Methods to Evaluate the Pharmacology of Oral Antiplatelet Drugs

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1 Herz Urban & Vogel 28 Methods to Evaluate the Pharmacology of Oral Antiplatelet Drugs Artur-Aron Weber 1, Michael Adamzik 2, Hagen S. Bachmann 3, Klaus Görlinger 2, Maria Grandoch 1, Kirsten Leineweber 4, Hannes Müller-Beißenhirtz 5, Folker Wenzel 6, Christoph Naber 7, for the Interdisciplinary Study Group Clinical Pharmacology of Haemostasis Abstract Principally, there are two reasons why the pharmacological response to antiplatelet drugs should be measured: on the one hand, an insufficient inhibition of platelet function may result in atherothrombotic complications; on the other hand, an excessive inhibition of platelet function may lead to bleeding complications. The clinical importance to measure the effects of antiplatelet drugs is demonstrated by increasingly growing evidence for an association of resistance to antiplatelet drugs with thromboembolic events. It is often claimed that there is no generally accepted definition of resistance and, instead, there is an ongoing semantic discussion about the correct term to be used to describe this phenomenon. From the pharmacological point of view, there is only one acceptable definition of resistance to antiplatelet drugs: the term resistance should be used when a drug is unable to hit its pharmacological target. Thus, laboratory methods used to evaluate the effects of antiplatelet drugs should be designed to measure the direct pharmacodynamic effect of a drug, rather than the consequences for global platelet function. Based on physiological/pathophysiological, pharmacological, and practical considerations, the authors propose the following assays to be used to measure the effects of oral antiplatelet drugs: for the detection of aspirin actions, thromboxane or arachidonic acid-induced responses (light aggregometry, whole-blood aggregometry) should be measured; for the detection of clopidogrel actions, VASP (vasodilator-stimulated phosphoprotein) phosphorylation (flow cytometry) or ADP-(adenosine diphosphate-)induced responses (light aggregometry, whole-blood aggregometry, possibly also flow cytometry) should be measured. 1 Institute of Pharmacology, University Hospital Essen, University of Duisburg- Essen, Germany, 2 Department of Anesthesiology and Intensive Care Medicine, University Hospital Essen, University of Duisburg-Essen, Germany, 3 Institute of Pharmacogenetics, University Hospital Essen, University of Duisburg-Essen, Germany, 4 Institute of Pathophysiology, University Hospital Essen, University of Duisburg-Essen, Germany, 5 Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Germany, 6 Institute of Clinical Chemistry, University Hospital Essen, University of Duisburg-Essen, Germany. 7 Department of Cardiology, University Hospital Essen, University of Duisburg-Essen, Germany, Key Words: Platelets Pharmacology Laboratory methods Aspirin Clopidogrel Methoden zur Evaluation der Pharmakologie von Thrombozytenfunktionshemmern Zusammenfassung Es gibt zwei prinzipielle Gründe für die Messung der pharmakologischen Wirksamkeit von Thrombozytenfunktionshemmern: Auf der einen Seite kann eine unzureichende Hemmung der Thrombozytenfunktion zu atherothrombotischen Komplikationen führen; auf der anderen Seite kann eine exzessive Hemmung der Thrombozytenfunktion in Blutungskomplikationen resultieren. Die klinische Bedeutung der Messung der Wirkungen von Thrombozytenfunktionshemmern zeigt sich in einer zunehmenden Evidenz für die Assoziation einer fehlenden pharmakologischen Wirksamkeit mit thromboembolischen Ereignissen. Es wird häufig postuliert, dass es keine allgemein akzeptierte Definition für Resistenz gegenüber Thrombozytenfunktionshemmern gibt. Stattdessen wird eine semantische Diskussion über den korrekten Begriff zur Beschreibung des Phänomens geführt. Aus pharmakologischer Sicht gibt es jedoch eine klare Definition der Resistenz gegenüber Thrombozytenfunktionshemmern: Der Begriff Resistenz sollte benutzt werden, wenn ein Pharmakon den für die klinische Wirksamkeit entscheidenden pharmakodynamischen Mechanismus nicht ausüben kann. Daher sollten bevorzugt solche Labormethoden eingesetzt werden, die möglichst direkt den pharmakodynamischen Effekt eines Pharmakons erfassen. Basierend auf physiologischen/ pathophysiologischen, pharmakologischen und praktischen Überlegungen wird vorgeschlagen, dass zur Erfassung der Wirkungen von Acetylsalicylsäure die Thromboxanbildung oder die arachidonsäureinduzierte Thrombozytenaggregation (Lichtaggregometrie, Vollblutaggregometrie) bestimmt werden sollte. Zur Erfassung der Wirkungen von Clopidogrel erscheint die Bestimmung der VASP-( vasodilatorstimulated phosphoprotein -)Phosphorylierung (Durchflusszytometrie) oder die ADP-(Adenosindiphosphat-)induzierte Thrombozytenaggregation (Lichtaggregometrie, Vollblutaggregometrie) bzw. Thrombozytenaktivierung (Durchflusszytometrie) sinnvoll. Schlüsselwörter: Thrombozyten Pharmakologie Labormethoden, Acetylsalicylsäure Clopidogrel Herz 28;33: DOI 1.17/ s Herz Nr. 4 Urban & Vogel 287

