Thrombelastography: Current clinical applications and its potential role in interventional cardiology

Platelets, December 2006; 17(8): 509–518 REVIEW Thrombelastography: Current clinical applications and its potential role in interventional cardiolog...
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Platelets, December 2006; 17(8): 509–518

REVIEW

Thrombelastography: Current clinical applications and its potential role in interventional cardiology

A. R. HOBSON, R. A. AGARWALA, R. A. SWALLOW, K. D. DAWKINS, & N. P. CURZEN Southampton University Hospital, Wessex Cardiac Unit, Southampton, UK (Received 28 March 2006; accepted 25 July 2006)

Abstract Thrombelastography is a bedside blood test used to assess patients’ haemostatic status. It has a well-established role in hepatobiliary and cardiac surgery and is also used in obstetrics and trauma medicine to assess coagulation and identify the causes of post-operative bleeding. It is not routinely used in the diagnosis or treatment of thrombosis although recently it has been shown to predict thrombotic events post-operatively and after percutaneous intervention (PCI). In cardiovascular medicine the importance of the platelet in the pathophysiology of vascular events is increasingly apparent. As a result antiplatelet therapy is a cornerstone of the treatment for coronary disease, particularly in the setting of acute coronary syndromes. The increasing utilization of stents, particularly drug-eluting devices, in PCI has also necessitated widespread use of antiplatelet agents to minimize the risk of stent thrombosis. A quick, accurate and reliable test to measure the effect of platelet inhibition by antiplatelet agents on clotting in an individual patient would be of profound clinical value. The results from such a test could provide prognostic information, allow treatment with antiplatelet agents to be tailored to the individual and identify resistance to one or more of these agents. Optimization and tailoring of anti-platelet therapy in patients with cardiovascular disease, particularly those undergoing PCI, using such a test may reduce morbidity and mortality from thrombotic and haemorrhagic complications. Current methods of assessing platelet activity measure platelet count and function in isolation. Optical aggregation is the most widely used method for assessing platelet function but it is relatively time consuming, measures platelet function in isolation rather than in the context of clot formation and is not a bedside test. By contrast the modified thrombelastograph platelet mapping kit marketed by Haemoscope can be used to assess the effects of antiplatelet agents on ex vivo blood clotting, thus giving a measurement more relevant to in vivo responses. This represents a potentially powerful tool to assess response of individual patients to antiplatelet therapy, particularly in the context of PCI.

Keywords: Platelets, clotting, vascular, aspirin, clopidogrel

Introduction

Principles of TEGÕ : The test and how it works

The ThrombelastographÕ (TEGÕ ) Haemostasis System (Haemoscope Corp, IL, USA) provides an overall assessment of haemostatic function [1, 2]. It provides a graphic representation of clot formation and lysis. First developed in 1948, it was used initially as a research tool [3]. In the last 20 years development and automation of TEGÕ has facilitated its utility in the clinical management of bleeding and haemostasis where it is used to guide clotting factor replacement, platelet transfusion and in fibrinolysis treatment [4]. Recent modifications have further added to its potential applications.

Kaolin activated blood at 37 C is placed in a cylindrical cuvette (cup) that oscillates by 4 degrees 450 at a frequency of 0.1 Hertz. Suspended within the cup by a torsion wire is a stationary pin. As the cup oscillates there is a 1 mm gap between it and the pin. The wire acts as a torque transducer [5, 6] (Figure 1). When whole blood is in its liquid form cup oscillation has no impact on the pin. As blood clots, fibrin strands link the pin and the cup and changes in the viscoelasticity of the blood are therefore transmitted to the pin. The resulting torque generates an electrical signal whose magnitude can be plotted as a

Correspondence: N. P. Curzen, PhD FRCP FESC, Consultant Cardiologist and Hon. Senior Lecturer, Wessex Cardiac Unit, Southampton University Hospital, Southampton SO16 6YD, UK. Tel: þ44 (0)2380 794972. Fax: þ44 (0)2380 794772. E-mail: [email protected] ISSN 0953–7104 print/ISSN 1369–1635 online ß 2006 Informa UK Ltd. DOI: 10.1080/09537100600935259

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function of time to produce a TEGÕ trace [5, 7] (Figure 2). Thus, as blood clots there is a progressive increase in the signal amplitude to a maximum. The standard TEGÕ trace can be analysed to provide several parameters defining the speed and strength of clot formation (Table I). Normal haemostasis involves the controlled activation of clot formation, spontaneously balanced by mechanisms of clot lysis; therefore a truly global analysis of haemostatic function requires assessment of both the fibrinolytic and coagulation systems. TEGÕ measurements incorporate both of these components by using the parameter of viscoelasticity of clotting blood. This assessment is dependent on a) cellular and plasma components b) the activity and concentration of coagulation elements as well as c) procoagulant and d) fibrinolytic activity. The TEGÕ trace can therefore

provide continuous real time information on the viscoelastic properties of the evolving clot from the time of initial fibrin formation, through platelet aggregation, fibrin cross linkage and clot strengthening to clot lysis [8]. Analysis can determine a) the speed of clot generation, b) its strength and c) its stability [9]. Clotting is a dynamic process. Conventional tests such as activated partial thromboplastin time and platelet count and function assess isolated components of the haemostatic system and are unable to predict the role of these components in the context of haemostasis as a whole. The advantage of TEGÕ is that it incorporates the interaction of all

Table I. Commonly assessed TEGÕ Parameters.

Parameter R time

K time

angle

MA (maximum amplitude)

Figure 1. How TEG works: blood is added to a cup into which a pin is placed. The cup oscillates. Forming clot transmits the

Area under TEGÕ curve

Description and rationale for assessment Reflects the time to initial fibrin formation. Relates to plasma clotting factor and inhibitor activity. The time taken for the blood to achieve a fixed level of viscoelasticity. Assesses the rapidity of fibrin cross linking. The angle formed by the gradient of the initial trace. Represents the speed of clot formation. This indicates the strength of the clot and reflects the activity of fibrin and platelets. Is dependent on both the MA and angle and therefore incorporates both the strength and speed of clot formation.

Figure 2. A TEG trace. The time to initial clot formation, rate of clot formation (initial angle of trace) and the strength of the clot (maximum amplitude of the trace) can all be established.

Thrombelastography of the components of coagulation including platelets, fibrin, clotting factors, and thrombin as well as providing information about the quality of the clot [10]. TEGÕ has been shown to be superior to either activated clotting time (ACT) or conventional tests at diagnosing postoperative coagulopathies [11] and can help predict post operative blood loss [12]. TEGÕ : Recent modifications Unmodified TEGÕ provides a non-specific assessment of global haemostasis; the effects of some abnormalities are obscured by other more dominant components of the coagulation system (such as thrombin). Recent modifications to TEGÕ allow more precise identification of abnormalities and have improved its ease of use and reproducibility (see Table II). Modifications include using sample activators to speed up result acquisition, and citrated samples to allow a longer delay before testing [13–15]. Alternatively blood can be taken into heparinised tubes, again allowing a longer delay before testing and also eliminating the effect of thrombin, allowing assessment of the contribution of platelets and fibrin to the clot. The addition of a platelet glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor in vitro inhibits platelet aggregation and allows the relative contribution of fibrinogen to haemostasis to be assessed. The TEGÕ trace produced in this context correlates with the plasma fibrinogen concentration [16]. Other modifications (including the use of specific platelet Table II. Modifications to standard TEGÕ . Reagent used Citrate Heparin

Heparinase

Activators (e.g. Celite, Kaolin, Tissue Factor) Glycoprotein IIb/IIIa inhibitors Antifibrinolytic drugs (e.g. Tranexamic acid) Activator FTM (Reptilase and Factor XIIIa) Arachidonic Acid

ADP

Rationale for use Enables prolonged storage of samples before analysis. Inhibits thrombin allowing the contribution of fibrin and platelets to be assessed. Reverses the effect of heparin, e.g. in patients on cardiopulmonary bypass. Speed up result acquisition. Inhibit platelet function allowing the contribution of fibrinogen to be assessed. Reverse fibrinolysis. Activates fibrin formation without affecting platelets. Activates platelets via the production of thromboxane A2. This pathway is affected by aspirin. Activates platelets via P2Y1 and P2Y12 receptors. Clopidogrel and other thienopyridines inhibit the P2Y12 ADP receptor.

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activators and activators of fibrin formation) allow the effects of antiplatelet therapies to be detected and whilst summarized in Table II will be covered in detail later. Together these modifications allow analysis of the functional importance of different components of the haemostatic system. This may make specific diagnosis and targeting of therapy possible. Furthermore potential therapies can be tested on patient’s blood ex-vivo to predict the clinical response before administration [13]. Limitations of TEGÕ Haemostasis is associated with a wide range of normal values due to extensive variability in components of the haemostatic system including platelet count and function, GPIIb/IIIa receptor number and fibrinogen concentration. Ideally therefore, each patient should have baseline TEGÕ measurements before initiating a treatment or procedure so that there is an internal, individualized reference for change. Difficulties with validation and standardization probably accounts for why TEGÕ has not been universally accepted by haematologists [15]. To some extent these issues have been overcome by the use of computer software to analyse the TEGÕ trace which allows for standardization of results. Further standardization has been achieved by use of disposable cups and pins, individual temperature control and use of activators such as kaolin to standardize the initiation of the clotting process. One fundamental challenge relating to the potential clinical applicability of TEGÕ is whether it is only useful in the assessment of a change in clotting behaviour, or whether ‘‘snapshot’’ values will be useful. Current clinical applications One of the main roles of TEGÕ in clinical practice is in hepatobiliary surgery where it is used to monitor haemostasis and guide therapy [17]. It has been shown to be more effective than conventional tests at assessing the risk of bleeding in this complex area [18, 19]. TEGÕ has been used in liver transplantation since 1980 where it has been shown to reduce transfusion requirements [16]. In obstetrics TEGÕ can be used to differentiate between the normal hypercoagulable state in pregnancy and the coagulopathic hypercoagulable state associated with preeclampsia. TEGÕ has also been applied to obstetric patients to identify those at risk of potentially dangerous bleeding from an epidural [20]. In cardiac surgery it is well established that CPB (cardio-pulmonary bypass) disturbs the haemostatic system in a number of ways including (i) haemodilution of procoagulants, fibrinogen and platelets [21], (ii) a reduction in levels of coagulation factors, (iii) the use and reversal of heparin, (iv) preoperative

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administration of platelets [22], (v) altered termperature and (vi) surface interaction in the bypass circuit. It has been demonstrated that routine use of TEGÕ during cardiac surgery reduces transfusion requirements and, in addition, when transfusion was required, the TEGÕ group were able to employ more specific therapy by identifying the cause of the coagulopathy [9]. TEGÕ can also be useful in the intraoperative period; for example, the use of heparinase in perioperative TEGÕ studies is able to neutralize the effects of heparin administered during CPB. Further, hypothermia used in CPB can affect coagulation in ways not detected by standard coagulation tests. In contrast, temperature adapted TEGÕ can detect abnormalities in the hypothermic patient enabling effective treatment of coagulopathy [23]. As well as its use in the management of haemostasis TEGÕ has more recently been investigated as a marker of risk for thrombotic events. In a study of 240 non-cardiac post-operative patients there was a significantly higher incidence of thrombotic events, including myocardial infarction, in those with maximum amplitude (MA) of 468 mm on TEGÕ [24]. Gurbel et al. have also shown that increased MA on TEGÕ (both pre- and post-clopidogrel loading at the time of procedure) provides a predictive tool for ischaemic events following PCI. On combining two measures from a standard TEGÕ trace, MA and a short R time (see Figure 2) they demonstrated an odds ratio for ischaemic events in the 6 months following PCI of 38 [25]. Assessment of the effects of antiplatelet therapy As our understanding of the pathophysiology of vascular events (for example in acute coronary syndromes (ACS) and stent thrombosis) has evolved the integral role of the platelet is increasingly recognized. Plaque rupture, platelet activation and aggregation and thrombus formation occur as a result of complex interactions between platelets, vascular endothelium, inflammatory cells and circulating proteins. These processes can result in vascular occlusion, ischaemia and infarction. Similarly, coronary vessel trauma and inflammation induced during the process of stent implantation, as well as the poorly understood subsequent role of stent endothelialisation combine to make some patients susceptible to stent thrombosis. A rapid and reliable method of assessing the contribution of platelets to clotting would be of considerable clinical value. Such a test would enable the optimization of antiplatelet therapy on an individual patient basis. Conventional treatment with aspirin and clopidogrel involves administration of standard doses to all patients, despite the well established evidence that responses, in terms of platelet function, are heterogeneous. Identification of patients resistant

to antiplatelet agents might allow additional antiplatelet therapy to be administered with the aim of reducing events in these patients [26]. Historical methods of measuring platelet activation and function are time consuming and cannot be performed at the bedside. Conventional tests measure parameters such as platelet numbers and isolated platelet function outside the context of clot formation. Optical aggregation is the gold standard method. However, it is performed only in specialized situations due to the cost and expertise required and hence is not suitable as a rapid point of care test [27]. Recently several assays have been developed which show some potential as point of care tests of the effects of antiplatelet medication. These include the PFA-100 (Dade Behring, Deerfield, Illinois, USA), the Accumetrics VerifyNow system (Accumetrics, San Diego, California, USA), Plateletworks (Helena Laboratories, Allen Park, Michigan, USA) and the Cone and Plate(let) analyser (DiaMed, Canton, Ohio, USA) as well as the modified TEGÕ platelet mapping system. The PFA-100 is a whole blood assay that measures the time for occlusion of an aperture in a membrane under high stress shear conditions, mimicking the forces in a stenotic artery. A cartridge containing a membrane coated with collagen and epinephrine has been used to study the effects of aspirin. There is some evidence of a higher incidence of clinical events in patients found not to respond to aspirin by PFA100 [28]. However, the PFA-100 is not a clear indicator of the effects of clopidogrel [29]. In addition the result depends on von Willebrandt’s factor, which is itself increased by PCI [30]. It may therefore not be able to differentiate between increased platelet reactivity due to PCI and a reduced response to aspirin. The Accumetrics VerifyNow system is a rapid, automated whole blood assay that measures agglutination of fibrinogen-coated beads in response to specific agonists for aspirin, the P2Y12 receptor (for thienopyridines) and Glycoprotein IIb/IIIa inhibitors. In the setting of PCI aspirin and clopidogrel resistance as measured by Accumetrics has been correlated with an increased incidence of periprocedural myocardial infarction [31, 32]. However, the utility of the aspirin and clopidogrel assays is limited in some emergency patients as their use is not recommended within 2 weeks of abciximab therapy. The plateletworks system uses collection tubes with EDTA as baseline and collagen and ADP agonists, which are then examined in a standard cell counter. This system is not yet well studied but there is some evidence for its use in detecting responses to thienopyridines and glycoprotein IIb/IIIa inhibitors. The pros, cons and evidence base for these tests are summarized in Table III. In standard TEGÕ the maximum amplitude (MA) is largely dependent on thrombin. Thrombin is a

Modified TEGÕ platelet mapping kit

Plateletworks

Accumetrics

PFA-100

Test

Widespread utility.

Ease of use. Whole blood assay, high shear stress. Ease of use, automated, rapid, whole blood assay. Whole blood assay. Ease of use.

Pros

Difficulties with aspirin and clopidogrel assays in emergency patients. Requires cell counter. Little evidence for use. Some sample preparation.

Depends on Von Willebrand factor (which is elevated by PCI). Uncertain sensitivity, specificity.

Cons

Yes

No

Yes

Yes

Ability to monitor aspirin

Yes

Yes

Yes

No

Ability to monitor clopidogrel

Table III. A comparison of currently utilised point of care ‘‘platelet function’’ assays.

Yes

Yes

Yes

Yes

Ability to monitor GPIIb/IIIa antagonist

Yes

No

Yes

No

Correlation with clinical events

Yes

Yes

Yes

No

Correlation with optical aggregation

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powerful platelet activator and overwhelms the effect of other less potent platelet activators such as Arachidonic Acid (AA) and adenosine diphosphate (ADP). In the presence of thrombin it is possible to detect some effect from potent antiplatelet agents such as Glycoprotein IIb/IIIa inhibitors [33], but the effect of other antiplatelet agents remains obscured [34]. However, by taking blood into a tube that contains heparin, thrombin is inhibited. The subsequent addition of Activator FTM generates a fibrin network in which platelets can interact independent of thrombin. Without alternative sources of platelet activation there is minimal platelet activation and therefore minimal response on the TEGÕ curve (low MA). However, other platelet activators (AA or ADP) can be added and (in the absence of inhibition of their specific pathways of action (e.g. with aspirin or clopidogrel respectively)) this increases the MA. Maximal platelet activation generates a curve similar to unmodified TEGÕ in the presence of thrombin. The effect of antiplatelet medication can therefore be established by comparing the unmodified TEGÕ curve (representing maximal platelet activation) and the modified TEGÕ curve with either AA or ADP stimulation. Aspirin achieves platelet inhibition by permanent inactivation of cyclooxygenase I, an enzyme in platelet AA metabolism. The percent inhibition due to aspirin can therefore be calculated by comparing the unmodified curve in the presence of thrombin (maximal platelet activation), the heparinised sample with Act F alone (no platelet activation) and the modified TEGÕ curve with AA stimulation (residual platelet activation due to AA in the presence of aspirin). The effect of Clopidogrel, a direct ADP inhibitor and the GPIIb/IIIa antagonist, abciximab, on platelets can be assessed in a similar fashion, utilizing ADP-induced platelet aggregation. These modifications are summarized in Table II. This system is marketed by Haemoscope as the ‘‘Platelet Mapping Kit’’. Experiments by our group have established the utility of modified TEGÕ in detecting time dependent effects of antiplatelet therapy in healthy volunteers [35]. With these modifications TEGÕ correlates closely with optical aggregation in the assessment of the effects of antiplatelet agents [36]. In the context of PCI Mobley et al. found a good correlation between the two techniques when used to detect the effects of clopidogrel [37]. A close correlation between modified TEGÕ and optical aggregation has also been found when used in the detection of aspirin resistance [38]. Effects of antiplatelet agents on platelet function – in clinical practice An easy, functional test of the effects of antiplatelet therapy on clotting would (i) identify resistance to

antiplatelet agents, (ii) facilitate tailoring these agents to an individual and (iii) optimize withdrawal of antiplatelet therapy for surgical purposes [36]. As platelet activation can persist for many months after a cardiovascular event [39, 40], TEGÕ assessment of this activation could tailor future management with regard to the timescale of treatment with antiplatelet agents. Of course, antiplatelet therapy does increase the risk of bleeding; these risks and the requirement for platelet transfusion could be reduced by ex-vivo monitoring of platelet function [41]. Aspirin and clopidogrel resistance – potential targets for diagnosis and treatment in clinical practice Aspirin causes platelet inhibition by irreversible acetylation of cyclooxygenase-1 preventing conversion of AA to prostaglandin –H and subsequent formation of the potent vasoconstrictor and platelet activator thromboxane A2. It is well established that long-term use of aspirin in patients with vascular disease decreases morbidity and mortality from cardiovascular events by 25% and it is a cornerstone of secondary prevention treatment in the setting of coronary artery disease [42]. The role of aspirin in primary prevention is still the subject of debate, although most trials support its use in high-risk patients [43]; the potential benefit must, however, be balanced with risk of bleeding. The anti-thrombotic effect of aspirin is saturable at doses in the range of 75–100 mg in normal adults [44]. Aspirin resistance is a genuine entity although difficult to define precisely and is reported in up to 20% of patients with stable coronary artery disease [45–47]. Recent studies using methods which specifically analyse platelet aggregation to AA (including modified TEGÕ ) suggest that the true incidence may be much lower [48, 49]; these studies have also highlighted the importance of compliance. Patients shown to be resistant to aspirin have higher rates of cardiovascular events [49]. Platelets from aspirin-resistant patients also appear to be more sensitive to the actions of ADP so that the addition of alternative antiplatelet therapies that inhibit ADPinduced platelet aggregation to these patients is therapeutically useful [50]. It is possible that increased sensitivity to ADP and other platelet activators explains why assays that are not entirely specific to AA induced activation give higher estimates on the incidence of aspirin resistance. Clopidogrel is a thienopyridine derivative that both selectively inhibits ADP-induced platelet aggregation and inhibits the conformational change of platelet GPIIb/IIIa so that fibrinogen can no longer bind to this receptor; Clopidogrel has no direct effects on the metabolism of AA. The CAPRIE trial suggested that clopidogrel was marginally more effective than aspirin in prevention of vascular events in a highrisk population [51]. Data from CURE suggest that

Thrombelastography

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Figure 3. Angiogram (AP projection) of a left coronary artery showing proximal left anterior descending artery (LAD) stent after insertion on the left and following proximal stent thrombosis and LAD occlusion on the right.

the addition of clopidogrel to aspirin in patients with ACS conveys prognostic benefit by reducing further cardiovascular events [52]. Recently CHARISMA has suggested a benefit with the addition of clopidogrel to aspirin in all patients with symptomatic atherosclerosis although there was a suggestion of harm in those with asymptomatic disease or multiple cardiovascular risk factors alone [53]. There is, however, considerable inter-individual variability in platelet inhibition in response to clopidogrel [54]. Patients with a raised body mass index (BMI) and those with type two diabetes mellitus have an increased sensitivity in platelet adhesion and aggregation to ADP [55]. Increased thromboxane production, increased GPIIb/IIIa receptor expression, greater thrombin generation and an attenuated response to the inhibitory effect of aspirin on platelets have also been reported [56]. Mobley et al. have demonstrated (using optical aggregation, Ichor plateletworks assay and TEGÕ ) that 30% of patients undergoing coronary angiography were resistant to clopidogrel [37]. Clopidogrel resistance (using ADP-induced optical platelet aggregation) has been shown to be associated with increased risk of recurrent thrombotic events in patients with acute myocardial infarction [57]. Recently Gurbel et al. have shown in patients post PCI that the degree of ADP induced platelet aggregation (by light transmittance aggregometry) was significantly more pronounced in those with subsequent ischaemic events [25]. PCI is now the commonest method of coronary revascularisation in the UK. The initial relatively common limitation of restenosis and the subsequent need for repeat revascularisation in patients treated with bare metal stents has been dramatically reduced as a result of widespread deployment of drug eluting

stents (DES). Key to this strategy has been the use of clopidogrel and aspirin to reduce the rate of stent thrombosis [58]. However there are important ongoing concerns over stent thrombosis, which continues to occur in 1–2% of cases in clinical practice and may be associated with mortality rates of up to 45% [59] (Figure 3). Specifically, there have also been reports of late thrombosis occurring after DES implantation particularly on reduction or cessation of antiplatelet therapy [60]. Importantly, altered responses to aspirin and clopidogrel have also been shown to convey an increased risk of stent thrombosis [61]. Such patients may require larger doses of aspirin and clopidogrel or alternative or additional antiplatelet therapy to provide adequate therapeutic protection. However, clinical practice is currently limited by the lack of a rapid, easily accessible point of care test to assess such issues. The discrepancy between the estimated rates of aspirin and clopidogrel resistance using tests that specifically assess isolated platelet function and preliminary investigations using modified TEGÕ may suggest some advantage of assessing ex vivo clotting as a complete entity [38]. Whilst it is still unclear to what extent variation in platelet function tests performed in isolation correlate with genuine effects on clotting tendency the current strategy of universally applied loading and maintenance doses of antiplatelet agents for all patients with CAD, including those undergoing PCI, is likely to be flawed. Some patients have a weak response and lack therapeutic protection, whereas others have an excessive response and are more susceptible to bleeding [62]. It remains to be established if identifying patients who appear to lack therapeutic protection and modifying their subsequent treatment would improve outcome.

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The addition of AA and ADP to the thrombin inhibited TEGÕ would provide measures of platelet inhibition by aspirin or clopidogrel or both as measured via these pathways. If detection of aspirin and clopidogrel resistance were possible via these methods, the values produced would be useful to tailor future antiplatelet therapy to the individual whether by increasing the dose of an existing agent or through the addition of an alternative antiplatelet agent. As a novel technique to detect aspirin and clopidogrel resistance it requires further validation, it does, however, have considerable potential particularly as it is a simple bedside test which could also be used on multiple occasions in the same patient to assess an individual’s response to different doses and combinations of antiplatelet agents.

Conclusions Modified thrombelastography is a rapid, simple, bedside test that provides an accurate, overall assessment of ex vivo blood clotting. Its use in liver transplant and cardiac surgery is established; by reducing transfusion requirements it has reduced morbidity in these groups of patients. The use of TEGÕ in identifying and monitoring coagulopathies and in directing treatment is also increasing in other areas such as obstetrics and in trauma. Modifications in TEGÕ facilitate greater clinical utility. In the field of cardiovascular medicine an easy and accurate test of platelet function would be of considerable clinical value. In patients with CAD antiplatelet therapy is the cornerstone of secondary prevention, modified TEGÕ could play an important role in optimizing antiplatelet treatment and reducing adverse events. Identification of patients who are resistant or non-compliant to antiplatelet agents such as aspirin or clopidogrel would enable additional treatments to be administered to reduce the risk of recurrent thrombotic events. Specifically, in the clinical setting of percutaneous intervention with stenting for coronary artery disease, the use of TEGÕ to target populations at risk of both thrombosis and of bleeding could reduce the most dreaded complication of stent thrombosis. The potential for clinical application of modified TEGÕ as a point of care test demands further investigation.

References 1. Kettner SC, Panzer OP, Kozek SA, Seibt FA, Stoiser B, Kofler J, Locker GJ, Zimpfer M. Use of abciximab-modified thrombelastography in patients undergoing cardiac surgery. Anesth Analg 1999;89:580–584. 2. Bowbrick VA, Mikhailidis DP, Stansby G. Value of thrombelastography in the assessment of platelet function. Clin Appl Thromb Hemost 2003;9:137–142.

3. Hartert H. Thrombelastography, a method for physical analysis of blood coagulation. Z Gesamte Exp Med 1951;117:189–203. 4. Mallett SV, Cox DJ. Thrombelastography. Br J Anaesth 1992;69:307–313. 5. Mousa SA, Khurana S, Forsythe MS. Comparative in vitro efficacy of different platelet glycoprotein IIb/IIIa antagonists on platelet-mediated clot strength induced by tissue factor with use of thrombelastography: Differentiation among glycoprotein IIb/IIIa antagonists. Arterioscler Thromb Vasc Biol 2000;20:1162–1167. 6. Waters JH, Anthony DG, Gottlieb A, Sprung JU. Bleeding in a patient receiving platelet aggregation inhibitors. Anesth Analg 2001;93:878–882. 7. Artang R, Jensen E, Pedersen F, Frandsen NJ. Thrombelastography in healthy volunteers, patients with stable angina and acute chest pain. Thromb Res 2000;97:499–503. 8. Samama CM. Thrombelastography: The next step. Anesth Analg 2001;92:563–564. 9. Shore-Lesserson L, Manspeizer HE, DePerio M, Francis S, Vela-Cantos F, Ergin MA. Thrombelastography-guided transfusion algorithm reduces transfusion complex cardiac surgery. Anesth Analg 1999;88:312–319. 10. Kaufmann CR, Dwyer KM, Crews JD, Dols SJ, Trask AL. Usefulness of thrombelastography in assessment of trauma patient coagulation. J Trauma 1997;42:716–722. 11. Spiess BD, Tuman KJ, McCarthy RJ, DeLaria GA, Schillo R, Ivankovich AD. Thrombelastography as an indicator of postcardiopulmonary bypass coagulopathies. J Clin Monit 1987;3:25–30. 12. Cammerer U, Dietrich W, Rampf T, Braun S, Richter J. The predictive vale of modified computerized thromboelastography and platelet function analysis for postoperative blood loss in routine cardiac surgery. Anesth Analg 2003;96:51–57. 13. Roysten D. Aprotinin prevents bleeding and has effects on platelets and Fibrinolysis. J Cardiothorac Vasc Anesth 1991;5:18–23. 14. Whitten CW, Greilich PE. Thrombelastography: Past, present, and future. Anesthesiology 2000;92:1223–1225. 15. Kang YG, Martin DJ, Marquez J, Lewis JH, Bontempo FA, Shaw BW, Starzl TE, Winter PM. Intraoperative changes in blood coagulation and thrombelastographic monitoring in liver transplantation. Anesth Analg 1985;64:888–896. 16. McCarthy RJ, Tuman KJ, Chen B, Ivankovich AD. Platelet integrin inhibition with c7E3 enhances the correlation between platelet aggregrometry and thrombelastographic (TEGÕ ) MA values. Anesth Analg 1998;86:S219. 17. Luddington RJ. Thrombelastography/thrombelastometry. Clin Lab Haem 2005;27:81–90. 18. Ewe K. Bleeding after liver biopsy does not correlate with indices of peripheral coagulation. Dig Dis Sci 1981;26:388–393. 19. Kelley DA, Tuddenham EG. Haemostatic problems in liver disease. Gut 1986;27:339–349. 20. Orlikowski CE, Payne AJ, Moodley J, Rocke DA. Thrombelastograph after aspirin ingestion in pregnant and non-pregnant subjects. Br J Anaesth 1992;69:159–161. 21. Dorman BH, Spinale FG, Bailey MK, Kratz JM, Roy RC. Identification of patients at risk of excessive blood loss during coronary artery bypass surgery: Thrombelastograph versus coagulation screen. Anesth Analg 1993;76:694–700. 22. Gelb AB, Roth RI, Levin J, London MJ. Changes in blood coagulation during and following cardiopulmonary bypass. Am J Clin Pathol 1996;106:87–99. 23. Kettner SC, Kozek SA, Groetzner JP, Gonano C, Schellongowski A, Kucera M, Zimpfer M. Effects of hypothermia on thrombelastography in patients undergoing cardiopulmonary bypass. Br J Anaesth 1998;80:313–317.

Thrombelastography 24. McGrath DJ, Ceboni E, Frumento RJ, Hirsh AL, Bennett GE. Thrombelastography maximum amplitude predicts postoperative thrombotic complications including myocardial infarction. Anesth Analg 2005;100:1576–1583. 25. Gurbel PA, Bliden KP, Gruger K, Cho PW, Zaman KA, Kreutz PR, Bassi AK, Tantry US. Platelet reactivity in patients and recurrent events post-stenting: Results of the Prepare Post-stenting Study. J Am Coll Cardiol 2005;46:1820–1826. 26. Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003;89:783–787. 27. Tuman KJ, McCarthy RJ, Patel RV, Ivankovich AD. Comparison of thrombelastography and platelet aggregometry. Anesthesiology 1991;75:A433. 28. Anderson K, Hurlen M, Arnesen H, Selejeflot I. Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease. Thromb Res 2003; 108:37–42. 29. Geiger J, Teichmann L, Grossmann R, Aktas B, Steigerwald U, Walter U, Schnizel R. Monitoring of clopidogrel action: Comparison of methods. Clin Chem 2005;51:957–965. 30. Gorog DA, Douglas H, Ahmed N, Lefroy DC, Davies GJ. Coronary angioplasty enhances platelet reactivity through von Willebrand factor release. Heart 2003;89:329–330. 31. Lev EI, Patel RT, Maresh KJ, Guthikonda S, Granada J, Delao T, Bray PF, Kleiman NS. Aspirin and clopidogrel drug response in patients undergoing percutaneous intervention: The role of dual drug resistance. J Am Coll Cardiol 2006;47:27–33. 32. Chen WH, Lee PY, Ng W, Tse HF, Lau CP. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous intervention despite clopidogrel pre-treatment. J Am Coll Cardiol 2004;43:1122–1126. 33. Bailey LA, Sistino JJ, Uber WE. Is platelet function as measured by Thrombelastography monitoring in whole blood affected by platelet inhibitors?. J Extra Corpor Technol 2005;37:43–47. 34. Tanaka KA, Sziam F, Kelly AB, Vega JD, Levy JH. Clopidogrel and cardiac surgical patients: Implications for platelet function monitoring and postoperative bleeding. Platelets 2004;15:325–332. 35. Swallow RA, Agarwala RA, Dawkins KD, Curzen NP. Thrombelastography: A novel bedside tool to assess the effects of antiplatelet therapy? Platelets 2006;17:385–92. 36. Craft RM, Chavez JJ, Bresee SJ, Wortham DC, Cohen E, Carroll RC. A novel modification of the thrombelastograph assay, isolating platelet function, correlates with optical aggregation. J Lab Clin Med 2004;143:301–309. 37. Mobley JE, Bresee SJ, Wortham DC, Craft RM, Snider CC, Carroll RC. Frequency of nonresponse antiplatelet activity of clopidogrel during pre-treatment for cardiac catheterisation. Am J Cardiol 2004;93:456–458. 38. Tantry US, Bliden KP, Gurbel PA. Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachadonic acid stimulation. J Am Coll Cardiol 2005;46:1705–1709. 39. Ault K, Cannon C, Mitchell J, McCahan J, Tracy RP, Novotny WF, Reimann JD, Braunwald E. Platelet activation in patients after an acute coronary syndrome: Results from the TIMI-12 trial. J Am Coll Cardiol 1999;33:634–639. 40. Mehta S, Yusuf S. Short- and long-term oral antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention. J Am Coll Cardiol 2003;41(4 Supp S):S9–S88.

517

41. Greilich PE, Alving BM, Longnecker D, et al. Near site monitoring of the antiplatelet drug abciximab using the Hemodyne Analyser and Modified Thromboelastograph. J Cardiothorac Vasc Anesth 1999;13:58–64. 42. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002;105:1650–1655. 43. Kubler W, Darius H. Primary prevention of coronary heart disease with aspirin. Z Kardiol 2005;94:66–73. 44. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287–1294. 45. Gum PA, Kottke-Marchant K, Poggio ED, Gurm H, Welsh PA, Brooks L, Sapp SK, Topol EJ. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001;88:230–235. 46. Christiaens L, Macchi L, Herpin D, Coisne D, Duplantier C, Allal J, Mauco G, Brizard A. Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease. Thromb Res 2002;108: 115–119. 47. Andersen K, Hurlen M, Arnesen H, Seljeflot I. Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease. Thromb Res 2003;108: 37–42. 48. Schwartz KA, Schwartz DE, Ghosheh K, Reeves MJ, Barber K, DeFranco A. Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction. Am J Card 2005;95:973–975. 49. Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. Am Coll Cardiol 2003;41:961–965. 50. Macchi L, Christiaens L, Brabant S, Sorel N, Allal J, Mauco G, Brizard A. Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. Thromb Res 2002;107:45–49. 51. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339. 52. CURE Steering Committee. Effects of clopidogrel in addition in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. 53. The CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706–17. 54. Jaremo P, Lindahl TL, Fransson SG, