Platelet function inhibitors and platelet functiontesting in neurointerventional proceduresChirag D Gandhi,1 Ketan R Bulsara,2 Johanna Fifi,3 Tareq Kass-Hout,1 Ryan A Grant,4

Josser Delgado Almandoz,5 Joey English,6 Philip M Meyers,7 Todd Abruzzo,8

Charles J Prestigiacomo,1 Ciaran James Powers,9 Seon-Kyu Lee,10 Barbara Albani,11

Huy M Do,12 Clifford J Eskey,13 Athos Patsalides,14 Steven Hetts,15

M Shazam Hussain,16 Sameer A Ansari,17 Joshua A Hirsch,18 Michael Kelly,19

Peter Rasmussen,20 William Mack,21 G Lee Pride,22 Michael J Alexander,23

Mahesh V Jayaraman,24 on behalf of the SNIS Standards and Guidelines Committee

For numbered affiliations seeend of article.

Correspondence toChirag D Gandhi, Departmentof Neurosurgery, RutgersUniversity-NJ Medical School,Newark, NJ, USA;gandhich@rutgers.edu

Accepted 30 June 2014

To cite: Gandhi CD,Bulsara KR, Fifi J, et al.J NeuroIntervent SurgPublished Online First:[please include Day MonthYear] doi:10.1136/neurintsurg-2014-011357

INTRODUCTIONOver the past decade there has been a growing useof intracranial stents for the treatment of bothischemic and hemorrhagic cerebrovascular disease,including stents to assist in the remodeling of theneck of aneurysms as well as the use of flow divert-ing devices for aneurysm treatment. With thisincrease in stent usage has come a growing needfor the neurointerventional (NI) community tounderstand the pharmacology of medications usedfor modifying platelet function, as well as thetesting methodologies available. Platelet functiontesting in NI procedures remains controversial.While pre-procedural antiplatelet assays might leadto a reduced rate of thromboembolic complica-tions, little evidence exists to support this as astandard of care practice. Despite the routine useof dual antiplatelet therapy (DAT) with aspirin anda P2Y12 receptor antagonist (such as clopidogrel,prasugrel, or ticagrelor) in most neuroembolizationprocedures necessitating intraluminal reconstruc-tion devices, thromboembolic complications arestill encountered.1–3 Moreover, DAT carries the riskof hemorrhagic complications, with intracerebralhemorrhage (ICH) being the most potentiallydevastating.4 5

Light transmission aggregometry (LTA) is the goldstandard to test for platelet reactivity, but it is usuallyexpensive and may not be easily obtainable at manycenters. This has led to the development of point-of-care assays, such as the VerifyNow (Accumetrics,San Diego, California, USA), which correlatesstrongly with LTA and can reliably measure thedegree of P2Y12 receptor inhibition.6–9 VerifyNowresults are reported in P2Y12 reaction units (PRUs),with a lower PRU value corresponding to a higherlevel of P2Y12 receptor inhibition and, presumably, alower probability of platelet aggregation, and ahigher PRU value corresponding to a lower level ofP2Y12 receptor inhibition and, hence, a higherchance of platelet activation and aggregation.While aspirin resistance is perhaps less common,

clopidogrel resistance may be more challenging asit is reported in the monitoring cohort to be ashigh as 30–35% and is usually due in part togenetic variation, which is reported to increasethromboembolic complications even with escalating

dosing of clopidogrel.3 4 10 11 Patients who haveCYP2C19 allelic variants are highly likely toexhibit clopidogrel resistance. The cardiology lit-erature, representing many large multicenter rando-mized controlled trials, did not show an overallclinical outcome benefit of antiplatelet therapymodification based on pre-procedural assays.12 13

However, there is evidence in the cardiology litera-ture to suggest that clopidogrel resistance leads to ahigher level of thrombotic complications. The val-idity of extrapolating the cardiology literature tothe NI population is questionable, especially sincethe underlying vessel in the setting of cerebralaneurysm treatment with concomitant stent place-ment may not be as diseased with atheroscleroticplaque and precedent angioplasty as in the coron-ary circulation. Furthermore, NI procedures usingstents and flow diverters have been associated withperioperative ICH, and some studies indicate thatP2Y12 receptor over-inhibition may play arole.4 5 14 Many NI procedures necessitate patienttreatment with mono antiplatelet therapy or DATfor variable periods of time, with or without pre-procedural loading doses. The purpose of this con-sensus paper is to develop recommendations forthe use of platelet function testing in this uniquepatient population.

METHODSRecommendations were developed based on theexisting literature, a robust discussion regarding theinterpretation of the literature, and the collectiveexperience of the members of the writing group(table 1). Experts from academic institutions inNorth America from the specialties of neurosur-gery, neurology, and interventional neuroradiologywere recruited based on their expertise related to eachscenario discussed. A computerized search of theMEDLINE database (PubMed) from 1 January 1991to 31 November 2013 was performed using thesearch terms ‘antiplatelet’, ‘treatment’, ‘VerifyNow’,‘LTA’, ‘PRUs’, ‘endovascular’, ‘neuro-endovascular’,and ‘interventional radiology’ with the purpose ofidentifying published articles on the utility of anti-platelet function tests in NI procedures. All relevantEnglish language articles published during thisperiod were taken into consideration while writing

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this consensus paper. The literature review consisted mostly ofcase series and non-randomized single-center studies.

