5

The most commonly used vitamin K antagonist (VKA) is warfarin.1 VKAs exert their anticoagulant effect by interfering with the synthesis of the vitamin K–dependent clotting factors II, VII, IX, and X.² VKAs inhibit the recycling of vitamin K epoxide to its reduced form. The reduced form of vitamin K is necessary for the γ-carboxylation of glutamate residues in the N-terminal region of the vitamin K–dependent coagulation factors. γ-Carboxylation is necessary for calcium binding, which creates a conformational change in the protein structure and promotes the binding of vitamin K–dependent factors to cofactors on phospholipid surfaces, thereby exerting their coagulant effect.

When the anticoagulant effect of VKA must be reversed, the urgency of the clinical situation (elective versus emergency surgery), the half-life of the drug, and the half-life of the vitamin K–dependent coagulation factors need to be considered.

Outpatient Management of Vitamin K Antagonist Reversal

The American College of Chest Physicians (ACCP) guidelines on the pharmacology and outpatient management of VKA delineate management options based on the international normalized ratio (INR) value and the presence of bleeding.2 If the INR is supra-therapeutic but < 5, a dose can be withheld or adjusted, the INR can be monitored more frequently, and therapy can be resumed when the INR is in the therapeutic range. If the INR is ≥ 5 but < 9, then one of more doses can be withheld, the INR monitored more frequently, and therapy can be resumed at an adjusted dose once the INR is in the therapeutic range. Alternatively, the guidelines call for the use of oral vitamin K in the following manner: omitting a dose of warfarin and administering 1 to 2.5 mg of vitamin K if the patient is at risk of bleeding, or administering 5 mg or less of vitamin K if the patient requires urgent surgery and rapid reversal with additional doses if the INR is still high after 24 hours. If the INR is > 9, and the patient has no serious bleeding, the guidelines call for withholding therapy and administering a higher dose of vitamin K (2.5 to 5 mg) with more frequent INR monitoring. In patients with serious bleeding and elevated INR, regardless of the magnitude of elevation, the guidelines recommend withholding warfarin, and administering 10 mg of vitamin K by slow intravenous infusion, along with fresh frozen plasma, prothrombin complex concentrate (PCC), or recombinant factor VIIa depending on the urgency of the situation. Vitamin K dosing can be repeated as necessary. These recommendations are summarized in Table 5.1.

Emergent Reversal of Vitamin K Antagonist Effect

Vitamin K

Oral vitamin K has excellent bioavailability, but intravenous administration has the advantage of more rapid onset of action, and there is variability in the efficacy of the various oral preparations of vitamin K.³ Intravenous vitamin K has a more rapid onset of action than does subcutaneous vitamin K, although the later was just as efficacious at 72 hours.⁴ Furthermore, subcutaneous vitamin K has unpredictable bioavailability and clinical efficacy.^5,6 Intravenous vitamin K was noted to be faster at 2 hours when the INR was > 10 but of equal efficacy when the INR was between 6 and 10.⁷ Thus intravenous vitamin K would be the route of choice if there is active hemorrhage; however, it is not recommended as a sole agent if more rapid correction of the INR is needed.⁸

Intravenous vitamin K must be infused slowly to prevent an anaphylactoid reaction. This reaction, although potentially fatal, remains rare (an estimated 3 cases per 100,000), and the benefits of hemostasis outweigh the risk, particularly in the setting of neurosurgical bleeding.⁹ The recommended infusion rate is 1 mg per minute, although lower rates, as low as 1 mg per hour, have been suggested.¹⁰ Common practice is to dilute vitamin K in 50 mL of intravenous fluid and administer it over 30 minutes.¹¹

The onset of the effect of vitamin K depends on the half-life of the coagulation factors. Factor VII, which has a half-life of 5 hours, is repleted most rapidly, whereas the level of factors II, IX, and X, with half-lives of 65, 25, and 40 hours, respectively, will not be restored to hemostatic levels for 24 to 72 hours. Consequently, replacement of coagulation factors with fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), or recombinant factor VIIa (rFVIIa) is necessary for rapid reversal of the effect of VKAs.

