The role of anticoagulants, antiplatelet agents, and their reversal strategies in the management of intracerebral hemorrhage

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New anticoagulant and antiplatelet medications have been approved and are prescribed with increased frequency. Intracranial hemorrhage is associated with the use of these medications. Therefore, neurosurgeons need to be aware of these new medications, how they are different from their predecessors, and the strategies for the urgent reversal of their effects. Utilization of intraluminal stents by endovascular neurosurgeons has resulted in the need to have a thorough understanding of antiplatelet agents. Increased use of dabigatran, rivaroxaban, and apixaban as oral anticoagulants for the treatment of atrial fibrillation and acute deep venous thrombosis has increased despite the lack of known antidotes to these medications.

Abbreviations used in this paper:AF = atrial fibrillation; DVT = deep venous thrombosis; FFP = fresh-frozen plasma; ICH = intracerebral hemorrhage; INR = international normalized ratio; PCC = prothrombin complex concentrate; rVIIa = recombinant factor VIIa.

New anticoagulant and antiplatelet medications have been approved and are prescribed with increased frequency. Intracranial hemorrhage is associated with the use of these medications. Therefore, neurosurgeons need to be aware of these new medications, how they are different from their predecessors, and the strategies for the urgent reversal of their effects. Utilization of intraluminal stents by endovascular neurosurgeons has resulted in the need to have a thorough understanding of antiplatelet agents. Increased use of dabigatran, rivaroxaban, and apixaban as oral anticoagulants for the treatment of atrial fibrillation and acute deep venous thrombosis has increased despite the lack of known antidotes to these medications.

Nontraumatic spontaneous ICH may occur in patients taking antiplatelet and/or anticoagulant medications and is associated with worse outcomes and increased mortality.8,10,11,21,23,25,36,57,60,70 Difficulty or delay in the reversal of the effects of anticoagulant medications can result in hematoma expansion or delayed surgical evacuation. By comparison, reversal of antiplatelet medication in a similar setting still has unproven benefit. Recently, FDA-approved oral antiplatelet and anticoagulant medications have found increased usage, but introduce new challenges into the emergency management of antiplatelet- and anticoagulant-related ICH. In this paper we review the relevant literature on antiplatelet- and anticoagulant-related ICH to familiarize practicing neurosurgeons with the medications now available, and to provide strategies for the emergency reversal of these medications, some of which have no direct antidote.

Anticoagulant-Related ICH

Anticoagulation medications are important treatments for numerous medical conditions including DVT, pulmonary embolism, and nonvalvular AF. Unfortunately, these medications are associated with an increased risk of ICH. Often the cause of the hemorrhage is directly related to a supratherapeutic effect of the anticoagulant. In other situations therapeutic levels can exacerbate an ICH of an alternate origin (such as trauma or cerebral aneurysm rupture).

All of the anticoagulant medications alter the coagulation cascade at various points along the extrinsic, intrinsic, or common pathways with an ultimate goal of reduced fibrin formation (Fig. 1). Because of the frequency that neurosurgeons are consulted to aid in the management of patients with anticoagulant-related ICH, neurosurgeons should at least maintain a cursory understanding of these pathways and how they relate to the various anticoagulant medications.

Fig. 1.
Fig. 1.

The clotting cascade including common anticoagulant medications and their site of action. vit = vitamin.

Injectable anticoagulants (unfractionated heparin and enoxaparin) are most commonly used during admission to a medical facility, whereas the most commonly prescribed outpatient anticoagulant is warfarin. Warfarin's immediate predecessor was designed as a rodenticide; in the 1950s, warfarin began common usage as a medical anticoagulation therapy.7 Warfarin is a vitamin K antagonist and prevents the hepatic formation of the vitamin K–dependent clotting factors (II, VII, IX, and X). Numerous randomized trials and meta-analyses have confirmed warfarin is highly effective at reducing the risk of stroke from AF.75 However, genetic polymorphisms, several common medications, as well as changes in a patient's diet can drastically alter the anticoagulation effect, which is compounded by warfarin's relatively narrow therapeutic window. As a result, frequent drug monitoring with a prothrombin time and the INR is required. Even with frequent drug monitoring, high INR levels are frequently encountered in the outpatient setting and medication adjustments must be made. The most frequently recommended INR level for the treatment of AF is between 2 and 3. Even in the setting of strict INR monitoring during clinical trials, it can be difficult to maintain patients in this narrow therapeutic window, and subtherapeutic and supratherapeutic levels are common.7 International normalized ratio levels greater than 4.0 have been reported to be associated with significantly increased risk for ICH.21 Warfarin-related ICH patients have a significantly increased risk of hematoma expansion (OR 6.2, 95% CI 1.7–22.9) compared with ICH patients not receiving anticoagulant therapy.23 After decades in which warfarin was the only oral anticoagulation therapy available to patients, new oral medications have recently gained approval by the FDA (www.fda.gov) that have much similar stroke protection, more reliable dose-response relationships, and do not require blood-level monitoring.12,54,75 These medications include dabigatran (a direct thrombin inhibitor), and rivaroxaban and apixaban, direct inhibitors of factor Xa.12 Many cardiologists and neurologists have been increasingly prescribing these medications over the last few years. However, this enthusiasm has been tempered by the lack of an antidote and fear of being unable to safely manage patients taking these new medications who experience anticoagulant-related ICH. The silver lining to these uncertainties is that the incidence of major hemorrhage in Phase III clinical trials for these new oral anticoagulants is lower than that of warfarin.15,29,52

A prospective randomized, open-label trial (Randomized Evaluation of Long-Term Anticoagulation Therapy, or RE-LY) compared 2 blinded doses of dabigatran (110 mg twice daily and 150 mg twice daily) with open-label adjusted dose warfarin (INR target 2.0–3.0) in 18,113 patients. Dabigatran 150 mg twice daily was found to be significantly better than warfarin at preventing stroke or systemic embolism, and dabigatran 110 mg twice daily was demonstrated as noninferior to warfarin. Both doses of dabigatran were found to produce a significant reduction in the rates of ICH and hemorrhagic stroke compared with warfarin (dabigatran 0.12%, 0.10% vs warfarin 0.38% per year; RR 0.31 and 0.26; p < 0.01 [both]).15 Only the 150-mg dose tested in the study is available in the US. Similar results were found in other prospective randomized, double-blind Phase III clinical trials including the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) and Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, in which rivaroxaban and apixaban were both found to demonstrate statistically significant reductions in hemorrhagic stroke compared with warfarin.29,52 Recently, the American College of Chest Physicians published their newest recommendations for antithrombotic therapy for atrial fibrillation; they are now suggesting dabigatran 150 mg twice daily rather than warfarin when oral anticoagulant therapy is recommended.77 As these newer oral anticoagulants are increasingly prescribed more frequently, we hope a real-world decrease in the frequency of anticoagulant-related ICH will follow. Nevertheless, there will be patients with anticoagulant-related ICH who need emergency attention and immediate reversal of the anticoagulating effects.

