH administered within 8 h, protamine sulfate should be dosed at 1 mg per 100 anti-Xa units of LMWH. If bleeding continues, a second dose of 0.5 mg per 100 anti-Xa units should be administered. For LMWH administered longer than 8 h ago, smaller doses of protamine sulfate can be administered  . Protamine sulfate therapy is not without risks. Serious adverse effects include severe hypotension and bradycardia. A slow intravenous injection can minimize these risks. Intravenous protamine sulfate should not exceed 50 mg over a 10-min period  .
Prothrombin complex concentrates
The prothrombin complex concentrates (PCCs) are commercially available products that are produced through the pooling of human plasma and contain clotting factors II, IX, and X, with variable amounts of factor VII.
Administration of PCCs replaces clotting factors that have been depleted by anticoagulation therapy. The PCCs are predominantly used for the reversal of warfarin, fondaparinux, and the direct thrombin inhibitor (DTIs). Because these products contain a small amount of heparin, PCCs should be used with caution in patients with heparin-induced thrombocytopenia  . Several dosing strategies for PCCs have been evaluated, but the optimal dosing strategy has yet to be determined. Doses of 25-100 IU/kg, on the basis of the factor IX composition, have been evaluated and are effective for anticoagulation reversal  . Alternatively, each IU of PCC/kg of body weight increases the plasma concentration of factor IX by 0.5-1 IU/dl  . During the infusion, patients should be monitored for the development of a headache, flushing, or changes in heart rate and blood pressure. If any of these events occur, the infusion rate should be decreased.
Similar to recombinant factor VIIa (rVIIa), correction of the INR occurs ~15 min after infusion of a PCC. The PCCs are most similar in blood clotting factor composition to fresh-frozen plasma (FFP), which is plasma that has been separated from whole blood and frozen blood. However, there are several advantages of administering PCCs compared with FFP. As the name implies, FFP must be thawed before administration, whereas PCCs are available as a powder for reconstitution and should be refrigerated. In addition, a patient's blood does not have to be typed and matched before administration of a PCC. The volume of PCC to be infused varies from 5 to 20 ml depending on the factor IX content of the product, which is significantly less than the 1000 ml of FFP that is often needed to achieve hemostasis  .
Recombinant factor VIIa
Like activated prothrombine complex concentrate (apcc), rVIIa was developed as a hemostatic agent in hemophilia patients with inhibitors. There have been no studies evaluating its efficacy for the reversal of new oral anticoagulants (NOACs) in patients with bleeding. rVIIa exerted no effect on aPTT prolongation or abnormal thrombin generation in healthy individuals receiving the oral direct thrombin inhibitor melagatran  . rVIIa failed to ameliorate bleeding complications in mice receiving dabigatran or rabbits receiving rivaroxaban, but reduced bleeding time in rats receiving edoxaban ,,, . In-vitro studies have shown that rVIIa corrected apixaban-induced abnormal thromboelastometry parameters and edoxaban-induced prothrombine time (PT) prolongation , . A recent meta-analysis evaluated the safety of off-label use of rVIIa in randomized clinical trials  . The rate of arterial thromboembolic events was higher in patients who received rVIIa than those who received placebo (5.5 vs. 3.2%, RR 1.68, 95% CI 1.20-2.36).
Hemodialysis and charcoal hemoperfusion. The use of hemodialysis for acute reversal is limited by practical concerns. However, acute hemodialysis can reduce dabigatran levels in cases of severe dabigatran-associated bleeding or in patients with renal impairment. Up to 68% of active dabigatran was removed after 4 h of hemodialysis in patients with end-stage renal disease  . Hemodialysis was used successfully to reduce the anticoagulant effect of dabigatran in a patient requiring urgent cardiac transplantation  . However, activated charcoal perfusion had a maximum binding capacity of 30 mg of dabigatran using an in-vitro assay  . Rivaroxaban and apixaban may not be dialyzable because of significant protein binding (95 and 87%, respectively)  . Charcoal hemoperfusion removes highly protein-bound drugs, but is not available routinely and has not been shown to remove rivaroxaban or apixaban. Edoxaban is only 54% protein bound, but the effectiveness of removal by dialysis or charcoal hemoperfusion has not been reported  .
Oral activated charcoal
Activated charcoal may be effective for reducing dabigatran absorption following recent ingestion (e.g. within 2 h). Activated charcoal absorbed more than 99.9% of dabigatran suspended in acidic water  . To our knowledge, there are no data on the effect of activated charcoal on factor Xa inhibitors.
Desmopressin and antifibrinolytic agents
Desmopressin (DDAVP) and antifibrinolytic agents (tranexamic acid, ε-aminocaproic acid) may be used as adjunctive therapies in the event of severe bleeding.
Serum electrolytes should be monitored in patients receiving desmopressin because of the potential for hyponatremia, which may lead to seizures. The effects of desmopressin and antifibrinolytic agents on the coagulation system raise concerns on the possibility of thrombotic events. In a meta-analysis of perioperative use of desmopressin, there was no increased risk of thromboembolic events compared with placebo  .
NOAC reversal in patients with major bleeding complications. Given the lack of specific reversal strategies and the paucity of clinical outcome data for nonspecific prohemostatic measures, supportive therapies and urgent referral for procedural or surgical intervention are the mainstays of management. Nonspecific prohemostatic agents may be considered in patients with severe or life-threatening bleeding on the basis of available, but methodologically limited evidence. Administration of aPCC (80 IU/kg) is preferred over 4-PCC (50 IU/kg) for patients receiving dabigatran on the basis of in-vitro and preclinical data ,,, .
For patients on rivaroxaban, apixaban, or edoxaban, 4-PCC (50 IU/kg) is preferred over a PCC (80 IU/kg) on the basis of in-vitro studies and studies in healthy volunteers , . The efficacy of 3-PCC for reversal is unclear. The net clinical benefit of these agents should be evaluated in light of their prothrombotic potential, especially in chronically anticoagulated patients with an increased baseline risk of thrombosis. FFP should be reserved for patients with coagulation factor deficiency such as dilutional coagulopathy or disseminated intravascular coagulation. Hemodialysis may be considered for dabigatran removal when feasible.
| Acknowledgements|| |
Conflicts of interest
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