Table 5.1 American College of Chest Physicians (ACCP) Guidelines on the Pharmacology and Management of Patients Receiving Vitamin K Aantagonists

Warfarin reversal is the most common indication for the use of FFP in the United States.12 The widely used dose of FFP is 15 mL/kg. There are data to suggest that this dose may be insufficient to correct the coagulopathy, as factor IX levels may remain low.¹³ Dosages up to 40 mL/kg have been recommended,¹⁴ and patients may require a total volume of 2 L.¹⁵ The disadvantage of the use of large volumes of FFP is the risk of fluid overload; in addition, each unit of FFP expands the plasma volume and reduces the effective increase in coagulation factor activity. Earlier administration of FFP increases the likelihood of correction of coagulopathy within 24 hours.¹⁶ A reduction in mortality and hemorrhage progression can be achieved by the implementation of institutional protocols aimed at rapid diagnosis and infusion of FFP.17 Nevertheless, several studies report difficulties with FFP administration primarily due to the time needed to prepare the product and the risk of fluid overload, as many patients receiving OAC may have heart disease.^16,18,19 As with any blood-derived product, FFP entails the risk of transmission of infectious agents. With these difficulties in mind, alternative therapies to FFP, such as PCCs and rVIIa, have been studied and have made their way into treatment guidelines.

Prothrombin Complex Concentrates

The PCCs are plasma-derived products that contain factors II, V, VII, and IX.²⁰ Their Food and Drug Administration (FDA)-approved indication is for the treatment of factor IX deficiency in hemophilia B, and their labeling cites only the measurement of factor IX activity. The formulations vary in their coagulation factor composition; most products available in the United States have much lower amounts of factor VII activity than factor IX activity. The available PCCs are summarized by Schulman and Bijsterveld.¹⁵ These products are derived from pooled human plasma; thus, they entail the risk of transmission of infectious agents. Consequently, all of these products are treated to eliminate viruses. The factor concentration is about 25 times higher than that of FFP; thus, much smaller volumes of these products are necessary for effective treatment. The ACCP guidelines on the pharmacology and management of VKAs emphasize that “immediate and full correction [of coagulopathy] can only be achieved by the use of factor concentrates”² due to the limitation associated with FFP as stated above.

A dose of 500 IU of PCC for VKA reversal, based on factor IX activity, has been recommended along with vitamin K in patients with an INR of ≤ 5.²¹ INR reversal was achieved in ≤ 10 minutes with a sustained effect at 12 to 24 hours. Higher doses, up to 1500 IU, may be required for patients with an INR > 5, or weight-based dosing at 26 IU/kg has been suggested.²² Dosing can also be calculated using the patient’s INR, target INR, and body weight.¹⁵ The factor levels can be roughly estimated based on the INR, and the difference between starting and target coagulation factor levels calculated. The difference is multiplied by the patient’s weight in kilograms, and the product is the number of units of coagulation factor concentrate or milliliters of FFP that need to be administered. This formula overestimates the amount of replacement necessary, because the coagulation factors are distributed in the plasma volume, which is about 70% of the body weight.

Prothrombin complex concentrate carries the risk of both venous and arterial thromboses.²⁰ High doses of PCC may increase the risk of thromboembolism due to the accumulation of coagulation factors with longer half-lives (factors II and X) and the presence of activated coagulation factors in the product. The risk varies, as some formulations contain different levels of activated coagulation factors, and some products have included protein C and S to provide a balance between procoagulant and anticoagulant proteins and antithrombin and heparin to inhibit the in vivo activation of clotting factors.

The use of PCCs in the setting of intracerebral hemorrhage (ICH) has been studied, and this treatment has a superior reversal of anticoagulant effect with respect to correction of the INR compared with FFP and vitamin K or vitamin K alone. Clinical outcomes include a decrease in hematoma size and in perioperative bleeding. INR reversal was achieved in 84% of patients who received PCC, 39% of patients who received FFP, and 0% of the patients who received vitamin K alone. There was, however, no statistically significant effect upon clinical outcome. Several of the patients in each of these studies developed thrombotic complications. Statistical analysis of data did not permit identification of the increased risk due to the treatment with PCCs. All of these studies were retrospective or the treatment group was compared with historical controls. These findings remain to be confirmed by randomized controlled study.17–21

Recombinant Factor VIIa

Recombinant factor VIIa (rFVIIa) was initially used to treat bleeding episodes in patients with hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency).²³ In the United States it is FDA approved for use in hemophilia A and B bleeding episodes, prophylaxis of bleeding in the surgical setting in those patients, in patients with factor VII deficiency, and in patients who have acquired factor VIII or IX deficiencies due to inhibitors. It is widely used off-label in a variety of scenarios that involve surgical bleeding of uncontrolled bleeding. In regard to ICH, rFVIIa has been studied in the settings of traumatic brain injuries, spontaneous ICH, and anticoagulant-associated ICH.