Hematoma expansion is common in the setting of anticoagulant-related ICH, leading to more deaths. Correcting the INR to 1.3 or less within 2 hours has been shown to decrease hematoma expansion.33 Advances and improvements have been made in methods for reversal of warfarin (a summary of common anticoagulants and their reversal methods can be found in Table 1). The first consideration for emergency management of anticoagulant-related ICH is to stop the anticoagulant agent. Blood pressure should be controlled, although there is little evidence to support a specific blood pressure goal. The authors' preference is to maintain the systolic blood pressure below 160 mm Hg. Medical management of elevated intracranial pressure should be initiated immediately. Fast-acting agents for reversal of anticoagulation by factor replacement include FFP, PCC, and rVIIa. Of these, FFP (the historical standard of care) is relatively deficient in factor IX, requires large volume infusion, and can lead to complications such as pulmonary edema and delayed reversal of INR.41 Recombinant factor VIIa is effective for immediate INR reversal and prevention of hematoma expansion, but is associated with increased thrombotic complications such as myocardial infarction, pulmonary embolism, and DVT. Recombinant factor VIIa has not been shown to improve survival or functional outcome and is generally not recommended for reversal in anticoagulant-related ICH.39,78 Prothrombin complex concentrate is increasing in popularity as a low-volume, rapid-reversal agent, and has been reported as superior to FFP in several studies.49,68,72,76 Individualized dosing of PCC may be the most effective method of reversal. In 1 study, individualized dosing of PCC based on the patient's body weight and initial INR was superior at reaching the target INR 15 minutes after dosing compared with the standard dosage of PCC.72 Similar data has led to support for PCC as the standard of care at many institutions.

TABLE 1:

Common anticoagulation medications*

Generic Name (trade name)Mechanism of ActionRecommended DosingPharmacokinetics/Metabolism/ExcretionLaboratory Monitoring of EffectEmergency Reversal OptionsAdditional Notes
injectable (IV/SQ)
unfractionated heparin7binds antithrombin III; at low doses, inactivates factor Xa, inhibits conversion of prothrombin to thrombin; at higher doses, inactivates factors IX, X, XI, XII, thrombin, inhibits conversion of fibrinogen to fibrin; also inactivates activation of factor VIIIIV: varies; SQ for DVT prophylaxis: 5000 u SQ BID or TIDmetabolism: partial liver, partial renal excretion; elimination: 60–90 min, longer athigher dosesaPTT, antifactor Xa (aPTT reference ranges vary btwn hospitals)w/in 4 hrs of dosing: 1 mg protamine sulfate for 100 u heparin administeredin 2009, a new USP unit dose was correlated to international unit dose; this results in a 10% reduction in effectiveness of new dosing units
enoxaparin (Lovenox)7LMWH; binds to antithrombin, increasing its ability to inhibit activated coagulation factors w/in intrinsic & common pathways (Xa), no effect on extrinsic pathwayDVT prophylaxis: 1 mg/kg SQ BID or 1.5 mg/kg SQ QDmetabolism: liver desulfation, depolymerization, renal excretion; elimination: 4.5 hrs (single dose), 7 hrs (repeated dosing)antifactor Xa assayprotamine sulfate (1 mg/1 mg enoxaparin given last 8 hrs) can be used although it will only partially (~60%) reverse effects of enoxaparin; consider rVIIa
fondaparinux (Arixtra)7inhibits factor XaDVT treatment: 5–10 mg weight-based SQ QD; prevention: 2.5 mg SQ QDrenal excretion elimination T1/2: 17–21 hrs; contraindicated in patients w/ severe renal impairmentantifactor Xa assayno specific antidote; consider rVIIa 90 μg/kg4 hemodialysis reduces by about 20%, protamine no effectsynthetic 5-saccharide analog of active pentasaccharide sequence found in heparin & LMWHs
lepirudin (Refludan)7direct thrombin inhibitor (binds to catalytic & exosite I of thrombin)HIT: 0.4 mg/kg IV over 20 sec, then 0.15 mg/kg/hr IV up to 10 daysrenal excretion T1/2: 1.3 hrsdaily monitoring of aPTT; goal 1.5–2.5x median of laboratory's normal aPTT rangeno specific antidote; consider FFP & cryoprecipitate16approved in US for treatment in heparin-induced thrombocytopenia
argatroban (Acova)7direct thrombin inhibitor (reversibly binds to catalytic site of thrombin)initial 2 μg/kg/min IV over 1–3 hrs until steady statemetabolism: hepatic CYP enzymes; biliary excretion T1/2: 40–50 minaPTT: maintain 1.5–3x baseline value; can also elevate PT making transitioning to warfarin difficult to monitorno specific antidote; consider FFP & cryoprecipitate16
oral
warfarin (Coumadin)7inhibits hepatic production of vitamin K–dependent coagulation factors (II, VII, IX, & X, & anticoagulant proteins C & S)2–5 mg/day for 2–4 days; INR adjusted dosing thereafter 1–10 mg/day99% bound to plasma proteins (albumin); CYP2C9 hepatic metabolism plasma T1/2: 25–60 hrs (mean 40 hrs); induction of hepatic enzymes including CYP2C9 can increase metabolic clearanceINR 2–3; difficult to keep in therapeutic range because of many drug & diet interactions & patient genetic variability1 of the following fast-acting agents: PCC (25–100 UI/kg) or FFP (15 ml/kg) & vitamin K 5–10 mg IVmedical usage began in 1950s, originally developed as a rodenticide, safe for nursing mothers
dabigatran (Pradaxa)7,54direct thrombin inhibitor150 mg BID80% renal excretion; plasma T1/2: 12–14 hrs; caution w/ renal impairment; contraindicated in severe impairmentroutine anticoagulation monitoring unnecessary; normal aPTT indicates no dabigatran effectconsider transfusion w/ FFP, rVIIa (10–90 μg/kg), & PCC; hemodialysis as last resort;75 PCC shown to be most efficacious yet unproven792010 FDA approval for prevention of stroke in AF
rivaroxaban (Xarelto)7,54factor Xa inhibitors20 mg QDplasma T1/2: 7–11 hrs; 33% renal excretion; 67% metabolized by liver, inactive metabolites excreted in urine & stoolroutine anticoagulation monitoring unnecessary; normal antifactor Xa assay indicates no anticoagulation effectPCC, FFP rVIIa (10–90 μg/kg)2011 FDA approval for prevention of stroke in AF & treatment of acute DVT
apixaban (Eliquis)54factor Xa inhibitors5 mg BIDmetabolism: liver (75%), renal excretion (25%); elimination T1/2: 8–15 hrsroutine anticoagulation monitoring unnecessary; normal antifactor Xa assay indicates no anticoagulation effectPCC, FFP rVIIa (10–90 μg/kg)2013 FDA approval for prevention of stroke in AF

* aPTT = activated partial thromboplastin time; BID = twice daily; CYP = cytochrome P450 isoenzyme; HIT = heparin-induced thrombocytopenia; IV = intravenous; LMWH = low-molecular-weight heparin; PT = prothrombin time; QD = each day; SQ = subcutaneous; T1/2 = half life; TID = three times daily; USP = United States Pharmacopeia convention.