2 Why Should the Pharmacological Effects of Antiplatelet Drugs Be Evaluated? Principally, there are two reasons why the pharmacological response to antiplatelet drugs should be measured: on the one hand, an insufficient inhibition of platelet function may result in atherothrombotic complications; on the other hand, an excessive inhibition of platelet function may lead to bleeding complications. The clinical importance to measure the effects of antiplatelet drugs is demonstrated by increasingly growing evidence for an association of resistance to antiplatelet drugs with thromboembolic events [11, 15, 17, 41, 44, 45, 49, 53]. Thus, at present, numerous studies are being carried out in order to correlate laboratory markers of resistance to antiplatelet drugs with the clinical outcome in patients with atherosclerosis. Other fields of application include the evaluation of the impact of antiplatelet drugs on perioperative coagulation management and the control of platelet transfusion, the bleeding risk in oncologic patients, as well as the assessment of the effect of antiplatelet drugs in patients with thrombocytopenia/ thrombocytosis or in patients with platelet function disorders [18]. What Should Be Evaluated (Function, Genetic Predisposition)? The observation, that some patients may be resistant to the pharmacological effect of antiplatelet drugs, has prompted the need of laboratory monitoring of antiplatelet therapy. However, many published studies have been performed using nonspecific tests of platelet function, which identify patients with pathologic laboratory results not necessarily reflecting resistance to antiplatelet drugs [7, 8]. In a recent study, six platelet function tests have been compared to measure aspirin resistance in patients with coronary artery disease [32]. From these data, it was concluded that the different platelet function tests are not equally effective in measuring the effects of antiplatelet drugs. In fact, there was only a poor correlation between the different tests studied. It is often claimed that there is no generally accepted definition of resistance and, instead, there is an ongoing semantic discussion about the correct term to be used to describe this phenomenon. In this context, the terms nonresponsiveness or treatment failure are often used [42]. However, as outlined below, this discussion is not very helpful with respect to the demands of this problem. In fact, from the pharmacological point of view, there is only one acceptable definition of resistance to antiplatelet drugs: the term resistance should be used when a drug is unable to hit its pharmacological target [7, 8]. Thus, laboratory methods used to evaluate the effects of antiplatelet drugs should be designed to measure the direct pharmacodynamic effect of a drug, rather than the consequences for global platelet function. In addition to functional studies, however, an evaluation of genetic factors, such as single nucleotide polymorphisms, appears to be a very promising approach to predict the individual response to antiplatelet drugs [1, 11, 14, 29, 31, 35, 48]. A methodological discussion of this issue, however, is beyond the scope of this paper. How Should the Pharmacological Effects of Antiplatelet Drugs Be Evaluated? Considerations Based on Platelet Physiology/Pathophysiology Platelets are critically involved in primary hemostasis. Upon vessel injury, platelets adhere to collagen-rich extracellular matrix in an initial, activation-independent way. For stable adhesion, however, platelet activation, eventually resulting in the activation of glycoprotein (GP) IIb/IIIa, is required (Figure 1a). Platelet activation can be achieved by different physical (shear stress), humoral (e.g., adrenaline, serotonin), or structural mediators (e.g., collagen). In parallel, the coagulation system is activated, resulting in the formation of thrombin, the most potent platelet activator. Often, however, this primary platelet activation (Figure 2) does not reach the threshold required for the activation of GP IIb/IIIa. To overcome this problem, platelets dispose of two different positive amplification loops of activation: (i) the release of adenosine diphosphate (ADP) from dense granules, and (ii) the cyclooxygenase-1-(cox-1-)dependent formation and release of thromboxane A 2 (TXA 2 ). These secondary mediators complete the primary activation, resulting in GP IIb/IIIa activation and ligand (e.g., fibrinogen) binding, which is necessary for stable adhesion. In addition, these soluble mediators are capable of activating other platelets in a paracrine fashion ( recruitment ). ADP activates purinergic receptors, coupled either to G q proteins (P2Y 1 ), resulting in an increase in the intracellular Ca 2+ concentration, or to G i proteins (P2Y 12 ), resulting in a decrease in the intracellular cyclic adenosine monophosphate (camp) concentration. TXA 2 activates TP receptors, resulting in an increase in the intracellular Ca 2+ concentration via G q proteins (Figure 2). Platelet function can be physiologically inhibited by nitric oxide (via cyclic guanosine monophosophate [cgmp]) or by vasodilatory prostaglandins, such as prostacyclin (via an IP receptor-mediated activation of G s proteins resulting in an increase in the intracellular camp concentration; Figure 2). Taken together, the formation of a platelet-rich thrombus is a complex adhesion process involving activation-independent and -dependent mecha- 288 Herz Nr. 4 Urban & Vogel