MECHANISMS OF INTRAPROCEDURAL THROMBOSISThere are four major platelet function factors which influencepotential complications in NI procedures: adherence,15 activa-tion and secretion,16 aggregation,17 and interaction with coagu-lation factors.18 When a foreign body (eg, aneurysm coil, stent,catheter, or wire) is introduced into the intravascular space, aprocess of thrombosis and inflammation is initiated.19

Leukocytes are summoned to the foreign body and expresstissue factor on exposed monocytes20 that can then activateplatelet aggregation. Additionally, released inflammatory media-tors can activate platelets, allowing for thrombus formation.19

Furthermore, a number of plasma proteins, including fibrino-gen, bind to foreign bodies within minutes, initiating aplatelet-induced thrombus cascade.21 22

How much platelet aggregation and thrombosis occurs onneuroendovascular foreign bodies is determined by the compos-ition of the implants/tools, surface charge, endothelial damage,as well as sheer stress.23 Similarly, when detachable coils aredetached via a positive charge, negatively charged blood pro-ducts including platelets and red blood cells may be attracted tothis site and this process may induce significant occlusion ofaneurysms during coiling.23 Likewise, some authors have theo-rized that high radial force stents, such as balloon-expandablestents, induce significant endothelial injury and more plateletaggregation and thrombus formation than would be seen withless traumatic low radial force nitinol self-expanding stents.23

While thought provoking, the validity of this theory and itslong-term significance remain unknown.

PHARMACOLOGY OF ANTIPLATELET AGENTSAcetylsalicylic acid (aspirin, ASA)Mechanism of actionAspirin is absorbed by the gastrointestinal tract and hydrolyzedto salicylic acid.24 It irreversibly acetylates cyclo-oxygenaseCOX-1 and COX-2, thereby blocking the conversion of arachi-donic acid to prostaglandins and eventually thromboxane A2.

25

This equates to a prolonged bleeding time secondary to plateletaggregation being blocked, rather than adhesion.15–17 Plateletslack the ability to regenerate COX, meaning that aspirin is asuicide inhibitor as it lasts for the life of the platelet, which isabout 7–10 days.25 Only low doses of aspirin are needed toinhibit COX-1 in healthy subjects,26 whereas higher doses areneeded to inhibit COX-2, with the latter providing analgesiaand reduction in inflammation.25

PharmacokineticsThe bioavailability of aspirin is approximately 50%,25 withactivity noted as early as 5 min after ingestion and peak plasmalevels obtained relatively quickly at about 30–60 min.23 Thisrapid maximal effect has been attributed to acetylation of COX

in the portal circulation.27 Enteric-coated preparations havelower bioavailability and a longer time to peak plasma levels of3–4 h.27 Interestingly, although aspirin has a short half-life of15–20 min, given that its acetylation is irreversible, its effect islong-acting.25 However, COX activity recovers at about 10%per day, given new platelet synthesis, and it has been shown thatas little as 20% of platelets with normal activity can result innormal hemostasis.28

DosingPlatelet prostaglandin synthesis is nearly completely inhibited by100 mg oral aspirin taken once or by 30 mg taken daily for 7–10 days.27 28 Doses below 100 mg result in dose-dependenteffects on thromboxane A2 production, and repeated dailydoses have a cumulative effect.28 To determine the best dose inpreventing any serious vascular event (including myocardialinfarction and stroke), a meta-analysis of 287 randomized trials,equating to 135 000 patients, found that doses of 75–150 mgresulted in a 32% reduction in vascular events, doses of 160–325 mg a 26% reduction, and higher doses of 500–1500 mg a19% reduction, whereas doses <75 mg produced only a 13%reduction.29 Overall, doses <75 mg or >325 mg are not aseffective, and today most practitioners agree with either an81 mg or 325 mg dose with no loading needed.

Resistance (non-response)Given the implications for blockade of thrombus formation inthe prevention of stroke, aspirin resistance is a substantialproblem. Outside non-adherence, the natural incidence ofaspirin resistance is between 5% and 40% at doses of 325mg.23 30 31 In those who are resistant, higher doses can help toovercome the resistance; for example, in one study 56% resist-ance was found at 81 mg and only 28% at 325 mg.32 Resistanceis even higher in those taking enteric-coated aspirin,32 and maydevelop with long-term therapy such as over several years.33 Inthe interventional cardiology population, aspirin resistance leadsto 300% higher rates of death, myocardial infarction, andstroke, observations that might have implications for the neu-roendovascular patient population.23 Biochemical mechanismsof resistance include drug–drug interactions, as seen withproton pump inhibitors which are commonly prescribed forchronic aspirin therapy to reduce the incidence of ulcers.34 Theresistance mechanism is secondary to increased gastric acidwhich ionizes aspirin, making it less readily absorbable, but theconsequence of this is unknown.34 Other mechanisms such asanion efflux pumps, esterase-mediated metabolism, competitiveinhibition by other non-steroidal anti-inflammatory drugs(NSAIDs), COX polymorphisms, high platelet turnover, COXregeneration, and tachyphylaxis have also been implicated.35

ReversalAfter stopping aspirin, normal hemostasis usually returns inabout 4 days36 although it may take up to 5–7 days. Restorationof platelet activity can be obtained more immediately with atransfusion of one pack (5 units) of platelets and/or administra-tion of desmopressin (ddAVP), 0.3 μg/kg body weight intraven-ously or intranasally once, with practically a normalization inthe platelet functional assay. The effect of desmopressin is seenwithin 30 min and lasts up to 4 h.37

Table 1 Consensus agreement on the definitions of levels ofevidence

Level of evidence

A Multiple randomized clinical trials or meta-analysesB Single randomized trial or non-randomized studiesC Expert opinion, case studies or standard of care

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Thienopyridines (P2Y12 inhibitors): ticlopidine (Ticlid),clopidogrel (Plavix), prasugrel (Effient), ticagrelor (Brilique,Brilinta), and cangrelorMechanism of actionFour oral antagonists have been developed in rapid sequence—ticlopidine, clopidogrel, prasugrel, and ticagrelor—with eachagent having a more reliable and rapid onset of action than theother. Ticlopidine and clopidogrel are oral pro-drugs that aremetabolized by hepatic cytochrome 450 enzymes to active meta-bolites that irreversibly prevent ADP from binding to the P2Y12platelet receptor.38 39 In doing so, platelet aggregation is inhib-ited because the glycoprotein GP IIb/IIIa cannot be induced toits high affinity state, which prevents fibrin cross-links resultingin a prolonged bleeding time. Ticlopidine was the first-generation thienopyridine but, given its side effect profile ofbone marrow suppression, the second-generation clopidogrelhas become the current thienopyridine of choice in the neuroen-dovascular suite, with ticlopidine reserved for patients intolerantof clopidogrel.23 In the Clopidogrel Aspirin Stent InternationalCooperative Study (CLASSICS), clopidogrel was safer, had afaster mechanism of action, and was equally efficacious in pre-venting thrombotic complications after coronary stenting.40