Prothrombin complex concentrate formulations vary worldwide, with the US receiving FDA approval for “3-factor” PCC (II, IX, X) whereas many clinical studies conducted outside the US involve “4-factor” PCC, which includes factor VII. It is unclear whether the difference in these preparations is significant and any review of the literature on this topic needs to have this critique in mind.55 Even though PCC formulations have variable amounts of factor VII, PCC replaces multiple factors compared with rVIIa, and is cost effective when compared with FFP for serious bleeding.32 When reversing warfarin one must remember that treatment with a fast-acting agent alone is not enough for a sustained reversal effect. It is necessary to also administer vitamin K (orally or intravenously) to maintain INR reversal.16 In emergency situations, vitamin K should not be used alone, but should be used in conjunction with faster-acting agents because vitamin K can take up to 24 hours to achieve INR correction.16 Additionally, intravenous (versus oral) vitamin K is associated with a low risk of anaphylaxis, but generally remains the preferred route of administration.

New oral anticoagulants (dabigatran, rivaroxaban, apixaban) have recently been approved by the FDA for use in patients with AF for the prevention of stroke and for the treatment of acute DVT (rivaroxaban). The advantages of these medications include a more reliable anticoagulant effect, decreased risk of associated ICH, and no need for monitoring of therapeutic levels. The biggest disadvantage of these medications is the lack of an antidote.41 For recent dosing or recent overdose, consider oral activated charcoal to help absorb the drug and reduce the bioavailability. Strategies for reversal may include FFP, PCC, and/or rVIIa administration, but current studies show that for dabigatran these methods may be ineffective and only moderately effective with rivaroxaban.20 Current evidence is too weak to support a specific reversal protocol for any of these medications; thus, supportive care is essential for ICH related to these medications. As dabigatran is cleared by renal excretion, optimizing renal function is necessary. Hemodialysis has been suggested as an emergency means of removal of dabigatran, and may be the most effective means in patients with impaired creatinine clearance. With dabigatran, a normal activated partial thromboplastin time suggests no active anticoagulation effect and can be used to guide reversal therapy or timing of surgical intervention.73 For rivaroxaban and apixaban, emergency reversal with PCC is likely the most effective option as both are Xa inhibitors and PCC is more likely to be effective with these medications than with dabigatran (a direct thrombin inhibitor; Fig. 1). Confirmation of normal antifactor Xa assay activity is useful in showing that rivaroxaban and apixaban are no longer causing an anticoagulation effect.54

In the case of anticoagulant-related ICH, warfarin remains the most commonly prescribed oral anticoagulant, but due to improved dose response, larger therapeutic windows, and reduced risk of ICH, newer oral agents such as dabigatran, rivaroxaban, and apixaban are being used with increasing frequency. Having a basic appreciation for the pharmacokinetics of these medications, including possible reversal strategies in the setting of ICH, are essential for patient safety. Although there are no specific antidotes to the newer oral anticoagulants, reversal strategies do exist and may be implemented in emergency situations. Additional research studies evaluating the best methods for reversal of these medications are ongoing and much needed.

Antiplatelet-Related ICH

Antiplatelet medication has been shown to be a risk factor for spontaneous ICH as well as increased ICH volume and increased mortality, but the exact increase has not been consistently demonstrated for any specific drug among many reports.8,10,11,25,37,57,60,70 The risk for ICH appears to be dose dependent with aspirin, the most studied agent, but exists with other agents as well.1,6,11,36,56,59,66,67,69,71 Naidech et al.42–44 demonstrated that increased platelet inhibition (as measured with VerifyNow ASA and P2Y12 tests [Accumetrics, Inc.] for aspirin and clopidogrel, respectively), correlated with increased ICH volume growth at 12 hours, volume of intraventricular hemorrhage, increased chance of death at 14 days, and poor outcome at 3 months. Additionally, Naidech et al.46 demonstrated that the chance of undergoing a craniotomy for ICH, when controlling for size of hemorrhage and location, was increased with pre-event aspirin use and platelet inhibition as determined by VerifyNow ASA. In a retrospective comparison of patients presenting with ICH on aspirin or Plavix (clopidogrel), Campbell et al.9 noted larger ICH size and decreased chance of discharge to home in the clopidogrel group. They also noted increased mortality, but this failed to reach statistical significance.

Given the likely association between antiplatelet use, ICH volume, intraventricular hemorrhage, and death, 1 possible strategy for reducing hematoma growth and mortality is to reverse the effect of antiplatelet medications by administering a platelet transfusion.3,40 A platelet transfusion of 10–12.5 units of platelets has been shown to restore normal platelet function in patients on aspirin and clopidogrel.74 Desmopressin has been known to increase platelet reactivity in patients treated with aspirin by releasing a greater number of von Willibrand multimers.24 The role of intravenous desmopressin in decreasing bleeding during cardiac surgery is controversial, whereas rVIIa has shown promise preclinically as a possible agent.2,30,53

Some authors have described variations of platelet reversal regimens as standard at their centers.3,45 Naidech et al.45 evaluated this hypothesis by treating 45 patients with spontaneous ICH and an assay consistent with platelet inhibition, with a platelet transfusion within 12 hours of admission. Transfusion resulted in a decrease of platelet inhibition out of therapeutic range for most patients, although the dose of platelets was not standardized. Within their cohort, they identified 32 patients with a high degree of platelet inhibition, and within this subset, those who received a transfusion within 12 hours had less hematoma growth and a better outcome than those who received a transfusion after 12 hours.