3 a Platelets Rolling and adhesion Detachment Endothelial cells Activation, shape change and stable adhesion Collagen-rich extracellular matrix b c d PRP Ω 45 s 1, g Slope LT 2 AU GP IIb/IIIa (inactive) GP IIb/IIIa (active) Fibrinogen Light PPP AU Figures 1a to 1d. Basic mechanisms and methods used to measure platelet adhesion/aggregation. a) Model of platelet adhesion and activation under flow conditions. b) Model of simultaneous platelet aggregation. c) Measurement of platelet aggregation in platelet-rich plasma (PRP) by turbidimetry. LT: difference in light transmittance = aggregation amplitude; slope: aggregation velocity; PPP: platelet-poor plasma. d) Measurement of platelet aggregation in whole blood by impedance aggregometry. Abbildungen 1a bis 1d. Grundlegende Mechanismen der Thrombozytenadhäsion/-aggregation sowie die wichtigsten Methoden für deren Messung. a) Modell der Thrombozytenadhäsion/-aggregation unter Flussbedingungen. b) Modell der simultanen Thrombozytenaggregation in Suspension. c) Messung der Thrombozytenaggregation im thrombozytenreichen Plasma (PRP) mittels Lichtaggregometrie (Turbidimetrie). LT: Zunahme der Lichtdurchlässigkeit = Aggregationsamplitude; Steilheit: Aggregationsgeschwindigkeit; PPP: thrombozytenarmes Plasma. d) Messung der Thrombozytenaggregation im Vollblut mittels Impedanzaggregometrie. nisms, primary activation via different mediators and two different secondary amplification loops. Many methods used to measure platelet function detect a simultaneous aggregation of most of the platelets in the sample under low shear conditions (Figure 1b). Although these methods do not reflect the physiological processes involved in the formation of a platelet-rich thrombus, they represent very valuable tools to measure specific platelet functions and their modification by antiplatelet drugs. For the assessment of the effects of antiplatelet drugs, however, it should be kept in mind that several redundant activation pathways can lead to the formation of a platelet-rich thrombus, resulting in atherothrombotic events [36]. Finally, it should be mentioned that platelets do adhere to immobilized fibrinogen in an activation-independent way [4], thus making some of the available assays using immobilized fibrinogen beads difficult to interpret. Considerations Based on Platelet Pharmacology Both types of oral antiplatelet drugs used in the clinical practice (mainly aspirin, clopidogrel) inhibit irreversibly only one of the two major amplification mechanisms of platelet activation (Figure 2). Neither the primary activation nor the ligand (fibrinogen) binding are directly affected by these drugs. Consequently, in contrast to GP IIb/IIIa antagonists, which completely inhibit platelet aggregation [61], currently available oral antiplatelet drugs can- Herz Nr. 4 Urban & Vogel 289

4 Primary activation PGI 2 Amplification vwf Clopidogrel IP [camp] GP Ib/V/IX ADP P2Y 1 P2Y 12 Collagen Aspirin TXA 2 GP IIb/IIIa not be considered potent inhibitors of platelet aggregation. This has two important implications: (i) The formation of a platelet-rich thrombus can occur even if one of the amplification loops is completely blocked. For example, when TXA 2 synthesis is completely inhibited by aspirin, ADP-mediated platelet activation or activation by strong stimuli (such as thrombin) is not affected. Therefore, aspirin or clopidogrel can only be effective in clinical situations where the respective amplification pathway is relevant for platelet activation. Thus, if an atherothrombotic complication (e.g., acute coronary syndrome) occurs despite concomitant antiplatelet therapy, this event cannot be automatically regarded as treatment failure because the antiplatelet drug can still have fully exerted its pharmacodynamic effect. In this case, the treatment failure cannot be attributed to resistance to a particular drug. Therefore, as outlined above, the term resistance should be used when a drug is unable to hit its direct pharmacological target. (ii) Many laboratory tests of platelet function measure complex processes that eventually lead to platelet aggregation or adhesion. While this degree of complexity is clearly advantageous if a global assessment of platelet function is required (e.g., to detect disorders of platelet function or to TP [Ca [camp] 2+ ] [Ca 2+ ] GP IIb/IIIa activation and ligand binding Figure 2. Basic mechanisms of platelet activation (primary activation, secondary amplification loops, and physiological inhibitors) and primary pharmacological targets of oral antiplatelet drugs. Abbildung 2. Grundlegende Mechanismen der Thrombozytenaktivierung (primäre Aktivierung, sekundäre Verstärkungsmechanismen, physiologische Inhibitoren) sowie die Angriffspunkte von Thrombozytenfunktionshemmern. assess a general bleeding tendency), most of these tests are not suitable to assess the pharmacological effects of antiplatelet drugs. According to the definition of resistance, assays should be used that detect the most direct pharmacodynamic action of a given drug. If complex aspects of platelet function are measured (e.g., platelet adhesion and activation under shear such as in the PFA-1 [platelet function analyzer]), there is the possibility that a particular activation pathway can be bypassed and that platelet function appears to be normal despite sufficient pharmacodynamic action of an antiplatelet drug ( pseudoresistance [59]). For example, aspirin irreversibly inhibits COX-1 activity, resulting in an inhibition of TXA 2 formation. Thus, for the detection of aspirin effects, assays should be used which either measure TXA 2 formation or platelet functions that absolutely depend on TXA 2 formation [5, 52]. In laboratory assays, measuring complex platelet functions, this thromboxane pathway may be often bypassed by other platelet activation mechanisms. Accordingly, the rates of aspirin resistance have been reported to be highly assay-dependent [2, 21]. Since the active metabolite of clopidogrel irreversibly inhibits the G i -coupled ADP