This has been confirmed in other randomized trials.41

Newer agents include the third-generation prasugrel andfourth-generation ticagrelor, which have different mechanismsof action to inhibit the P2Y12 receptor. Prasugrel is an orallyactive thienopyridine that is not affected by clopidogrel resist-ance seen with some cytochrome P450 polymorphisms.42

Prasugrel has more potent antiplatelet effects, a lower incidenceof interpatient variability in antiplatelet response, and a reducedtime to onset of antiplatelet activity compared with clopido-grel.43 Prasugrel is superior to clopidogrel in preventing ische-mic events in patients undergoing coronary interventions, buthas a higher bleeding risk.43 Ticagrelor is an orally active P2Y12blocker that does not require conversion to an active metaboliteand inhibits platelet aggregation more completely than clopido-grel or prasugrel.44 45 The PLATO trial demonstrated that tica-grelor is superior to clopidogrel when treating patients withacute coronary syndrome with similar overall bleeding rates.46

However, this has been challenged, with others showing higherbleeding rates with ticagrelor and advising continued use of clo-pidogrel.47 Both of these newer agents have been tested in theneuroendovascular suite in observational studies; some groupshave reported similar bleeding rates with prasugrel and ticagre-lor compared with clopidogrel48–50 while others have reportedan increased bleeding risk with prasugrel.5 14 51 Lastly, cangre-lor45 is a potent intravenous P2Y12 inhibitor which, in a rando-mized trial (CHAMPION-PHOENIX), significantly reduced therate of ischemic events during percutaneous coronary interven-tions (PCIs), including stent thrombosis, with no significantincrease in severe bleeding compared with clopidogrel.52

However, it is not currently available in the USA or Europe forclinical use.

Pharmacokinetics and dosingClopidogrel (Plavix)The bioavailability of clopidogrel is approximately 50% with ahalf-life of 6 h.38 Following oral administration, clopidogrel israpidly absorbed in the intestine and activated in the liver.53 It isan irreversible inhibitor and thus, like aspirin, its effects last thelifespan of platelets at 7–10 days.53 It takes 12–24 h to have sig-nificant platelet inhibition (25–30%) if a standard daily dose of75 mg is used, which equates to about 3–7 days (average 5 days)

to achieve maximal steady state with 50–60% platelet inhib-ition.54 55 A loading dose of 300–600 mg results in maximalsteady state within 2–6 h which lasts up to 48 h.54 55 Theloading dose needs to be given at least 6 h prior to the endovas-cular procedure to have benefit.23 Lastly, it has several drug–drug interactions due to shared metabolism by the cytochromeP450 system.53

Prasugrel (Effient)Prasugrel is a pro-drug that is metabolized to one active metab-olite with rapid absorption.56 Time to peak plasma concentra-tion is approximately 30 min with a half-life of 4–7 h, andmaximal steady state is achieved in 3–5 days with 70–80% plate-let inhibition.56 It has a more rapid and more potent plateletaggregation inhibition than clopidogrel and also has no signifi-cant drug–drug interactions.56 A typical loading dose is 60 mg,and within 1 h patients will have 50% platelet inhibition, whichis much faster than clopidogrel.57 A normal daily dose is 10 mgand results in more platelet inhibition than a clopidogrel dose of75 mg or even double dosing.57 Patients can be transitionedimmediately from clopidogrel to prasugrel without an interrup-tion of antiplatelet effects.57 Given that this is an irreversibleinhibitor, it takes 7–10 days for platelet function to return tonormal.

Ticagrelor (Brilinta, Brilique)Ticagrelor is the first oral P2Y12 antagonist that is a reversibleallosteric binder, with a bioavailability of 36%.46 It is absorbedquickly and reaches its peak concentration after about 1.5 hwith a half-life of 7–9 h.46 Given its pharmacokinetics, it has tobe taken twice a day. The loading dose is 180 mg and the main-tenance dose is 90 mg twice daily.58 Of note, patients can betransitioned immediately from clopidogrel to ticagrelor withoutan interruption of antiplatelet effects, and do not require aload.46 It is recommended that, if taken with aspirin, the aspirindose should not exceed 100 mg.

Resistance (non-response)The pharmacodynamic response to clopidogrel is quite variable,with 20–40% of patients being classified as non-responders,poor responders, or resistant.59 More specifically, investigatorshave reported resistance in 31% within 24 h to 5 days ofdosing, but this effect decreases to 15–20% at 30 days after a300 mg load and then 75 mg daily,60 61 and remains in 18–19%of patients after 2 years.62 Clopidogrel resistance does notdevelop with time and a durable antiplatelet effect is main-tained.63 The mechanism of resistance is thought to be second-ary to variable absorption,64 as well as variable activation in theliver secondary to cytochrome P450 polymorphisms.59 65

Resistance to prasugrel is rare, and this drug is a recommendedalternative for individuals with clopidogrel resistance.59 In therare setting of prasugrel resistance, which may be secondary tohepatic metabolic polymorphisms or interference from anti-retroviral drugs, ticagrelor is an attractive alternative.66 67 Lastly,as expected, a poor response to clopidogrel correlates with sig-nificant clinical effects in the cardiovascular arena leading tohigher death, stent stenosis, myocardial infarction, and stroke.62

ReversalAfter stopping P2Y12 inhibitors, platelet function usually takesabout 7–10 days to return to normal (lifespan of a platelet). Forimmediate restoration of platelet activity, a transfusion of twopooled packs of platelets (∼10 units) are required because thelonger half-life of the inhibitors will consume the first pooled

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pack.68 Also, desmopressin results in partial reversal69 and isemployed by many centers. Additionally, some cardiothoracicand orthopedic surgeons use aprotinin or tranexamic acid forreversal.70

Cyclic AMP inhibitors: dipyridamole (Persantine),dipyridamole + aspirin (Aggrenox), cilostazol (Pletal)Mechanism of actionDipyridamole and cilostazol inhibit the phosphodiesteraseenzymes that break down cAMP, thereby increasing cAMP levelsthat block the platelet response to ADP and prevent platelet acti-vation.71 72 In addition, dipyridamole blocks thromboxane syn-thase and the thromboxane receptor preventing thromboxaneA2 formation,71 which inhibits platelet aggregation. Lastly,dipyridamole increases plasma adenosine levels73 and potenti-ates nitric oxide signaling through cyclic GMP,74 which inhibitsplatelet aggregation.