The limited positive outcome of antiplatelet reversal is counterbalanced by many studies showing no benefit. Ducruet et al.19 compared the clinical course and outcomes in 35 patients presenting with ICH on antiplatelet therapy reversed with platelet transfusion, to 31 patients without platelet transfusion, and found no difference in hematoma growth or outcome. Nishijima et al.47 performed a retrospective meta-analysis of ICH secondary to trauma in patients receiving antiplatelet medication before injury. These authors identified 635 studied patients in 5 retrospective reviews in which 3 studies revealed no benefit, 1 revealed higher mortality in the transfusion cohort, and 1 demonstrated decreased mortality with transfusion (although there were 92 patients in the transfusion arm and 19 in the no-transfusion arm).47 Another literature review by Campbell et al.8 also found no clear evidence of benefit with platelet transfusion, but suggested the following protocol as a starting point for further investigation: 1) for a patient with ICH on aspirin alone, transfuse 1 pack of platelets; 2) for a patient with a small ICH on clopidogrel or a combination of therapies, administer 2 units of platelets; 3) for patients with large ICH on clopidogrel or multiple agents, administer desmopressin 3 mcg/kg intravenously and 1 pack of platelets every 12 hours for 48 hours. There is a randomized trial currently underway to evaluate antiplatelet agent reversal in ICH (Platelet Transfusion in Cerebral Hemorrhage [PATCH] trial).17

One limitation of testing strategies that use platelet assays is the variability in the types of assays available. As described in Table 2, platelet activity and levels of inhibition can be measured by many different types of platelet function assays. There are multiple laboratory and point-of-care testing systems available and results are reported in units of time, change in light transmission, platelet count, surface area covered, and flow cytometry.62 On many of these systems, high platelet inhibition has been associated with bleeding events and low platelet inhibition with in-stent thrombosis after coronary artery stenting.5,64 Moreover, aspirin and clopidogrel resistance has been associated with poor outcome in patients with stroke.31,61 Nonetheless, multiple comparison studies have been unable to establish a correlation between the results of the various testing systems.28,35,38,48,50,51 Furthermore, point-of-care testing tends to have greater inaccuracy than hematology lab testing.62 There is currently no established standard to define inappropriate platelet activity.62

TABLE 2:

Common antiplatelet medications*

Generic Name (trade name)Mechanism of Action (essential steps)Recommended DosingPharmacokinetics/Metabolism/ExcretionLaboratory Monitoring of EffectReversal MethodAdditional Notes
oral
acetylsalicylic acid (aspirin)7irreversible COX-1 inhibition → decreased TXA2 production → decreased TXA2 receptor activation → decreased intracellular Ca++ levels81–325 mg/daymetabolism: hepatic; excretion: urine (80%–100%), sweat, saliva, feces; elimination T1/2: 20 min (may reach 15–30 hrs when higher doses are ingested)arachidonic acid-based tests (VerifyNow ASA [aspirin test])platelet transfusion (5 concentrate units), desmopressin (0.3 μg/kg), rVIIa8prevalence of clinical aspirin resistance is 5%–60%26,27,65
ticlopidine (Ticlid)7thienopyridines (prodrugs): selective irreversible platelet P2Y12 receptor inhibition → decreased ADP binding to P2Y12 → increased cAMP levelsmay use 500 mg loading then 250 mg BIDmetabolism: hepatic; excretion: urine (60%), feces (23%); elimination T1/2: 13 hrs (after single dose), 4–5 days (after repeat dosing)bleeding time, variability of response has not been reportedNAeffective in 96.5% of patients w/ clopidogrel resistance; frequent side effects including life-threatening neutropenia & thrombotic thrombocytopenic purpura
clopidogrel (Plavix)7thienopyridines (prodrugs): selective irreversible platelet P2Y12 receptor inhibition → decreased ADP binding to P2Y12 → increased cAMP levels300–600 mg (loading) followed by 75–150 mg/daymetabolism: hepatic, 15% undergoes metabolic activation (dependent on CYP2C19), remainder 85% inactivated by esterases; excretion: urine (50%), feces (46%); elimination T1/2: 6 hrs (30 min for active metabolite)tests to identify patient's CYP2C19 genotype; P2Y12 platelet receptor cascade tests (VerifyNow P2Y12 [PRU Test])platelet transfusion (10 concentrate units every 12 hrs for the next 48 hrs), desmopressin (0.3 μg/kg)8more potent & has a more favorable toxicity profile than ticlopidine; prevalence of clinical clopidogrel resistance is 8%–35%;18,26,27 omeprazole & esomeprazole significantly reduce the antiplatelet activity of clopidogrel
prasugrel (Effient)7thienopyridines (prodrugs): selective irreversible platelet P2Y12 receptor inhibition → decreased ADP binding to P2Y12 → increased cAMP levels60 mg (loading) followed by 10 mg/day (5 mg/day if weight <60 kg or age >75 yrs)intestinal esterase plays important role; therefore drug requires fewer hepatic metabolic steps for activation; metabolism independent of CYP genotype; excretion: urine (68%), feces (27%); elimination T1/2: 2–15 hrs (active metabolite)P2Y12 platelet receptor cascade tests (VerifyNow P2Y12 [PRU test])platelet transfusion >6 hrs after loading dose or >4 hrs after maintenance dose; active metabolite not removed by dialysisfaster & more predictable action (than clopidogrel); CYP2C19 polymorphism is less important for metabolic activation
ticagrelor (Brilinta)7cyclopentyltriazolopyrimidine: reversible allosteric (non-competitive) platelet P2Y12 receptor antagonist → decreased ADP binding to P2Y12 → increased cAMP levels180 mg (loading) followed by 90 mg BIDdoes not require metabolic activation (independent of CYP genotype); metabolism: hepatic; excretion (ticagrelor): feces (58%), urine (26%); excretion (active metabolite): biliary excretion, urine (<1%); elimination T1/2: 7 hrs (ticagrelor), 9 hrs (active metabolite)NANA, not removed by dialysistransitioning from clopidogrel to ticagrelor resulted in absolute IPA increase of 26.4%; transitioning from ticagrelor to clopidogrel resulted in absolute IPA decrease of 24.5%
dipyridamole (Persantine)7inhibitor of phosphodiesterases, blocker of platelet adenosine uptake → increased cAMP levels75–100 mg q6hmetabolism: hepatic; excretion: feces; elimination T1/2: 10–12 hrsNAdialysis is not likely to be of benefitAggrenox: combination of 200 mg of extended-release dipyridamole w/ 25 mgaspirin
IV
abciximab (ReoPro)7GP IIb/IIIa receptor antagonists: inhibit vWf & fibrinogen-mediated platelet aggregation0.25 mg/kg bolus followed by 0.125 μg/kg/minmetabolism: proteolytic cleavage; elimination T1/2: 30 minthrombin receptor activating peptide-based tests (VerifyNow IIb/IIIa test)platelet transfusionscurrently approved only for hospital administration in ACS patients undergoing PCI
eptifibatide (Integrilin)7GP IIb/IIIa receptor antagonists: inhibit vWf & fibrinogen-mediated platelet aggregation180 μg/kg bolus followed by 2 μg/kg/minmetabolism: renal clearance 50% total body clearance; majority excreted unchanged, deaminated form (metabolites detected in urine but not in plasma); excretion: urine; elimination T1/2: 2.5 hrs; prolonged in renal insufficiencythrombin receptor activating peptide-based tests (VerifyNow IIb/IIIa test)may be removed by dialysiscurrently approved only for hospital administration in ACS patients undergoing PCI
tirofiban (Aggrastat)7GP IIb/IIIa receptor antagonists: inhibit vWf & fibrinogen-mediated platelet aggregation0.4 μg/kg/min for 30 min, then 0.1 μg/kg/minmetabolism: limited; excretion: urine (65%), feces (25%); elimination T1/2: 2 hrs, prolonged in renal insufficiencyNAremoved by dialysiscurrently approved only for hospital administration in ACS patients undergoing PCI

* ACS = acute coronary syndrome; ADP = adenosine diphosphate; cAMP = cyclic adenosine monophosphate; COX = cyclooxygenase; GP = glycoprotein; IPA = inhibition of platelet aggregation; NA = not available; P2Y = family of G protein–coupled purinergic receptors; PCI = percutaneous coronary intervention; TXA2 = thromboxane A2; vWf = von Willebrand factor.