receptor (P2Y 12 ) on the platelet surface, an assay should be used which measures ADP-mediated actions on the ADP receptor/g i system (e.g., inhibition of prostacyclin- or prostaglandin E 1 -[PGE 1 -]stimulated camp formation). Preanalytical Considerations Traditionally, citrated blood is used for platelet studies. However, in some laboratories, heparinized or hirudin-anticoagulated blood is used with good results. Thus, the choice of a suitable anticoagulant depends both on the pharmacological question as well as on the method used. For example, in some impedance aggregometers, citrate does not appear to be an ideal anticoagulant. Furthermore, it should be kept in mind that citrate lowers extracellular calcium concentrations and results in an artificial TXA 2 formation upon ADP stimulation [6]. EDTA-anticoagulated blood should not be used, because a complete reduction in extracellular calcium concentrations leads to an irreversible loss of function of GP IIb/IIIa receptors [38]. For the measurement of serum thromboxane, blood clotting should be performed under standardized conditions (time, temperature). Another consideration is timing. Although this has not been studied systematically, storage times (room temperature) of blood samples should not exceed 2 h. A high sample stability has been demonstrated for the VASP (vasodilator-stimulated phosphoprotein) assay [1]. 29 Herz Nr. 4 Urban & Vogel

5 a b c d TX (% control) Inhibition of TX formation (%) TX (% control) TX (% control) Single aspirin dose (mg) Aspirin 4 mg/d Days of treatment [Aspirin] (µm) [Indomethacin] (µm) e AA ADP Collagen g AA Aspirin Aspirin Aspirin Aspirin 1 mg/d p.o. + Aspirin + Aspirin + aspirin Aspirin 1 mg/d p.o. + Aspirin 1 µm in vitro f h CD62P expression (RFU) Aspirin + Aspirin 9 Basal AA 6 3 Aspirin + Aspirin Figures 3a to 3h. Basic pharmacology (a d) and methods used to measure the plateletinhibitory effects of aspirin (e h). Abbildungen 3a bis 3h. Pharmakologie (a d) sowie Methoden zur Messung der Thrombozytenfunktionshemmung durch Acetylsalicylsäure (e h). Considerations Based on Practicability The test should be easy (bedside) and reproducible, with a standardized definition of response, and, of course, it should directly measure the pharmacodynamic action of a particular antiplatelet drug (see above). Unfortunately, such an ideal test does not exist at present [34, 47]. Whole-blood assays, such as impedance aggregometry (Figure 1c, [51]) are advantageous, because no time-consuming isolation procedures are required. On the other hand, isolation of platelet-rich plasma (PRP) from citrated blood can be performed within 1 min by a single centrifugation step in a bench-top centrifuge (Figure 1d). This method does not result in a measurable platelet activation [52] principally allowing the application for point-of-care assays. However, it should be kept in mind that a subpopulation of platelets may be lost during the isolation procedure. This problem particularly applies to flow cytometric methods using whole blood, where a subpopulation of (possibly activated) platelets may be lost from the scatter gate when platelet-leukocyte aggregates are formed. Measurements of serum thromboxane are advantageous in that the generation of the specimens is easy and does not require any experimental equipment. TXB 2 is a stable metabolite and, principally, serum can be shipped to a laboratory specialized in this analysis. Generally, it should be considered that only a few of the commercially available assays are certified for diagnostic use. Critical Evaluation of Methods Aspirin As outlined above, the term aspirin resistance should only be utilized as a description of the failure of aspirin to inhibit thromboxane formation. Since even a completely inhibited COX-1 activity can be bypassed by different platelet activation pathways, several functional assays will detect aspirin resistance even if COX-1 is completely blocked ( pseudoresistance, [59]). Thus, the determination of thromboxane (either in serum or in stimulated PRP) is the most specific method to assess the platelet-inhibitory effects of aspirin. In healthy volunteers, a single dose of aspirin dose-dependently (ID 5 = 26 mg) inhibits platelet thromboxane formation with a complete inhibition at 1 mg (Figure 3a). By con- Herz Nr. 4 Urban & Vogel 291

6 trast, at lower aspirin doses (e.g., 4 mg/d), the inhibitory effects of aspirin are cumulative on repeated doses and maximum inhibition occurs after several days of treatment (Figure 3b). It is generally accept - ed that, for a sufficient clinical efficacy of aspirin, a > 95% reduction in thromboxane synthesis is required. However, as compared to competitive inhibitors, aspirin has a very steep concentration-response relationship ( all-or-nothing response ) with a very unlikely chance to achieve in vivo concentrations that would only partially inhibit thromboxane formation (Figures 3c and 3d). On the other hand, platelet renewal can considerably interfere with aspirin effects at once-daily dosing. Based on these considerations, a sufficient pharmacodynamic effect of aspirin can be clearly confirmed by the demonstration of an almost complete (> 95%) inhibition of serum thromboxane formation. Thromboxane can be measured by determining its stable degradation product TXB 2 using specific immunologic methods, such as radioimmunoassay [43]. Alternative assays, such as the determination of malondialdehyde, may also be used [25]. However, in many laboratories, rather nonspecific platelet function assays, such as light-transmission aggregometry or whole-blood aggregometry (such as the Multiplate system) are probably the most-applied methods to study the antiplatelet effects of aspirin. Using carefully selected platelet activators, a high degree of specificity may be achieved (Figures 3e and 3f). ADP is widely used but is clearly not suitable to measure aspirin effects because, even at artificially low Ca 2+ concentrations (such as in citrated blood or PRP, [6]), ADP does not stimulate a marked thromboxane formation and, more importantly, ADP-induced platelet aggregation does not depend on the thromboxane amplification loop. Accordingly, the aggregation amplitude of ADP-stimulated platelets is not affected by aspirin. A variable reversal of platelet second-wave aggregation is the only effect of aspirin after stimulation with ADP (Figure 3e). By contrast, platelet aggregation, induced by low concentrations of collagen (< 1 µg/ml), usually depends on endogenous thromboxane formation. However, in some individuals, even low concentrations of collagen do stimulate platelet aggregation despite a complete inhibition of thromboxane formation by aspirin ( pseudoresistance, [59]). Thus, collagen-induced platelet aggregation is far from being the optimal method to measure aspirin effects. By contrast, due to the mechanism of action (COX-dependent conversion to prostaglandin endoperoxides/ TXA 2 ), arachidonic acid-induced platelet aggregation constantly depends on endogenous thromboxane formation [26]. However, it should be noted, that, due to high protein binding in whole blood or in PRP, high arachidonic acid concentrations (up to 1 mm) are required in order to induce reproducible platelet aggregation responses. Taken together, if aggregometry is preferred over thromboxane measurements, arachidonic acid-induced platelet aggregation appears to be the most useful tool to assess the antiplatelet actions of aspirin. In contrast to clopidogrel [6], aspirin is effective in vitro, this compound can be added to whole blood or to PRP in order to determine if the platelets from a particular individual are principally susceptible to its pharmacodynamic effect [9, 59, 65]. In many cases, where no inhibition of thromboxane formation or arachidonic acid-induced platelet aggregation after oral aspirin treatment can be detected, addition of aspirin (e.g., 1 µm) in vitro will completely block thromboxane formation (Figure 3g). Principally, this constellation can be explained by an insufficient oral bioavailability of aspirin (e.g., due to an increased activity of intestinal esterases). Thus, this type of resistance was designated the pharmacokinetic type [59]. However, in most cases, patient noncompliance is the underlying reason [57] and the compliance issue should be discussed with the patient. In some cases, aspirin is not effective in inhibiting thromboxane formation in vitro. This type of resistance, designated as the pharmacodynamic type [59], may be due to genetic alterations of the COX-1 gene, posttranslational COX modifications, alterations in cellular aspirin transport mechanisms, or other unknown mechanisms [55, 58, 62, 64]. Very recently, a drug interaction resulting in the prevention of aspirin effects has been described for metamizole and some of its metabolites [27]. It has also recently been proposed that flow cytometry (e.g., arachidonic acid-induced CD62P externalization) can be used to monitor aspirin-mediated inhibition of platelet COX [28]. This method, which has already been used several years ago (e.g., [65] and Figure 3h), is far from being ideal because dilution of PRP (which is necessary to prevent aggregation) also results in a dilution of auto-/paracrine mediators, such as thromboxane. Thus, for flow cytometric analysis, undiluted samples should be used with the addition of RGDS peptide or a GP IIb/IIIa antagonist to prevent platelet aggregation [65]. Assays which detect complex platelet functions, such as the PFA-1 or the VerifyNow, have the advantage that they can be used as point-of-care tests providing immediate information without the requirements of sample transport, time delays or a specialized laboratory [12]. However, as outlined above, in these assays there is the possibility that one specific activation pathway can be bypassed and that platelet function is normal despite sufficient pharmacodynamic action of an antiplatelet drug ( pseudoresistance, [59]). 292 Herz Nr. 4 Urban & Vogel

7 a camp (pmol/ml) ADP + ADP Clopidogrel b Clopidogrel PGE 1 PGE 1 ADP P-VASP VASP d e ADP + Clopidogrel Clopidogrel Clopidogrel Figures 4a to 4f. Methods used to measure the plateletinhibitory effects of clopidogrel. Abbildungen 4a bis 4f. Methoden zur Messung der Thrombozytenfunktionshemmung durch Clopidogrel. + Clopidogrel c Clopidogrel + Clopidogrel Events PGE 1 + ADP P-VASP PGE 1 Events PGE 1 P-VASP PGE 1 + ADP f CD62P expression (RFU) 3 Basal ADP 2 1 Clopidogrel + Clopidogrel Clopidogrel For the measurement of clopidogrel effects, the most specific assays measure the P2Y 12 -mediated activation of inhibitory G proteins [16, 63]. However, P2Y 12 activation does not measurably reduce platelet camp concentrations under basal conditions (Figure 4a). Thus, for the assessment of P2Y 12 function, a stimulation of receptors, coupled to stimulatory G proteins is required. For this purpose, vasodilatory prostaglandins (such as PGE 1 or iloprost) can be used. In this system, ADP (via G i -coupled P2Y 12 receptors) can prevent receptor-mediated (via G s -coupled