Pharmacokinetics and dosingFollowing oral administration of dipyridamole, the time to peakplasma concentration is 1–2 h (mean 75 min),75 with a complexmetabolic breakdown yielding a half-life of 10–13 h,76 withsome reports up to 24 h.75 Given its poor bioavailability, anextended release form is typically prescribed and, in terms ofstroke prevention, it has been formulated with aspirin asAggrenox (25 mg aspirin + 200 mg dipyridamole) given twicedaily, as determined by the European Stroke PreventionStudy.77 78 Cilostazol is dosed at 100 mg twice a day and haspeak concentrations at about 3 h, a half-life of 11 h, andachieves steady state in 4 days.72 In patients resistant to clopido-grel undergoing carotid stenting, adding cilostazol for tripletherapy instead of increasing the clopidogrel dose resulted in adecrease in ischemic lesions and no increase in bleeding.79

Resistance (non-response)Dipyridamole resistance has not been reported but, in its usuallyprescribed form as Aggrenox, patients can be expected to haveresistance to the aspirin component as discussed above.

ReversalThere are no clear reversal guidelines, but centers practicing NIprocedures commonly administer two pooled packs of platelets(∼10 units) and one dose of desmopresssin (0.3 μg/kg).

Newer agentsGiven the importance of antiplatelet agents in the endovascularsuite, several new groups of drugs have been developed or areunder development. Thrombin is the most potent platelet acti-vator and thus blockade of this interaction would be paramount.Protease-activated receptor-1 (PAR-1; thrombin receptor)antagonists such as vorapaxar and atopaxar block thrombin-mediated platelet activation but do not interfere with thrombin-mediated cleavage of fibrinogen,80 meaning they are pureantiplatelet agents. They have shown mixed results in PCIs.81 82

PLATELET FUNCTION EVALUATIONThe ability to assess the efficacy of an individual’s platelet func-tion is valuable for patient management to evaluate appropriateantiplatelet effects and also when emergency reversal is requiredfor a hemorrhagic complication or need for emergency opensurgery. Additionally, as described above, many individuals haveeither inherent resistance to some agents or are poor respon-ders, meaning they are unprotected during procedures forwhich antiplatelets are recommended (eg, stenting). Below we

discuss the range of assays available including platelet counting,platelet aggregometry, bleeding time, platelet function assays,and point-of-care assays.

Platelet countingThis is the first-line test for platelet function which continues tobe used by surgeons and interventionalists alike, with a goalcount of ≥80–100 000/μL being the recommended cut-off toproceed with an intervention. The gold standard is a manualcount via phase contrast microscopy,83 but the majority ofcenters employ automated cell counter methods, optical count-ing methods, or flow cytometry.84 However, the absolute plate-let count does indicate functionality of the platelets. Plateletfunction can only be measured by formal functional assays.

Platelet function by platelet count ratio methodAn indirect measurement of platelet function can be employedwith available automated cell counters by stimulating plateletswithin anticoagulated whole blood samples with agonists suchas ADP or epinephrine, inducing aggregation. A ratio betweenthe platelet count in the control sample and the activatedsample is then calculated, which correlates well with plateletaggregometry.85 This technique has been commercialized as theICHOR Point of Care Hematology Counter for the acutesetting.86

Platelet aggregometryOptical aggregometryLTA was developed in the 1960s and has become the gold stand-ard to test platelet function.87 In this assay, blood is centrifugedslowly to obtain platelet-rich plasma that is continuously stirredwhile a light source is shone through the sample. Platelet ago-nists such as ADP are then added to induce aggregation whichresults in increased light transmission, given a decrease in theturbidity of the platelet-rich plasma. A series of platelet agonistsare employed through a range of concentrations to assess shapechanges and aggregation responses. The test is labor-intensiveand requires technical expertise, and may not be easily obtain-able at all centers.88 Additionally, this test underestimates thedegree of GP IIb/IIIa inhibitors,89 is not sensitive enough to testaggregates of <100 platelets (micro-aggregates), and is not reli-able at detecting pre-existing aggregates, which is important inpatients with hyperfunctioning of platelets.90 Resistance tovarious antiplatelet agents is monitored by selection of theappropriate platelet aggregation agonist. For example, aspirintherapy is monitored with ADP, arachidonic acid, or collagen,23

clopidogrel is monitored by platelet responses to ADP, and IIb/IIIa inhibitors are measured by the platelet response to ADP andthrombin receptor agonists.23

Whole blood aggregometry, flow cytometry, and laser plateletaggregometryBecause of the limitations of classic aggregometry, whole bloodaggregometry was developed. In this assay, whole blood isstirred between two platinum electrodes which then becomeplatelet-covered with aggregates after the addition of agonists,thereby changing the impedance in the circuit.91 This method issuperior to measuring antiplatelet therapy with classic aggrego-metry, but is still insensitive to micro-aggregates.85 Nevertheless,the method is in widespread use in Europe.92 In order to assesssmall micro-aggregates, flow cytometry can be employed withhigh accuracy, but the equipment is expensive and requires aspecialized operator. Employing a laser to detect platelet aggre-gates as small as a few platelets via light scattering has gained

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attention because of its accuracy,93 but its adoption has beenlimited.

Bleeding timeThis was the first test for platelet function and studies naturalhemostasis using a simple technique used at the bedside. Itrequires a skin incision, often on the forearm, to a depth todisrupt capillaries. It has been used to predict surgical bleedingas it is a good test of platelet function.94 It does not require anyspecial equipment but it has been criticized as invasive, insensi-tive, irreproducible, and with a subjective endpoint.95

Platelet function assaysIn an effort to mimic in vivo physiology including platelet adhe-sion, activation, and aggregation, several platelet function assayshave been developed. Many of them seek to mimic vessel walldamage and thus base their assays on shear-induced platelet acti-vation.96 For example, the clot signature analyzer measures theability of flowing non-anticoagulated blood to form hemostaticplugs via fibrin formation in a tube of punched holes.97 Thethrombotic status analyzer test employs hemodynamic forces onblood drawn through a capillary tube to induce platelet activa-tion and capillary tube occlusion.98 The more well-known plate-let function analyzer (PFA) exposes platelets in whole blood tohigh shear stress within a capillary tube coated with collagenand ADP/epinephrine and monitors the drop in flow rate as theplatelets form a hemostatic plug.99 The test is used as a screen-ing tool to assess platelet abnormalities and is simple and rapidin execution, but is limited by the absolute platelet count,blood count, and von Willebrand factor levels.100

Thromboelastography (TEG) is another method of testing theefficiency of blood coagulation. It is mainly used in surgery andanesthesiology and has been established as a sensitive test forhemostatic function assessment in several clinical settings.101

Although few centers are capable of performing it, TEG canassess platelet function, clot strength, and fibrinolysis by trigger-ing clot formation followed by computerized coagulation ana-lysis.102 The TEG trace is analyzed for the reaction time, whichrepresents the rate of initial fibrin formation, and for themaximal amplitude, which correlates with the absolute strengthof the clot.103 The use of TEG in NI procedures is underutilizedand rarely described in the literature.104

Point-of-care platelet function assays (ICHOR andVerifyNow)The ICHOR Point of Care Hematology Counter86 employs aratio to measure platelet functionality pre- and post-activation.The VerifyNow Assay, previously known as the Ultegra RapidPlatelet Function Assay, was developed based on the premisethat, in order to achieve significant clinical efficacy with antipla-telet agents, ≥80% of platelet receptors need to be blocked.105

Thus, monitoring of receptor blockade is crucial to ensureoptimal dosing for patient outcomes. This system allows forrapid measurements of aspirin,95 clopidogrel,95 and IIb/IIIainhibitor function106 at the bedside using a whole blood sample.The assay is based upon fibrinogen-coated bead agglutination inresponse to the proportion of available GP IIb/IIIa receptors.For aspirin, the activator is arachidonic acid, for P2Y12 inhibi-tors it is ADP, and for IIb/IIIa inhibitors it is thrombin receptoractivating peptides, all with results that are available in minutes.In 2014 the US Food and Drug Administration (FDA) recalledthe VerifyNow IIb/IIIa test due to concerns in the reporting oferroneous platelet aggregation unit results.

SPECIFIC NEUROINTERVENTIONAL PROCEDURESElective coil embolization of cerebral aneurysmsElective coil embolization of unruptured cerebral aneurysmscarries a very low overall complication rate of 3.4–6.1%.107

Antiplatelet premedication with aspirin and clopidogrel hasbeen proposed for reducing the thromboembolic risk and isused in some centers (Class C evidence).23 107 108 The hesitancyin applying DAT in elective coil embolization due to concernsregarding hemorrhagic complications was eased after ourexperience with DAT during stent-assisted coiling showed alower risk of thromboembolic events with a relatively low riskof hemorrhage related to antiplatelet therapy.109 Responsivenessto aspirin and/or clopidogrel is quite variable, and althoughresistance has been reported to be associated with thrombo-embolic events in the setting of NI procedures, a general con-sensus on a definition for aspirin and clopidogrel resistance isstill missing.110 Even though recent large cardiology studiesfailed to show clear clinical benefit to increasing platelet inhib-ition in resistant patients,111 112 the available data to answer thisquestion in the NI population are still scant. A recent report ona cohort undergoing stenting procedures showed a non-significant decrease in thromboembolic events in patients whoseclopidogrel dose was tailored to the VerifyNow assay.113

Moreover, the marked variability in individual response toroutine clopidogrel premedication108 based on VerifyNowtesting makes clopidogrel a less attractive antiplatelet in NI pro-cedures. This inconsistency in both the clopidogreldose-response effect and the VerifyNow test definitions/inter-pretation has prompted some neurointerventionalists to pursuemore potent antiplatelet regimens derived from the cardiac lit-erature (such as prasugrel and ticagrelor).49 50 However, the lit-erature to support this practice is generally lacking (Class Cevidence).

Stent-assisted coil embolization of cerebral aneurysmsThe fundamental goal of stent-assisted coil embolization of cere-bral aneurysms is to keep the cerebral blood flow hemodynamic-ally stable after coil embolization. Even though self-expandablestents are used during coil embolization of wide-necked cerebralaneurysms in order to maintain a normal cerebral blood flow, itsuse poses a higher risk for thromboembolic complications. Thisis reflected in the World Federation of Interventional andTherapeutic Neuroradiology (WFITN) recommendation of pre-and post-treatment administration of DAT for a variable dur-ation depending on the stent model used (Class C evidence).114

The routine standard of care monitoring of the response to anti-platelet agents in the setting of stent-assisted coil embolization,as in any other cerebrovascular disease, has not been proven,although clearly resistance to antiplatelet medications or asupratherapeutic effect can lead to complications.115 Moreover,the response to aspirin and clopidogrel may differ according tothe method of measurement, which necessitates a standardizedmethod of measurement of the resistance level such as theVerifyNow test.116 With a relatively low risk of hemorrhagiccomplications, DAT in the setting of stent-assisted coiling has alower risk of thromboembolic events.109 Accordingly, in thesetting of antiplatelet resistance, it is reasonable to increase theloading dose (eg, increase the loading dose of clopidogrel from300 mg to 600 mg) and/or the maintenance dose (eg, increasethe maintenance dose of clopidogrel from 75 mg/day to150 mg/day),117 although this may be associated with a higherbleeding risk.118 Other options to overcome antiplatelet resist-ance include avoiding smoking,119 better control of other

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medical comorbidities,116 and avoiding administration ofNSAIDs, competitors of COX inhibition, with aspirin. Finally,based on the cardiology literature, newer antiplatelet agents(such as prasugrel, ticagrelor, and cangrelor) and triple antiplate-let therapy with the administration of cilostazol are believed tobe superior to conventional regimens in preventing stent throm-bosis.120–122 The applicability of these new regimens in the NIpopulation is yet to be proven.