In the setting of traumatic ICH, the efficacy of rFVIIa was studied in patients with traumatic brain injuries who were not anticoagulated in a randomized controlled trial.²⁴ Patients were randomized to placebo or to escalating doses of rFVIIa ranging from 40 to 200 µg/kg. There was no significant difference in mortality or adverse event, but there was a trend toward decreased hematoma volume in those receiving a dose of 80 µg/kg or higher. There was also a trend toward increased rate of DVTs.

In the setting of spontaneous ICH, rFVIIa was studied by Mayer et al^25–28 in four randomized controlled trials. In the larger of the two dose-escalation trials, 399 patients with ICH were randomized to either placebo or escalating doses of rFVIIa (40, 80, or 160 µg/kg).²⁵ Patients with oral anticoagulant use were excluded. Patients treated with rFVIIa had decreased hematoma expansion and improved mortality and functional outcomes at 90 days. The treatment arm, though, experienced a higher rate of thromboembolic events (7% compared with 2% in the placebo arm). In a phase 3 trial conducted by the same group,²⁸ 841 patients were randomized to receive placebo or 20 or 80 µg/kg of rFVIIa. Again, decreased hematoma expansion was noted, but there was no difference in mortality or incidence of poor clinical outcomes. There was an increase in the incidence of arterial thromboembolic events in the group treated with 80 µg/kg. Hence, rFVIIa has not been approved for use in spontaneous ICH.

The efficacy of rFVIIa in reversing anticoagulation has been studied. In a case series of 13 patients, rFVIIa was given to patients receiving oral anticoagulation who had clinically significant bleeding or who had excessively high INR (> 10).²⁹ Doses varied from 15 to 90 µg/kg. In all patients, the INR was immediately reduced. Factor activities were measured, and only factor VII was increased. In a prospective study of patient receiving oral anticoagulation with an acute major bleeding event, rFVIIa was given at a fixed dose of 1.2 mg for reversal of anticoagulation.³⁰ Mean INR was significantly reduced and a favorable hemostatic effect was noted in 14 of the 16 patients in the trial. Some patients, however, received vitamin K and FFP.

In a case series of patients with central nervous system hemorrhages, rFVIIa was given in conjunction with FFP.³¹ Each patient received 1.2 mg of rFVIIa. All had normalization of their INR within 2 hours. Surgical blood loss was ≤ 100 mL. Another similar case series reported the use of rFVIIa in addition to FFP and vitamin K (dose range 15–90 µg/kg). The INR decreased from a mean of 2.7 to 1.08. In a retrospective, controlled study of warfarin-associated ICH, 12 patients who received rFVIIa in addition to FFP and vitamin K were compared with 15 who did not.32 Mortality was higher in the rFVIIa group, but these patients had worse Glasgow Coma Scale scores at presentation. Time to correction of INR was earlier in the rFVIIa group (8.8 versus 32.2 hours), and the volume of FFP was almost half. One patient in the rFVIIa group developed disseminated intravascular coagulation, but this patient had renal disease and had received multiple doses of rFVIIa. In another retrospective study, the efficacy of an emergency department protocol to administer 1.2 mg of rFVIIa to patients with warfarin use and traumatic ICH was studied.³³ Twenty patients were included in each cohort. Time to normalization of INR was earlier in the rFVIIa cohort (4.8 versus 12.5 hours). No difference in mortality or incidence of thrombotic events was noted.

In light of the evidence above, rFVIIa seems to play no major role in the management of ICH, either related or unrelated to warfarin treatment, and its use should be reserved for situations in which other therapies have failed.

Heparins

Heparins are routinely used in acute coronary syndromes and for treatment and prophylaxis of DVT. They are also used as bridging therapy for patients with prosthetic heart valves and high-risk atrial fibrillation. Treatment in acute coronary syndromes is usually short term, only during acute hospitalization. For DVT, where anticoagulation is usually for longer durations, heparins are often used until the therapeutic effect of VKAs is achieved. The wide use of these drugs often impacts the perioperative management of neurosurgical patients.³⁴

Unfractionated Heparin

Unfractionated heparin (UFH) is a heterogeneous mixture of sulfated glycosaminoglycans derived from porcine intestines.³⁵ It exerts its anticoagulant effect by binding to antithrombin via a high-affinity pentasaccharide present in about a third of heparin molecules. The heparin–antithrombin complex has a high affinity for factor Xa, and the inactivation of this coagulation factor provides the majority of the anticoagulant activity of heparin. Larger molecules of heparin can also inactivate thrombin (factor IIa) and provide additional anticoagulant effect.