† Physiologically, the net effect of increased intracellular Ca++ and decreased cAMP is to activate glycoprotein IIb/IIIa, which binds soluble adhesive substrates (including vWf and fibrinogen), leading to platelet anchoring to foreign surfaces and platelet aggregation into platelet-rich “white” thrombus.

‡ Require hepatic biotransformation into active metabolites.

The impact of these limitations is illustrated in multiple studies that have attempted to use platelet assay–guided therapy protocols to tailor patient medical regimens with poor results. Collet et al.13 randomized patients undergoing coronary artery stenting into 2 groups, 1 receiving antiplatelet medication without monitoring and 1 with monitoring utilizing the VerifyNow P2Y12 assay with medication adjustments made as necessary. At 1 year there was no difference between the 2 groups in any of the outcome measures, including death, myocardial infarction, stroke, urgent revascularization, or major bleeding event.13 Along similar lines, Depta et al.18 retrospectively reviewed patients with ischemic stroke who were subsequently placed on antiplatelet therapy, comparing patients given antiplatelet medication without testing to those followed by platelet aggregometry with appropriate dose adjustments. The authors describe a higher rate of death, ischemic events, and bleeding in the patients followed by aggregometry who subsequently received dose increases.18

Stopping antiplatelet medication is not without risk. Withdrawal of antiplatelet agents before elective surgery has been shown to be a risk factor for heart attack and death.14 Cessation of antiplatelet therapy for those with cardiac stents is associated with a high rate of stent thrombosis and infarction, especially for drug-eluting stents.22,34,63 Patients with intracranial stents are at increased risk of stroke and transient ischemic attack with early withdrawal of an antiplatelet agent or resistance.58

When considering antiplatelet-related ICH, determining the exact role that antiplatelet agents play in ICH formation, growth, and outcome as well as the role for antiplatelet reversal in patients with ICH requires significantly more clinical data. Currently, there is no well-supported algorithm for treating these patients. The decision to stop all antiplatelet medication needs to be carefully considered, weighing the size and morbidity of the ICH against the reason the agents were initiated. The value of platelet function assays in patients presenting with ICH is uncertain at this time. Reversing antiplatelet medication with transfusion, desmopressin, or other factors is not currently supported by strong clinical data and should be considered investigational at this juncture.

Conclusions

Anticoagulant- and antiplatelet-related ICH involve the risks of hematoma expansion and poor outcome. Reversal of antiplatelet medications is an option to prevent worsening of the ICH, but the effectiveness for improved clinical outcomes remains unproven. Reversal of warfarin to prevent enlargement of the ICH is recommended. Physicians should consider utilizing PCC over FFP in addition to vitamin K for the reversal of warfarin anticoagulation. Dabigatran reversal may benefit from PCC but the evidence is weak and efforts should be directed toward improving renal clearance with consideration of hemodialysis in emergency situations. Rivaroxaban and apixaban are more likely to benefit from PCC administration than dabigatran but are unlikely to benefit from hemodialysis.

Disclosure

Dr. James is an investor/stockholder in Remedy Pharmaceuticals, Inc.

Author contributions to the study and manuscript preparation include the following. Conception and design: James. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: James, Simon. Critically revising the article: James, Simon. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: James. Administrative/technical/material support: James. Study supervision: James. Table creation: Palys, Lomboy. Figure preparation: Lamm.

Acknowledgement

The authors would like to thank Kristin J. Wainwright for her help in editing the manuscript.

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    Campbell PGSen AYadla SJabbour PJallo J: Emergency reversal of antiplatelet agents in patients presenting with an intracranial hemorrhage: a clinical review. World Neurosurg 74:2792852010

    • Search Google Scholar
    • Export Citation
  • 9

    Campbell PGYadla SSen ANJallo JJabbour P: Emergency reversal of clopidogrel in the setting of spontaneous intracerebral hemorrhage. World Neurosurg 76:1001042011

    • Search Google Scholar
    • Export Citation
  • 10

    Cantalapiedra AGutierrez OTortosa JIYañez MDueñas MFernandez Fontecha E: Oral anticoagulant treatment: risk factors involved in 500 intracranial hemorrhages. J Thromb Thrombolysis 22:1131202006

    • Search Google Scholar
    • Export Citation
  • 11

    Caso VPaciaroni MVenti MAlberti APalmerini FMilia P: Effect of on-admission antiplatelet treatment on patients with cerebral hemorrhage. Cerebrovasc Dis 24:2152182007

    • Search Google Scholar
    • Export Citation
  • 12

    Cervera AAmaro SChamorro A: Oral anticoagulant-associated intracerebral hemorrhage. J Neurol 259:2122242012

  • 13

    Collet JPCuisset TRangé GCayla GElhadad SPouillot C: Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 367:210021092012

    • Search Google Scholar
    • Export Citation
  • 14

    Collet JPMontalescot GBlanchet BTanguy MLGolmard JLChoussat R: Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 110:236123672004

    • Search Google Scholar
    • Export Citation
  • 15

    Connolly SJEzekowitz MDYusuf SEikelboom JOldgren JParekh A: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:113911512009

    • Search Google Scholar
    • Export Citation
  • 16

    Crowther MAAgeno WSchnurr TManfredi EKinnon KGarcia D: Oral vitamin K produces a normal INR within 24 hours of its administration in most patients discontinuing warfarin. Haematologica 90:1371392005

    • Search Google Scholar
    • Export Citation
  • 17

    de Gans Kde Haan RJMajoie CBKoopman MMBrand ADijkgraaf MG: PATCH: platelet transfusion in cerebral haemorrhage: study protocol for a multicentre, randomised, controlled trial. BMC Neurol 10:192010

    • Search Google Scholar
    • Export Citation
  • 18

    Depta JPFowler JNovak EKatzan IBakdash SKottke-Marchant K: Clinical outcomes using a platelet function-guided approach for secondary prevention in patients with ischemic stroke or transient ischemic attack. Stroke 43:237623812012