receptors) increases in intracellular camp concentrations. In platelets isolated from clopidogrel-treated individuals, this inhibitory effect of ADP cannot be detected due to inhibition of P2Y 12 receptors (Figure 4a). However, camp measurements are difficult to perform (radioimmunoassay) and the results are highly variable (Figure 4a). Thus, functional camp concentrations are frequently assessed by the measurement of camp/ protein kinase A-mediated VASP phosphorylation. This can be done using biochemical methods, such as Western blot (Figure 4b). In these experiments, inhibitory effects of ADP on basal VASP phosphorylation (which is low) can sometimes be detected (Figure 4b, [56]). Importantly, PGE 1 -induced VASP phosphorylation is inhibited by ADP (via G i -coupled P2Y 12 receptors). This inhibitory effect of ADP cannot be measured in platelets, isolated from clopidogrel-treated individuals (Figure 4b). However, although this assay is quite specific to detect clopidogrel effects on platelets, platelet isolation, removal of plasma proteins, as well as demanding and time-consuming laboratory procedures are required. In our hands, even using the rapid platelet isolation method (see above) this assay takes at least 1 h total (estimated hands-on time 4 h). Thus, Western blotting, although a quite reliable technique, does not appear to be suitable for routine measurement of clopidogrel effects. Similar considerations also apply to enzyme immunoassays [16]. However, VASP phosphorylation can also be measured by flow cytometry. In this method, originally described by Schwarz et al. [46], ADP either alone or in combination with a vasodilatory prostaglandin (PGE 1 or iloprost) is added to anticoagulated whole blood. After fixation with methanol-free formaldehyde and intracellular permeabilization with Triton X-1, platelets are gated according to scatter properties and a platelet-specific marker (such as Herz Nr. 4 Urban & Vogel 293

8 CD61, CD41, or CD42b). VASP phosphorylation is then measured using a phosphospecific VASP antibody (such as 16C2). In accordance with the Western blot experiments, PGE 1 -induced VASP phosphorylation is inhibited by ADP, an effect that cannot be detected in platelets isolated from clopidogrel-treated individuals (Figure 4c). This method was successfully applied to detect a variability in the responsiveness to clopidogrel in patients after coronary stenting [3, 5, 19]. Importantly, this method allows to specifically detect the effects of clopidogrel irrespective of concomitant antiplatelet therapy, such as aspirin or GP IIb/IIIa inhibitors [13]. A further advantage of this method is a high stability of the blood specimens during transport and storage at room temperature [1]. The VASP phosphorylation assay appeared to be advantageous for the assessment of clopidogrel action compared to impedance aggregometry (Multiplate ) [37]. However, in platelet VASP phosphorylation measurements by flow cytometry did not always correspond to Western blot results [23], possibly reflecting the technical demands of these methods. Thus, simple methods to detect clopidogrel actions would clearly be advantageous. Light-transmission aggregometry using ADP as stimulus is probably the most-applied method to study both platelet physiology and platelet pharmacology [2, 4, 3] and it has been stated that, both light-transmission aggregometry and the VASP phosphorylation assay detect, in a comparable way, the pharmacological inhibition of the platelet P2Y 12 ADP receptor [39]. It should be noted, however, that ADP-induced platelet aggregation cannot be completely inhibited by clopidogrel (Figure 4d). Wholeblood aggregometers, such as the Multiplate system (Figure 4e), have the advantage of a rapid and easy analysis of platelet function. For the measurement of clopidogrel effect, ADP should be used. In a recent study, impedance aggregometry, flow cytometry (ADP-induced CD62P expression), and light-transmission aggregometry have been comparatively analyzed to detect clopidogrel effects. Based on correlation analysis, it was concluded that the whole-blood assay cannot substitute for light-transmission aggregometry or flow cytometric determination of ADP-induced CD62P expression [24]. However, this may be different, when assays are used where a vasodilatory prostaglandin (iloprost or PGE 1 ) is added because this increases the specificity of the assay to measure P2Y 12 -dependent activation of inhibitory G proteins. For this approach, the concentration of the prostaglandin needs to be carefully determined because agonists acting on G s -coupled receptors concentration-dependently inhibit ADP-induced aggregation [56]. Thus, low prostaglandin concentrations have to be used, that do not have inhibitory effects on platelet aggregation. Principally, the effects of clopidogrel can also be measured by flow cytometric analysis of the expression of platelet activation markers (such as CD62P or CD4L, [22, 54]) upon stimulation with ADP (Figure 4f). However, this method requires expensive instrumentation, is technically demanding, and has some technical limitations (see above). In addition, it should be noted that ADP-induced platelet secretion, as measured by CD62P externalization, can be observed and is inhibitable by clopidogrel, but probably requires some additional receptor stimulation by agonists acting at receptors other than ADP receptors. Assays which detect complex platelet functions, such as the PFA-1 or the VerifyNow, are also often used [33] but, as for aspirin, in these assays platelet function may be normal despite sufficient pharmacodynamic action of an antiplatelet drug ( pseudoresistance, [59]). Conclusion Based on these physiological/pathophysiological, pharmacological, and practical considerations, we propose the following assays to be used to measure the effects of oral antiplatelet drugs: for the detection of aspirin actions, thromboxane or arachidonic acid-induced responses (light aggregometry, whole-blood aggregometry) should be measured; for the detection of clopidogrel actions, VASP phosphorylation (flow cytometry) or ADP-induced responses (light aggregometry, whole-blood aggregometry, possibly also flow cytometry) should be measured. Disclosure: The authors declare that they have no financial or personal relations to other parties whose interests could have affected the content of this article in any way, either positively or negatively. References 1. Aleil B, Meyer N, Cazenave JP, et al. High stability of blood samples for flow cytometric analysis of VASP phosphorylation to measure the clopidogrel responsiveness in patients with coronary artery disease. Thromb Haemost 25;94: Asai F, Jakubowski JA, Naganuma H, et al. Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a single ascending dose study in healthy humans. Platelets 26;17: Barragan P, Bouvier JL, Roquebert PO, et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Cathet Cardiovasc Interv 23;59: Herz Nr. 4 Urban & Vogel

9 4. Beckerath N von, Pogatsa-Murray G, Wieczorek A, et al. Correlation of a new point-of-care test with conventional optical aggregometry for the assessment of clopidogrel responsiveness. Thromb Haemost 26;95: Bonello L, Paganelli F, Arpin-Bornet M, et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutanecous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 27;5: Bretschneider E, Glusa E, Schror K. ADP-, PAF- and adrenaline-induced platelet aggregation and thromboxane formation are not affected by a thromboxane receptor antagonist at physiological external Ca ++ concentrations. Thromb Res 1994;75: Cattaneo M. Laboratory detection of aspirin resistance : what test should we use (if any)? Eur Heart J 27;28: Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 27;5:Suppl 1: Cornelissen J, Kirtland S, Lim E, et al. Biological efficacy of low against medium dose aspirin regimen after coronary surgery: analysis of platelet function. Thromb Haemost 26;95: Cuisset T, Frere C, Quilici J, et al. Lack of association between the 87 C/T polymorphism of glycoprotein Ia gene and post-treatment platelet reactivity after aspirin and clopidogrel in patients with acute coronary syndrome. Thromb Haemost 27;97: Cuisset T, Frere C, Quilici J, et al. High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-st elevation acute coronary syndromes. Thromb Haemost 27;97: DiChiara J, Bliden KP, Tantry US, et al. Platelet function measured by VerifyNow TM identifies generalized high platelet reactivity in aspirin treated patients. Platelets 27;18: Dropinski J, Jakiela B, Sanak M, et al. The additive antiplatelet action of clopidogrel in patients with coronary artery disease treated with aspirin. Thromb Haemost 27;98: Dropinski J, Musial J, Jakiela B, et al. Anti-thrombotic action of clopidogrel and P1(A1/A2) polymorphism of beta3 integrin in patients with coronary artery disease not being treated with aspirin. Thromb Haemost 25;94: Fefer P, Hod H, Matetzky S. Clopidogrel resistance the cardiologist s perspective. Platelets 27;18: Geiger J, Teichmann L, Grossmann R, et al. Monitoring of clopidogrel action: comparison of methods. Clin Chem 25;51: Geisler T, Gawaz M. Variable response to clopidogrel in patients with coronary artery disease. Semin Thromb Haemost 27;33: Görlinger K, Jambor C, Hanke AA, et al. Perioperative coagulation management and control of platelet transfusion by point-of-care function analysis. Transfus Med Hemother 27;34: Grossmann R, Sokolova O, Schnurr A, et al. Variable extent of clopidogrel responsiveness in patients after coronary stenting. Thromb Haemost 24;92: Gurbel PA, Bliden KP, DiChiara J, et al. Evaluation of dose-related effects of aspirin on platelet function. Results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation 27;115: Gurbel PA, Bliden KP, Etherington A, et al. Assessment of clopidogrel responsiveness: measurements of maximum platelet aggregation, final platelet aggregation and their correlation with vasodilator-stimulated phosphoprotein in resistant patients. Thromb Res 27;121: Hermann A, Rauch BH, Braun M, et al. Platelet CD4 ligand (CD4L) subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets 21;12: Hezard N, Metz D, Garnotel R, et al. Platelet VASP phosphorylation assessment in clopidogrel-treated patients: lack of agreement between Western blot and flow cytometry. Platelets 25;16: Hochholzer W, Trenk W, Frundi D, et al. Whole blood aggregometry for evaluation of the antiplatelet effects of clopidogrel. Thromb Res 27;119: Hohlfeld T. Aspirin resistance. J Lab Med 26;3: Hohlfeld T, Weber A-A, Junghans U, et al. Variable platelet response to aspirin in patients with ischemic stroke. Cerebrovasc Dis 27;24: Hohlfeld T, Zimmermann N, Weber A-A, et al. Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. J Thromb Haemost 28;6: Hübl W, Assadian A, Lax J, et al. Assessing aspirin-induced attenuation of platelet reactivity by flow cytometry. Thromb Res 27;121: Hulot J-S, Bura A, Villard E, et al. Cytochrome P45 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 26;18: Kobzar G, Mardla V, Ratsep I, et al. Platelet activity before and after coronary artery bypass grafting. Platelets 26; 17: Lepantalo A, Mikkelsson J, Resendiz JC, et al. Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients. Thromb Haemost 26;95: Lordkipanidzé M, Pharand C, Schampaert E, et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 27;28: Malinin A, Pokov A, Spergling M, et al. Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12 rapid analyzer: the VERIfy Thrombosis rik ASsessment (VERITAS) study. Thromb Res 27;119: Mani H, Linnemann B, Luxembourg B, et al. Response to aspirin and clopidogrel monitored with different platelet function methods. Platelets 26;17: Maree AO, Curtin RJ, Chubb A, et al. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost 25;3: Moliterno DJ, Campbell CL. Unraveling questions surrounding clopidogrel resistance and stent thrombosis. J Am Coll Cardiol 27;49: Mueller T, Dieplinger B, Poelz W, et al. Utility of whole blood impedance aggregometry for the assessment of clopidogrel action using the novel Multiplate analyzer comparison with two flow cytometric methods. Thromb Res 27;121: Nomura S, Nagata H, Oda K, et al. Effects of EDTA on the membrane glycoproteins IIb-IIIa complex analysis using flow cytometry. Thromb Res 1987;47: Pampuch A, Cerletti C, de Gaetano G. Comparison of VASP-phosphorylation assay to light-transmission aggregometry in assessing inhibition of the platelet ADP P2Y12 receptor. Thromb Haemost 26;96: Savage B, Ruggeri ZM. Selective recognition of adhesive sites in surface-bound fibrinogen by glycoprotein IIb-IIIa on nonactivated platelets. J Biol Chem 1991;266: Schafer A, Bonz AW, Eigenthaler M, et al. Late thrombosis of a drug-eluting stent during combined anti-platelet therapy in a clopidogrel nonresponsive diabetic patient: shall we routinely test platelet function? Thromb Haemost 27;97: Herz Nr. 4 Urban & Vogel 295

10 Address for Correspondence Artur-Aron Weber, MD Institut für Pharmakologie Universität Duisburg-Essen Universitätsklinikum Essen Hufelandstraße Essen Germany Phone (+49/21) , Fax uk-essen.de 42. Schrör K, Hohlfeld T, Weber A-A. Aspirin resistance does it clinically matter? Clin Res Cardiol 26;95: Schrör K, Seidel H. Blood-vessel wall arachidonate metabolism and its pharmacological modification in a new in vitro assay system. Naunyn Schmiedebergs Arch Pharmacol 1988;337: Schror K, Weber AA, Hohlfeld T. Clopidogrel resistance. Thromb Haemost 24;92: Schrör K, Weber A-A, Hohlfeld T. Clopidogrel resistance and statin cotreatment significant for cardiocoronary prevention in real life? Thromb Haemost 25;94: Schwarz UR, Geiger J, Walter U, et al. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost 1999;82: Siller-Matula J, Schrör K, Wojta J, et al. Thienopyridines in cardiovascular disease: focus on clopidogrel resistance. Thromb Haemost 27;97: Snoep JD, Hovens M, Eikelboom JCJ, et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 27;154: Snoep JD, Hovens M, Eikelboom JC, et al. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med 27;167: Stampfuss JJ, Schror K, Weber A-A. Inhibition of platelet thromboxane receptor function by a thrombin receptor-targeted pepducin. Nat Med 23;9: Toth O, Calatzis A, Penz S, et al. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 26;96: Undas A, Placzkiewicz-Jankowska E, Zielinski L, et al. Lack of aspirin-induced decrease in thrombin formation in subjects resistant to aspirin. Thromb Haemost 27;97: Valles J, Santos MT, Fuset MP, et al. Partial inhibition of platelet thromboxane A 2 synthesis by aspirin is associated with myonecrosis in patients with ST-segment elevation myocardial infarction. Am J Cardiol 27;99: Weber A-A, Braun M, Hohlfeld T, et al. Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers. Br J Clin Pharmacol 21;52: Weber A-A, Heim HK, Schumacher M, et al. Effects of selective cyclooxygenase isoform inhibition on systemic prostacyclin synthesis and on platelet function at rest and after exercise in healthy volunteers. Platelets 27;18: Weber A-A, Hohlfeld T, Schrör K. camp is an important messenger for ADP-induced platelet aggregation. Platelets 1999;1: Weber A-A, Liesener S, Hohlfeld T, et al. 4 mg of aspirin are not sufficient to inhibit platelet function under conditions of limited compliance. Thromb Res 2;97: Weber A-A, Liesener S, Schanz A, et al. Habitual smoking causes an abnormality in platelet thromboxane A 2 metabolism and results in an altered susceptibility to aspirin effects. Platelets 2;11: Weber A-A, Przytulski B, Schanz A, et al. Towards a definition of aspirin resistance: a typological approach. Platelets 22;13: Weber A-A, Reimann S, Schrör K. Specific inhibition of ADP-induced platelet aggregation by clopidogrel in vitro. Br J Pharmacol 1999;126: Weber A-A, Schrör K. Differential inhibition of adenosine diphosphate- versus thrombin receptor-activating peptide-stimulated platelet fibrinogen binding by abciximab due to different glycoprotein IIb/IIIa activation kinetics. Blood 21;98: Weber A-A, Zimmermann KC, Meyer-Kirchrath J, et al. Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet 1999;353: Weerakkody GJ, Brandt JT, Payne CD, et al. Clopidogrel poor responders: an objective definition based on Bayesian classification. Platelets 27;18: Zimmermann N, Kienzle P, Weber AA, et al. Aspirin resistance after coronary artery bypass grafting. J Thorac Cardiovasc Surg 21;121: Zimmermann N, Wenk A, Kim U, et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 23;18: Herz Nr. 4 Urban & Vogel

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