Unfractionated heparin can be used intravenously for full-dose systemic anticoagulation or, at lower doses, for DVT prophylaxis. The therapeutic effect of intravenous UFH is monitored with the partial thromboplastin time (PTT). In patients receiving UFH who experience life-threatening bleeding, as in the case of ICH, the drug must be promptly withheld and its therapeutic effect reversed. Because the half-life of intravenous UFH is short (60–90 minutes), interruption of the dosing is the most common means to treat bleeding episodes caused by this medication.

More immediate correction of heparin-induced coagulopathy can be achieved by treatment with protamine. Protamine sulfate is a basic protein derived from fish sperm and can rapidly reverse heparin by binding to it and forming a stable salt³⁶; 1 mg of protamine sulfate will neutralize approximately 100 U of UFH. The dose of protamine is calculated from the amount of UFH given in the previous 3 hours. Thus, for a dose of 1,200 U per hour of UFH, 12 mg of protamine will reverse the dose of the past hour, 6 mg for the hour before that, and 3 mg for the hour before that, for a total dose of 21 mg. The maximum dose of protamine is 50 mg, and it has a short half-life of about 7 minutes. The effect of protamine can be monitored with the PTT. Severe side effects of protamine can include bradycardia and hypotension, which can be avoided by slow infusion. Patients who may have received protamine-containing insulin, undergone vasectomy, or have a sensitivity to fish may have preformed antibodies to protamine and are at risk of allergic reactions including anaphylaxis. Such patients may be pretreated with corticosteroids and antihistamines.

Low molecular weight heparins (LMWHs) are synthesized from UFH by chemical or enzymatic depolymerization.36 These LMWHs include enoxaparin, dalteparin, danaparoid sodium, nadroparin, and tinzaparin. They have a greater inhibition of factor Xa compared with thrombin. They similarly bind to thrombin by a pentasaccharide chain present in less than a third of all molecules. LMWH is typically administered in a weight-based dose and has a renal clearance, so it should be given with caution to patients with creatinine clearances of < 30 mL/min. The therapeutic effect of LMWH can be monitored by obtaining the anti-Xa level with a therapeutic level of 0.4 to 0.8 units/mL. Routine monitoring of the anti-Xa level is usually not required; however, it may be necessary during pregnancy (where the plasma volume increases over time) or in patients with borderline renal function.

Heparin Pentasaccharide

Heparin pentasaccharide (fondaparinux; trade name Arixtra, Glaxo Smith Kline, Parsippany, NJ) is a synthetic analogue of the antithrombin-binding pentasaccharide motif of heparins.³⁶ It selectively inhibits factor Xa and has a longer half-life, allowing for once daily dosing. Fondaparinux has been studied in the treatment and prophylaxis of DVT and in the treatment of acute coronary syndromes.³⁷ It has a safety profile similar to that of unfractionated heparin and LMWH with respect to bleeding complications. It is contraindicated in patients with creatinine clearance < 30 mL/min. It has also been used safely in patients with heparin-induced thrombocytopenia. The dose for DVT prophylaxis and acute coronary syndromes is 2.5 mg. A higher dose of 7.5 mg is used for DVT treatment. It can be weight adjusted, with 5 mg used in patients with a body weight of < 50 kg and 10 mg in patients with a body weight of > 100 kg.

Unlike UFH, the half-lives of LMWHs and fondaparinux are long (8–12 hours and 17–21 hours, respectively). Should a patient experience bleeding while being treated with these agents, interruption of dosing will not lead to a rapid decline in anticoagulant activity.

Protamine sulfate can be given to reverse the anticoagulant effect of LMWH, but it is not completely effective. Protamine primarily binds to the larger heparin molecules and reverses the antithrombin effect; it has minimal impact on the anti-Xa effect. The ACCP guidelines recommend using 1 mg of protamine for each 100 anti-Xa units of LMWH. For enoxaparin, 1 mg is equivalent to ~100 anti-Xa units.