    • Search Google Scholar
    • Export Citation
  • 19

    Ducruet AFHickman ZLZacharia BEGrobelny BTDeRosa PALandes E: Impact of platelet transfusion on hematoma expansion in patients receiving antiplatelet agents before intracerebral hemorrhage. Neurol Res 32:7067102010

    • Search Google Scholar
    • Export Citation
  • 20

    Eerenberg ESKamphuisen PWSijpkens MKMeijers JCBuller HRLevi M: Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 124:157315792011

    • Search Google Scholar
    • Export Citation
  • 21

    Fang MCChang YHylek EMRosand JGreenberg SMGo AS: Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 141:7457522004

    • Search Google Scholar
    • Export Citation
  • 22

    Ferrari EBenhamou MCerboni PMarcel B: Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 45:4564592005

    • Search Google Scholar
    • Export Citation
  • 23

    Flibotte JJHagan NO'Donnell JGreenberg SMRosand J: Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 63:105910642004

    • Search Google Scholar
    • Export Citation
  • 24

    Flordal PASahlin S: Use of desmopressin to prevent bleeding complications in patients treated with aspirin. Br J Surg 80:7237241993

    • Search Google Scholar
    • Export Citation
  • 25

    Foerch CSitzer MSteinmetz HNeumann-Haefelin T: Pretreatment with antiplatelet agents is not independently associated with unfavorable outcome in intracerebral hemorrhage. Stroke 37:216521672006

    • Search Google Scholar
    • Export Citation
  • 26

    Fong JCheng-Ching EHussain MSKatzan IGupta R: Predictors of biochemical aspirin and clopidogrel resistance in patients with ischemic stroke. J Stroke Cerebrovasc Dis 20:2272302011

    • Search Google Scholar
    • Export Citation
  • 27

    Fukuoka TFuruya DTakeda HDembo TNagoya HKato Y: Evaluation of clopidogrel resistance in ischemic stroke patients. Intern Med 50:31352011

    • Search Google Scholar
    • Export Citation
  • 28

    Godino CMendolicchio LFigini FLatib ASharp ASCosgrave J: Comparison of VerifyNow-P2Y12 test and Flow Cytometry for monitoring individual platelet response to clopidogrel. What is the cut-off value for identifying patients who are low responders to clopidogrel therapy?. Thromb J 7:42009

    • Search Google Scholar
    • Export Citation
  • 29

    Granger CBAlexander JHMcMurray JJLopes RDHylek EMHanna M: Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:9819922011

    • Search Google Scholar
    • Export Citation
  • 30

    Gratz IKoehler JOlsen DAfshar MDeCastro NSpagna PM: The effect of desmopressin acetate on postoperative hemorrhage in patients receiving aspirin therapy before coronary artery bypass operations. J Thorac Cardiovasc Surg 104:141714221992

    • Search Google Scholar
    • Export Citation
  • 31

    Grotemeyer KHScharafinski HWHusstedt IW: Two-year follow-up of aspirin responder and aspirin non responder. A pilot-study including 180 post-stroke patients. Thromb Res 71:3974031993

    • Search Google Scholar
    • Export Citation
  • 32

    Guest JFWatson HGLimaye S: Modeling the cost-effectiveness of prothrombin complex concentrate compared with fresh frozen plasma in emergency warfarin reversal in the United Kingdom. Clin Ther 32:247824932010

    • Search Google Scholar
    • Export Citation
  • 33

    Huttner HBSchellinger PDHartmann MKöhrmann MJuettler EWikner J: Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 37:146514702006

    • Search Google Scholar
    • Export Citation
  • 34

    Iakovou ISchmidt TBonizzoni EGe LSangiorgi GMStankovic G: Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 293:212621302005

    • Search Google Scholar
    • Export Citation
  • 35

    Jakubowski JALi YGSmall DSPayne CDTomlin MELuo J: A comparison of the VerifyNow P2Y12 point-of-care device and light transmission aggregometry to monitor platelet function with prasugrel and clopidogrel: an integrated analysis. J Cardiovasc Pharmacol 56:29372010

    • Search Google Scholar
    • Export Citation
  • 36

    Lacut KLe Gal GSeizeur RPrat GMottier DOger E: Antiplatelet drug use preceding the onset of intracerebral hemorrhage is associated with increased mortality. Fundam Clin Pharmacol 21:3273332007

    • Search Google Scholar
    • Export Citation
  • 37

    Lacut Kvan der Maaten JLe Gal GCornily GMottier DOger E: Antiplatelet drugs and risk of venous thromboembolism: results from the EDITH case-control study. Haematologica 93:111711182008

    • Search Google Scholar
    • Export Citation
  • 38

    Mangiacapra FPatti GPeace AGatto LVizzi VRicottini E: Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. Am J Cardiol 106:6196232010

    • Search Google Scholar
    • Export Citation
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    Mayer SABrun NCBegtrup KBroderick JDavis SDiringer MN: Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 358:212721372008

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    McMillian WDRogers FB: Management of prehospital antiplatelet and anticoagulant therapy in traumatic head injury: a review. J Trauma 66:9429502009

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    Naidech AMBernstein RALevasseur KBassin SLBendok BRBatjer HH: Platelet activity and outcome after intracerebral hemorrhage. Ann Neurol 65:3523562009

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    Naidech AMJovanovic BLiebling SGarg RKBassin SLBendok BR: Reduced platelet activity is associated with early clot growth and worse 3-month outcome after intracerebral hemorrhage. Stroke 40:239824012009

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    Naidech AMLiebling SMRosenberg NFLindholm PFBernstein RABatjer HH: Early platelet transfusion improves platelet activity and may improve outcomes after intracerebral hemorrhage. Neurocrit Care 16:82872012

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    Naidech AMRosenberg NFBernstein RABatjer HH: Aspirin use or reduced platelet activity predicts craniotomy after intracerebral hemorrhage. Neurocrit Care 15:4424462011

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    Nishijima DKZehtabchi SBerrong JLegome E: Utility of platelet transfusion in adult patients with traumatic intracranial hemorrhage and preinjury antiplatelet use: a systematic review. J Trauma Acute Care Surg 72:165816632012

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    Ozben SOzben BTanrikulu AMOzer FOzben T: Aspirin resistance in patients with acute ischemic stroke. J Neurol 258:197919862011

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    Pabinger IBrenner BKalina UKnaub SNagy AOstermann H: Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 6:6226312008

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    Paniccia RAntonucci EGori AMMarcucci RGiglioli CAntoniucci D: Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost 5:183918472007

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    Paniccia RAntonucci EMaggini NMiranda MGori AMMarcucci R: Comparison of methods for monitoring residual platelet reactivity after clopidogrel by point-of-care tests on whole blood in high-risk patients. Thromb Haemost 104:2872922010

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    Pleym HStenseth RWahba ABjella LTromsdal AKarevold A: Prophylactic treatment with desmopressin does not reduce postoperative bleeding after coronary surgery in patients treated with aspirin before surgery. Anesth Analg 98:5785842004

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    Potpara TSPolovina MMLicina MMStojanovic RMProstran MSLip GY: Novel oral anticoagulants for stroke prevention in atrial fibrillation: focus on apixaban. Adv Ther 29:4915072012

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    Rolfe SPapadopoulos SCabral KP: Controversies of anticoagulation reversal in life-threatening bleeds. J Pharm Pract 23:2172252010

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    Roquer J: Previous antiplatelet treatment and mortality in patients with intracerebral hemorrhage. Stroke 38:8638642007. (Letter)

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    Roquer JRodríguez Campello AGomis MOis APuente VMunteis E: Previous antiplatelet therapy is an independent predictor of 30-day mortality after spontaneous supratentorial intracerebral hemorrhage. J Neurol 252:4124162005

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    Rossen JDChalouhi NWassef SNThomas JAbel TJJabbour PM: Incidence of cerebral ischemic events after discontinuation of clopidogrel in patients with intracranial aneurysms treated with stent-assisted techniques. Clinical article. J Neurosurg 117:9299332012

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    Saloheimo PAhonen MJuvela SPyhtinen JSavolainen ERHillbom M: Regular aspirin-use preceding the onset of primary intracerebral hemorrhage is an independent predictor for death. Stroke 37:1291332006

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    Sansing LHMesse SRCucchiara BLCohen SNLyden PDKasner SE: Prior antiplatelet use does not affect hemorrhage growth or outcome after ICH. Neurology 72:139714022009

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    Schwammenthal YTsabari RShenkman BSchwartz RMatetzky SLubetsky A: Aspirin responsiveness in acute brain ischaemia: association with stroke severity and clinical outcome. Cerebrovasc Dis 25:3553612008

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    Seidel HRahman MMScharf RE: Monitoring of antiplatelet therapy. Current limitations, challenges, and perspectives. Hamostaseologie 31:41512011

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    Sharma AKAjani AEHamwi SMManiar PLakhani SVWaksman R: Major noncardiac surgery following coronary stenting: when is it safe to operate?. Catheter Cardiovasc Interv 63:1411452004

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    Sibbing DSchulz SBraun SMorath TStegherr JMehilli J: Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 8:2502562010

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    Snoep JDHovens MMEikenboom JCvan der Bom JGHuisman MV: Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med 167:159315992007

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    Sorimachi TFujii YMorita KTanaka R: Predictors of hematoma enlargement in patients with intracerebral hemorrhage treated with rapid administration of antifibrinolytic agents and strict blood pressure control. J Neurosurg 106:2502542007

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    Stetler WRChaudhary NThompson BGGemmete JJMaher COPandey AS: Prasugrel is effective and safe for neurointerventional procedures. J Neurointerv Surg [epub ahead of print]2012

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    Taberner DAThomson JMPoller L: Comparison of prothrombin complex concentrate and vitamin K1 in oral anticoagulant reversal. BMJ 2:83851976

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    Thrift AGMcNeil JJForbes ADonnan GA: Risk of primary intracerebral haemorrhage associated with aspirin and nonsteroidal anti-inflammatory drugs: case-control study. BMJ 318:7597641999

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    Toyoda KOkada YMinematsu KKamouchi MFujimoto SIbayashi S: Antiplatelet therapy contributes to acute deterioration of intracerebral hemorrhage. Neurology 65:100010042005

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    Tuhrim S: Aspirin-use before ICH: a potentially treatable iatrogenic coagulopathy?. Stroke 37:452006

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    van Aart LEijkhout HWKamphuis JSDam MSchattenkerk MESchouten TJ: Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: an open, prospective randomized controlled trial. Thromb Res 118:3133202006

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    van Ryn JStangier JHaertter SLiesenfeld KHWienen WFeuring M: Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103:111611272010

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    Vilahur GChoi BGZafar MUViles-Gonzalez JFVorchheimer DAFuster V: Normalization of platelet reactivity in clopidogrel-treated subjects. J Thromb Haemost 5:82902007

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    Watanabe MSiddiqui FMQureshi AI: Incidence and management of ischemic stroke and intracerebral hemorrhage in patients on dabigatran etexilate treatment. Neurocrit Care 16:2032092012

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    Yasaka MOomura MIkeno KNaritomi HMinematsu K: Effect of prothrombin complex concentrate on INR and blood coagulation system in emergency patients treated with warfarin overdose. Ann Hematol 82:1211232003

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    You JJSinger DEHoward PALane DAEckman MHFang MC: Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141:2 Supple531Se575S2012

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    Yuan ZHJiang JKHuang WDPan JZhu JYWang JZ: A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia. J Clin Neurosci 17:6856932010

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    Zhou WSchwarting SIllanes SLiesz AMiddelhoff MZorn M: Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 42:359435992011

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Article Information

Address correspondence to: Robert F. James, M.D., ECU Neurosurgical and Spine Center, 2325 Stantonsburg Road, Greenville, North Carolina 27834. email: jamesro@ecu.edu.

Please include this information when citing this paper: DOI: 10.3171/2013.2.FOCUS1328.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    The clotting cascade including common anticoagulant medications and their site of action. vit = vitamin.

References

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    Altman RScazziota ALourdes DEHerrera MGonzalez C: Recombinant factor VIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel on in vitro thrombin generation. J Thromb Haemost 4:202220272006

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    Beshay JEMorgan HMadden CYu WSarode R: Emergency reversal of anticoagulation and antiplatelet therapies in neurosurgical patients. A review. J Neurosurg 112:3073182010

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    Bijsterveld NRMoons AHBoekholdt SMvan Aken BEFennema HPeters RJ: Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 106:255025542002

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    Breet NJvan Werkum JWBouman HJKelder JCRuven HJBal ET: Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 303:7547622010

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    Broderick JPDiringer MNHill MDBrun NCMayer SASteiner T: Determinants of intracerebral hemorrhage growth: an exploratory analysis. Stroke 38:107210752007

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    • Export Citation
  • 7

    Brunton LLChabner BAKnollmann BC: Goodman & Gilman's The Pharmacological Basis of Therapeutics ed 12New YorkMcGraw-Hill2011

  • 8

    Campbell PGSen AYadla SJabbour PJallo J: Emergency reversal of antiplatelet agents in patients presenting with an intracranial hemorrhage: a clinical review. World Neurosurg 74:2792852010

    • Search Google Scholar
    • Export Citation
  • 9

    Campbell PGYadla SSen ANJallo JJabbour P: Emergency reversal of clopidogrel in the setting of spontaneous intracerebral hemorrhage. World Neurosurg 76:1001042011