Balloon-assisted coil embolization of cerebral aneurysmsBalloon-assisted coil embolization (BACE) was first describedby Moret in 1997 as a safe technique for embolization ofwide-necked aneurysms.123 Antiplatelet therapy in BACEremains an area of debate. Even though the WFITN did recom-mend post-treatment aspirin, pre-treatment loading with antipla-telet was not emphasized114 as the efficacy of premedicationwith an antiplatelet agent in the setting of BACE has not beenestablished; the use of an antiplatelet loading regimen for BACEis still mostly center-dependent. A significant reduction in therate of thromboembolic complications by clopidogrel pre-medication of patients undergoing BACE has previously beenreported.124 In this report the use of clopidogrel alone or com-bined with aspirin was the only pre-procedural predictor of asignificant difference in local thrombus formation (p=0.01) orsymptomatic thromboembolic complication (p=0.04). The useof antiplatelet agents or antiplatelet function testing prior toBACE is still not supported and requires more investigation in arandomized prospective trial (Class C evidence).

Flow-diverting stentsFlow diverters such as the Pipeline embolization device (PED;Covidien/ev3, Irvine, California, USA), Silk flow diverter(SFD; Balt Extrusion, Montmorency, France), FlowRe-Direction Endoluminal Device (FRED; Microvention,Tustin, California, USA) and the Surpass flow diverter(StrykerNeurovascular, Fremont, California, USA) have beendeveloped to treat wide-necked aneurysms (neck >4 mm) withunfavorable dome/neck ratios (<1.5).125 Flow diversionrequires deployment of the stent within the lumen of theparent artery, allowing the artery to endothelialize along thestent to isolate the aneurysm from the circulation. The PED iscurrently the most studied and the only FDA-approved flowdiverter in the USA. PED deployment is typically performedunder DAT with aspirin and a P2Y12 receptor antagonistbecause of the potential risk of thromboembolic events, esti-mated to be 0–14%,5 14 126–140 due to either in situ stentthrombosis or distal embolization. PED deployment alsocarries a risk of hemorrhagic complications potentially due toDAT, estimated to be 0–11%,5 14 126–140 with parenchymalICH being the most serious complication.

In most studies of the PED patients were treated with a dailyregimen of aspirin 81–325 mg and clopidogrel 75 mg. Patientsare usually pretreated for several days or loaded with aspirin325–650 mg and clopidogrel 300–600 mg h prior to the pro-cedure. DAT is continued for at least 6 months after the proced-ure in most studies. Aspirin is typically continued indefinitelywhile clopidogrel may be stopped, depending on angiographicand clinical results. In studies addressing the use of plateletaggregometry, point-of-care platelet function testing such asVerifyNow used P2Y12 inhibition of 20–40% as a minimumdegree of pre-procedure inhibition required.51 135 137

However, since August 2012, VerifyNow assays report the PRUvalue only. The Assessment of Dual Anti-Platelet Therapy withDrug Eluting Stents (ADAPT-DES) registry proposed that the

optimal clopidogrel therapeutic window to minimize bothischemic and hemorrhagic complications after coronary arterystenting is 95–207 PRU.141 Most recently, a few retrospectivereports have suggested that a therapeutic window of 60–240 PRU could reasonably be used in the setting of flow diver-sion with PED to reduce both thromboembolic events in the‘clopidogrel hyporesponsive population’ and hemorrhagiccomplications in the ‘clopidogrel hyper-responsive popula-tion’.5 14 However, a PRU therapeutic window is yet to be vali-dated in randomized controlled studies.

NEUROINTERVENTIONAL COMPLICATIONS OFANTIPLATELET AGENTSAntiplatelet agents prevent the formation of platelet-rich whitethrombi, especially during intimal wall disruption. Given thewidespread use of mono, dual, or triple antiplatelet therapy tohelp prevent thromboembolic complications in NI procedures,an assessment of actual antiplatelet complications might be war-ranted. The question remains whether the reduction inthromboembolic complications outweighs the risks of hemor-rhagic complications. Furthermore, the duration of treatmentwith dual or triple antiplatelet therapy in patients who haveundergone NI procedures is not well-defined and thus the long-term hemorrhagic outcomes are not known. Here we review thecurrent data, with several outcome measures extrapolated fromthe interventional cardiology literature. DAT is used for at least1 month in the majority of cases and some practitioners con-tinue beyond 1 month because of concerns for late thrombo-embolic events while others discontinue DAT earlier given theconcern for intracranial hemorrhage.

The Management of Atherothrombosis with Clopidogrel inHigh-risk patients (MATCH) trial found that adding aspirin toclopidogrel in high-risk patients with recent ischemic stroke hadno significant impact on ischemic outcome, but life-threateningintracranial hemorrhage was higher in the DAT group.142 Thiswas confirmed in a subsequent trial,143 but a meta-analysisdemonstrated that aspirin and clopidogrel DAT only had anincreased rate of intracranial hemorrhage when compared withclopidogrel but not with aspirin monotherapy.144

Similarly, the Clopidogrel for High Atherothrombotic Riskand Ischemic Stabilization, Management, and Avoidance(CHARISMA) trial which compared aspirin and clopidogrelversus aspirin monotherapy found a non-significant increase inintracranial hemorrhage in the DAT group.52 Conversely, theFast Assessment of Stroke and Transient Ischemic Attack toPrevent Early Recurrence (FASTER) trial found a higher risk ofintracranial hemorrhage with aspirin and clopidogrel that wasnot offset by the decreased risk of ischemic stroke.145 Thesestudies assessed patients with ischemic stroke and not specific-ally patients with stents. Although a potential complication ofstenting is thromboembolic events, the direct applicability ofthese studies remains unclear.

Congruently, the Japanese Registry of NeuroendovascularTherapy (JR-NET) is a nationwide survey from January 2005 toDecember 2009 that assessed periprocedural adverse events.146

They found that, as antiplatelet therapy became standard in thelater years, there was a significantly decreased rate of ischemiccomplications (4.2–2.1%) but a significantly increased rate ofintracranial hemorrhagic complications (2.1–5.3%), as well as asignificantly increased rate in death or severe disability (1.5–2.1%).94 More recently, a study of 110 patients treated with neu-roendovascular angioplasty and/or stent placement maintainedon DATwith aspirin and clopidogrel did not find a significantlyincreased bleeding rate at 3 months, with only one intracranial

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hemorrhage in the cohort.147 In terms of carotid artery stenting,DATwith clopidogrel plus aspirin in a series of 139 patients onlyfound one intracranial hemorrhage at 30 days and an ischemicstroke or death rate of 4.3%.148 Similarly, a randomized con-trolled trial of 47 patients with carotid artery stenosis (>70%)showed that clopidogrel and aspirin significantly reduced theincidence of adverse neurological outcomes at 1 month withoutan additional increase in bleeding.149 The Stenting ofSymptomatic Atherosclerotic Lesions in the Vertebral orIntracranial Arteries (SSYLVIA) trial150 recommends aspirin(minimum 100 mg) for 1 year and clopidogrel (75 mg) for atleast 4 weeks after stenting, but given concerns for late stenting,the SAMMPRIS (Stenting vs Aggressive Medical Managementfor Preventing Recurrent Stroke in Intracranial Stenosis) trialrecommends DAT for 3 months post-procedure.151 However,only limited large trial data beyond 1 month for DAT followingneuroendovascular procedures are available. Caution is currentlyadvised, as large trials in patients with a history of ischemicstroke maintained on DAT have a higher rate of intracranial hem-orrhage. These trials include the CURE (Clopidogrel in Unstableangina to prevent Recurrent Events),152 CREDO (Clopidogrelfor the Reduction of Events During Observation),153 andCOMMIT (Clopidogrel and Metoprolol in MyocardialInfarction)154 trials, in addition to the already mentionedCHARISMA and FASTER trials. The MATCH trial showed thatthe incidence of primary intracranial hemorrhage between thetwo treatment groups is the same for the first 3 months, butincreases in the DAT group after 3.5 months.

In summary, the use of DAT following a neuroendovascularprocedure may decrease the risk of thromboembolic complica-tions, but this may be at the expense of increasing the risk ofhemorrhagic complications. More controlled studies specific tothe NI patient population are needed to clarify this importantissue.

LIMITATIONS OF CURRENT TESTINGOne major limitation in the evaluation of platelet function inpatients treated with antiplatelet medication is the lack of con-sensus on the optimal method of measuring platelet reactivity.The clinical tests in current use for measurement of plateletfunction all have some limitations. The more established test or‘gold standard’ is LTA,155 but it has major disadvantages includ-ing cost, slow assay time, and poor reproducibility, with theneed for sample preparation and a skilled technician. Becausethe performance of the test (including the concentration ofADP used and the platelet concentration) is not standardized,there is no universal metric for the detection of high plateletreactivity.156 Flow cytometry can be used to measure variousmarkers of platelet activity such as vasodilator-stimulatedphosphoprotein phophorylation. Again, this is labor-intensiveand not standardized. Ease of use is a major advantage of thenewer tests that are now more widely used. There arepoint-of-care devices that can be used at the patient’s bedside.Two of the more commonly used assays are the PFA-100 ana-lyzer and the VerifyNow system. The VerifyNow assay is asimple rapid method that has been shown to correlate (r∼0.7)with LTA measurements.157 It is commonly used in the cardi-ology setting where much of the published data originate. In theneurovascular literature, this is also the most commonly usedtest.2–5 10 14 50 51 108 116 158 159

Data for thresholds on antiplatelet testingBecause there is no standard definition for high on treatmentplatelet reactivity, neurovascular specialists have relied on data

from cardiovascular patients. However, even in this literature,there is again no clear cut-off value associated with adverse clin-ical events. Bonello et al156 addressed these concerns anddescribed a range of values in the literature over which plateletactivity appears to be safe for PCI. Initial studies using LTA useda change in platelet aggregation of ≤10% as a definition of anti-platelet medication resistance.9 Several studies have been pub-lished regarding the level of platelet activity measured by theVerifyNow P2Y12 assay and risk of thromboembolic complica-tions in the PCI patient population.13 160 161 This relationshiphas been confirmed in numerous studies using other types ofplatelet activity measurements. The cut-off value for subsequentthrombotic events using the VerifyNow assay has been evaluatedusing receiver operating characteristic curve analysis. A PRUcut-off value of around 230 appears to predict thromboticevents of all types in the cardiovascular literature.13 160 161

ADAPT-DES is a recently published registry of patients treatedwith drug eluting cardiac stents aimed to determine the relation-ship of PRU and clinical outcomes in a study of 8583 patientsin the USA. It suggests a target window of PRU 95–208 inorder to minimize the risk of both ischemic and hemorrhagiccomplications.141 Interestingly, although PRU levels correlatedwith stent thrombosis, there was no independent correlationwith 1-year mortality in this cardiovascular patient population.The applicability of these data to the neurovascular patientpopulation is yet to be proven.

Neurointerventional-specific concernsNI patients and cardiovascular patients differ in demographicsand risk factors. The clinically significant risk of cardiovascularstenting is largely stent thrombosis, as well as potential risksassociated with DAT such as gastrointestinal tract hemorrhage,intracranial hemorrhage, and epistaxis. In neurovascularpatients, hemorrhagic as well as thromboembolic complicationsare serious concerns. While these are important differences,lessons can be learned from the similarities in the data. Therates of platelet activity in neurovascular patients on antiplateletmedications have been found to be similar to those in cardiovas-cular patients.2 3 10 108 116 158 159 The neurovascular datalinking platelet activity and complications are currently limitedbut are increasing in volume. One report of 48 PED proceduresfound that a PRU value of >240 predicted thromboembolicevents while a PRU value of <60 predicted hemorrhagic eventsin the follow-up period.5 14 In addition, the same PRU cut-offvalues predicted thromboembolic and hemorrhagic events in100 patients undergoing different types of elective endovasculartreatment of cerebral aneurysms.108 Similarly, an associationbetween a hyper-response of ≥72% platelet inhibition using theVerifyNow assay and hemorrhagic complications has beenreported.4 Notably, the ADAPT-DES trial found an associationbetween lower PRU values and clinically relevant bleeding inpatients treated with a cardiac stent.141

Increasing platelet inhibitionVarious studies have demonstrated that resistant patients canhave platelet inhibition increased in a number of ways. The firstis increased medication compliance. Second, increased doses ofaspirin or clopidogrel may reduce resistance in some patients. Inaddition, switching to a different antiplatelet agent can reduceplatelet activity. In patients resistant to clopidogrel, doubledosing has been shown to produce therapeutic platelet activityin some patients.3 13 162 However, this reduction in plateletactivity has not decreased thrombotic complications. The tworandomized clinical trials which studied this are both in the

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cardiology literature. In GRAVITAS, resistant patients were ran-domized to receive either standard or double dose clopidogrelafter PCI and no difference was seen between the two groups inthe number of deaths or the development of myocardial infarc-tion or stent thrombosis.13 However, patients were given doubledose clopidogrel and not targeted to a specific PRU level. In theARCTIC trial, patients undergoing PCI were given additionalclopidogrel loading or prasugrel. Again there was no differencein outcomes. However, PRU values <230 were not achieved in15% of patients on follow-up testing. There are limited data onmodification of treatment in neurovascular patients. One studyfound a non-significant decrease in thromboembolic complica-tions with double dose for patients with ≤20% platelet inhib-ition.3 Nevertheless, if changes to the dose or type of P2Y12receptor antagonist administered are made in order to increasethe degree of platelet inhibition prior to a NI procedure, obtain-ing follow-up platelet reactivity testing could be considered tominimize the risk of trading thromboembolic complications forhemorrhagic complications.

Decreasing platelet inhibitionThere are no reliable data regarding hyper-responders to clopi-dogrel and reduction of clopidogrel dosing to achieve moreplatelet activity. In one study, reduction of clopidogrel dosing toevery other day, every third day, twice weekly, or once weekly toachieve a PRU value in the optimal range was described.14

However, the correlation between such clopidogrel dose reduc-tions to achieve a target PRU value and reduction in hemor-rhagic complications is yet to be proven.

CONCLUSIONSWe have summarized the currently available antiplatelet medica-tions available, their mechanisms of action and typical dosages.We have also summarized the currently available testing method-ology for platelet inhibition and reviewed the current literaturein this area. Both the cardiology and NI literature indicate thatsubtherapeutic platelet inhibition may lead to thrombotic com-plications and supratherapeutic inhibition may lead to a higherhemorrhage complication rate. There are a few studies associat-ing the results of platelet function testing to thromboembolicand hemorrhagic complications in the NI field.

However, at present there are insufficient data to recommendroutine platelet function testing prior to NI procedures.Individual centers may choose to use testing for their local prac-tice, and we encourage those centers to collect and publish theirdata. Having a larger body of literature specific to NI patientswill allow us to better understand the role of antiplatelet testingin the management of our patients.

Author affiliations1Rutgers University-New Jersey Medical School, Department of Neurosurgery,Newark, New Jersey, United States2Yale University School of Medicine, Department of Neurosurgery, New Haven,Connecticut, United States3St. Luke’s Roosevelt Hospital Center, Hyman Newman Institute of Neurology andNeurosurgery New York, New York, United States4Yale University School of Medicine, Department of Neurosurgery, New Haven,Connecticut, United States5Abbott Northwestern Hospital, Department of Interventional Neuroradiology,Minneapolis, Minnesota, United States6UCSF, Department of Neurology and Radiology, San Francisco, California, USA7Columbia Presbyterian Hospital, Department of Neurointerventional Surgery,New York, New York, United States8University of Cincinnati, Department of Neurosurgery, Cincinnati, Ohio, UnitedStates9Wexner Medical Center, Department of Neurosurgery, Columbus, Ohio,United States

10The University of Chicago, Department of Radiology, Chicago, Illinois, UnitedStates11Christiana Care Health Systems, Department of Neurointerventional Surgery,Newark, Delaware, United States12Stanford University, Department of Neurosurgery and Radiology, Stanford,California, United States13Dartmouth-Hitchcock Medical Center, Department of Radiology, Neurology andNeurosurgery, Lebanon, New Hampshire, United States14New York Presbyterian Hospital, Weill Cornell Medical College, Department ofNeurological Surgery, New York, New York, United States15WUCSF, Department of Radiology, San Francisco, California, United States16Cleveland Clinic, Cleveland Clinic Stroke Program, Cleveland Heights, Ohio,United States17Northwestern University, Feinberg School of Medicine, Chicago, Illinois,United States18Massachusetts General Hospital, NeuroEndovascular Program, BostonMassachusetts, United States19Royal University Hospital, University of Saskatchewan, Departmentof Neurosurgery, Saskatoon, Saskatchewan, Canada20Cleveland Clinic, Neurosurgery Department, Cleveland, Ohio, United States21University of Southern California, Department of Neurosurgery, Los Angeles,California, United States22UT Southwestern, Department of Neuroradiology, Dallas, Texas, United States23Cedars-Sinai Medical Center, Department of Neurosurgery, Los Angeles, California,United States24Warren Alpert School of Medical at Brown University, Rhode Island, United States

Competing interests None.

Provenance and peer review Commissioned; internally peer reviewed.

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doi: 10.1136/neurintsurg-2014-011357 published online July 23, 2014J NeuroIntervent Surg

 Chirag D Gandhi, Ketan R Bulsara, Johanna Fifi, et al. proceduresfunction testing in neurointerventional Platelet function inhibitors and platelet

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