Fondaparinux has no approved antidote. The anticoagulant effect cannot be inhibited by protamine. Because its mechanism of action is to antagonize factor Xa, generation of excess Xa by treatment with rVIIa has been investigated. In a study of 16 healthy volunteers, subjects were randomized to receive 10 mg of fondaparinux and 90 µg/kg of rFVIIa (n = 8), fondaparinux and placebo (n = 4), or placebo and rFVIIa (n = 4).38 Thrombin generation and activity were measured. Fondaparinux doubled the thrombin generation time, decreased the thrombin potential, and decreased the prothrombin activation peptide fragment 1 + 2 (F 1 + 2). All of these measures were reversed with rFVIIa. Furthermore, the modestly slightly increased activated partial thromboplastin time (aPTT) and prothrombin time (PT) after fondaparinux administration was normalized by rFVIIa. There are no clinical studies examining the role rFVIIa in reversing fondaparinux in the setting of bleeding.

Oral Direct Xa Inhibitors

Oral Xa inhibitors are small synthetic molecules that bind to factor Xa and inhibit its enzymatic function.³⁸ Rivaroxaban has been approved by the FDA for DVT prophylaxis after orthopedic surgery in a dose of 10 mg daily and for prevention of arterial embolization in patients with nonvalvular atrial fibrillation at a dose of 20 mg daily.³⁸ It was shown to be noninferior to enoxaparin for treatment of DVT and was equally effective as warfarin in atrial fibrillation in the ROCKET AF trial (Rivaroxaban once daily, Oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation).³⁹ As with fondaparinux, there is no antidote for rivaroxaban, but rFVIIa has been shown to partially reverse rivaroxaban-induced prolongation of bleeding time, PT, and thrombin generation in animal models.³⁸

Direct Thrombin Inhibitors

Direct thrombin inhibitors (DTIs) are synthetic molecules that inhibit soluble and fibrin-bound thrombin.⁴⁰ There are four FDA-approved DTIs that are given intravenously: lepirudin, desirudin, bivalirudin, and argatroban. An oral alternative is available; the one furthest along in development is dabigatran.

Lepirudin can be used in the management of heparin-induced thrombocytopenia (HIT). It is given with or without a bolus of 0.4 mg/kg followed by an infusion at a rate of 0.15 mg/kg/h. Drug may accumulate due to the formation of antibodies that delay renal clearance, so the dose must be adjusted based on aPTT values.

Desirudin is FDA approved for DVT prophylaxis in patients undergoing hip surgery. It is given subcutaneously at a dose of 15 mg twice daily and was shown to be superior to unfractionated heparin and enoxaparin. In severe renal impairment, dose reduction and monitoring of aPTT has been recommended.

Bivalirudin is a synthetic molecule that reversibly binds to thrombin that accounts for its better safety profile with respect to bleeding compared with lepirudin and desirudin. It has a short half-life of 25 minutes, and therapeutic effect can be reached within 5 minutes. Its use is limited to the percutaneous coronary intervention setting for acute coronary syndromes. It is contraindicated in patients with severe renal impairment.

Argatroban also binds reversibly to thrombin. It is approved in the United States for use in patients with HIT. It is given as an intravenous infusion at a rate of 2 µg/kg/h. It is cleared by the liver, so dose adjustments are not needed for patients with renal failure. The therapeutic effect can be monitored by aPTT. It also prolongs the PT, so when used in conjunction with warfarin as a bridging therapy, higher INR values are needed, typically > 4.

There is no specific antidote for the reversal of any of the DTIs. Management of bleeding remains supportive, and although hemodialysis can remove some of the drug from the bloodstream, the efficacy of this treatment for clinical bleeding has not been shown.41

The reversal of anticoagulant effect of dabigatran and rivaroxaban with PCCs has been studied in human volunteers.⁴² Although parameters of coagulation (including the INR, PTT, thrombin time, and endogenous thrombin potential) could be normalized in patient’s receiving rivaroxaban, no effect was seen in patients receiving dabigatran.

In a human study, desmopressin was given to 10 healthy volunteers.⁴³ Samples showed an increase in factor VIII; C levels and a decrease in the hirudin induced prolongation of aPTT. This was not noted at higher doses of hirudin. In another study in which blood samples were analyzed ex vivo, rFVIIa improved bleeding parameters in argatroban- and bivalirudin-containing blood samples.⁴⁴ There are case reports of the successful use of a variety of options, including FFP for argatroban overdose,⁴⁵ and hemodialysis with modified ultrafiltration in conjunction with FFP, cryoprecipitate, and rFVIIa in a patient with persistent hemorrhage after cardiopulmonary bypass.⁴⁶ Thus, desmopressin, rFVIIa, or clotting factors can be considered, but there are no clinical studies demonstrating clinical efficacy.

These observations suggest that none of the currently available approaches to anticoagulant reversal will be useful in patients who have bleeding events when taking dabigatran. Careful consideration should be given to its use in patients (particularly the elderly) who might have impaired renal clearance of the medication or who are at a high risk for falls and head trauma.

Antiplatelet Agents

Aspirin

Aspirin is one of the most commonly used medications. It has anti-inflammatory, antipyretic, and antiplatelet activities. It exerts its antiplatelet effect by irreversibly inactivating cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).⁴⁷ These enzymes catalyze the first step in prostaglandin synthesis. COX-1 is responsible for the synthesis of thromboxane, an important prostaglandin for platelet aggregation. The half-life of aspirin is 15 to 20 minutes, but platelets do not have the ability to synthesize new enzyme, so platelets are inhibited for the duration of their life span. The effect of aspirin dissipates 5 to 7 days after the last dose as the inactivated platelets are removed and replaced by cells with intact thromboxane synthesis. The acute reversal of the antiplatelet effect of aspirin requires platelet transfusion.

Another approach to the reversal of aspirin-mediated platelet dysfunction is to administer desmopressin. Desmopressin, also known as 1-deamino-8-D-arginine vasopressin (DDAVP), is used in the management of patients with hemophilia A and von Willebrand disease.48 It does not increase platelet number or enhance platelet aggregation, but it does enhance platelet adhesion to the vessel wall, possibly by its ability to increase the concentrations of factor VIII and von Willebrand factor. It is used routinely in uremic patients to improve platelet function. Its use has been suggested in patients treated with aspirin. In a randomized double-blind study, aspirin or placebo was administered to healthy volunteers.⁴⁹ DDAVP was given as one or two intravenous doses. DDAVP increased platelet adhesiveness in both groups, and it normalized in the group treated with aspirin. Also noted was shortening of the bleeding time in the aspirin-treated group. This effect lasted about 3 hours and was extended with the second dose of DDAVP. A dose of 0.3 µg/kg is routinely given. Of note, there are no studies evaluating its effect on aspirin-medicated platelet dysfunction and bleeding in a clinical setting.

Thienopyridines

Clopidogrel is the most widely used drug in this category. It inhibits adenosine diphosphate (ADP)-mediated platelet activation by irreversibly binding to the P2Y12 receptor.⁵⁰ It has a half-life of 8 hours. As with aspirin, the effect of clopidogrel persists after the clearance of the drug, and dissipation of its anticoagulant effect depends on the production of platelets with functioning P2Y12 receptors. Consequently, immediate reversal of the clopidogrel effect would require platelet transfusion. In a retrospective study of patients with ICH, the impact of platelet transfusion was examined.⁵¹ More patients taking clopidogrel with or without aspirin experienced hematoma enlargement. Platelet transfusion had no impact, but the number of patients in this category was small. There was also an increased trend toward in-hospital mortality. Desmopressin also has been evaluated as an agent to reverse the antiplatelet effect of clopidogrel. Healthy volunteers were given clopidogrel and then randomized to receive nasal desmopressin or placebo.⁵² Platelet reactivity and function was improved. Once again, there are no studies evaluating desmopressin in the setting of bleeding.

Prasugrel is another thienopyridine that is used in the management of coronary artery disease. It has a mechanism similar to that of clopidogrel and a shorter half-life of 3.7 hours.⁵³ Its safety and efficacy were compared with those of clopidogrel in a phase 3 trial. There was an increase in fatal bleeding with prasugrel. The incidence of ICH was rare but similar.⁵⁴ There are no data on reversal strategies, but one may hypothesize that they would be similar to those of clopidogrel.

Conclusion

Anticoagulant drugs have complex pharmacokinetics and narrow therapeutic indices. Patients who require anticoagulation are often medically complex and are subject to complications should they require either elective or emergent neurosurgery. It is essential that the risks and benefit of interruption, reversal, or initiation of anticoagulation be coordinated between the treating surgeons and physicians to enhance the safe care of the patient in this high-risk area of medicine.