    • Search Google Scholar
    • Export Citation
  • 10

    Cantalapiedra AGutierrez OTortosa JIYañez MDueñas MFernandez Fontecha E: Oral anticoagulant treatment: risk factors involved in 500 intracranial hemorrhages. J Thromb Thrombolysis 22:1131202006

    • Search Google Scholar
    • Export Citation
  • 11

    Caso VPaciaroni MVenti MAlberti APalmerini FMilia P: Effect of on-admission antiplatelet treatment on patients with cerebral hemorrhage. Cerebrovasc Dis 24:2152182007

    • Search Google Scholar
    • Export Citation
  • 12

    Cervera AAmaro SChamorro A: Oral anticoagulant-associated intracerebral hemorrhage. J Neurol 259:2122242012

  • 13

    Collet JPCuisset TRangé GCayla GElhadad SPouillot C: Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 367:210021092012

    • Search Google Scholar
    • Export Citation
  • 14

    Collet JPMontalescot GBlanchet BTanguy MLGolmard JLChoussat R: Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 110:236123672004

    • Search Google Scholar
    • Export Citation
  • 15

    Connolly SJEzekowitz MDYusuf SEikelboom JOldgren JParekh A: Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:113911512009

    • Search Google Scholar
    • Export Citation
  • 16

    Crowther MAAgeno WSchnurr TManfredi EKinnon KGarcia D: Oral vitamin K produces a normal INR within 24 hours of its administration in most patients discontinuing warfarin. Haematologica 90:1371392005

    • Search Google Scholar
    • Export Citation
  • 17

    de Gans Kde Haan RJMajoie CBKoopman MMBrand ADijkgraaf MG: PATCH: platelet transfusion in cerebral haemorrhage: study protocol for a multicentre, randomised, controlled trial. BMC Neurol 10:192010

    • Search Google Scholar
    • Export Citation
  • 18

    Depta JPFowler JNovak EKatzan IBakdash SKottke-Marchant K: Clinical outcomes using a platelet function-guided approach for secondary prevention in patients with ischemic stroke or transient ischemic attack. Stroke 43:237623812012

    • Search Google Scholar
    • Export Citation
  • 19

    Ducruet AFHickman ZLZacharia BEGrobelny BTDeRosa PALandes E: Impact of platelet transfusion on hematoma expansion in patients receiving antiplatelet agents before intracerebral hemorrhage. Neurol Res 32:7067102010

    • Search Google Scholar
    • Export Citation
  • 20

    Eerenberg ESKamphuisen PWSijpkens MKMeijers JCBuller HRLevi M: Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 124:157315792011

    • Search Google Scholar
    • Export Citation
  • 21

    Fang MCChang YHylek EMRosand JGreenberg SMGo AS: Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 141:7457522004

    • Search Google Scholar
    • Export Citation
  • 22

    Ferrari EBenhamou MCerboni PMarcel B: Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 45:4564592005

    • Search Google Scholar
    • Export Citation
  • 23

    Flibotte JJHagan NO'Donnell JGreenberg SMRosand J: Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 63:105910642004

    • Search Google Scholar
    • Export Citation
  • 24

    Flordal PASahlin S: Use of desmopressin to prevent bleeding complications in patients treated with aspirin. Br J Surg 80:7237241993

    • Search Google Scholar
    • Export Citation
  • 25

    Foerch CSitzer MSteinmetz HNeumann-Haefelin T: Pretreatment with antiplatelet agents is not independently associated with unfavorable outcome in intracerebral hemorrhage. Stroke 37:216521672006

    • Search Google Scholar
    • Export Citation
  • 26

    Fong JCheng-Ching EHussain MSKatzan IGupta R: Predictors of biochemical aspirin and clopidogrel resistance in patients with ischemic stroke. J Stroke Cerebrovasc Dis 20:2272302011

    • Search Google Scholar
    • Export Citation
  • 27

    Fukuoka TFuruya DTakeda HDembo TNagoya HKato Y: Evaluation of clopidogrel resistance in ischemic stroke patients. Intern Med 50:31352011

    • Search Google Scholar
    • Export Citation
  • 28

    Godino CMendolicchio LFigini FLatib ASharp ASCosgrave J: Comparison of VerifyNow-P2Y12 test and Flow Cytometry for monitoring individual platelet response to clopidogrel. What is the cut-off value for identifying patients who are low responders to clopidogrel therapy?. Thromb J 7:42009

    • Search Google Scholar
    • Export Citation
  • 29

    Granger CBAlexander JHMcMurray JJLopes RDHylek EMHanna M: Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365:9819922011

    • Search Google Scholar
    • Export Citation
  • 30

    Gratz IKoehler JOlsen DAfshar MDeCastro NSpagna PM: The effect of desmopressin acetate on postoperative hemorrhage in patients receiving aspirin therapy before coronary artery bypass operations. J Thorac Cardiovasc Surg 104:141714221992

    • Search Google Scholar
    • Export Citation
  • 31

    Grotemeyer KHScharafinski HWHusstedt IW: Two-year follow-up of aspirin responder and aspirin non responder. A pilot-study including 180 post-stroke patients. Thromb Res 71:3974031993

    • Search Google Scholar
    • Export Citation
  • 32

    Guest JFWatson HGLimaye S: Modeling the cost-effectiveness of prothrombin complex concentrate compared with fresh frozen plasma in emergency warfarin reversal in the United Kingdom. Clin Ther 32:247824932010

    • Search Google Scholar
    • Export Citation
  • 33

    Huttner HBSchellinger PDHartmann MKöhrmann MJuettler EWikner J: Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 37:146514702006

    • Search Google Scholar
    • Export Citation
  • 34

    Iakovou ISchmidt TBonizzoni EGe LSangiorgi GMStankovic G: Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 293:212621302005

    • Search Google Scholar
    • Export Citation
  • 35

    Jakubowski JALi YGSmall DSPayne CDTomlin MELuo J: A comparison of the VerifyNow P2Y12 point-of-care device and light transmission aggregometry to monitor platelet function with prasugrel and clopidogrel: an integrated analysis. J Cardiovasc Pharmacol 56:29372010

    • Search Google Scholar
    • Export Citation
  • 36

    Lacut KLe Gal GSeizeur RPrat GMottier DOger E: Antiplatelet drug use preceding the onset of intracerebral hemorrhage is associated with increased mortality. Fundam Clin Pharmacol 21:3273332007

    • Search Google Scholar
    • Export Citation
  • 37

    Lacut Kvan der Maaten JLe Gal GCornily GMottier DOger E: Antiplatelet drugs and risk of venous thromboembolism: results from the EDITH case-control study. Haematologica 93:111711182008

    • Search Google Scholar
    • Export Citation
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    Mangiacapra FPatti GPeace AGatto LVizzi VRicottini E: Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. Am J Cardiol 106:6196232010

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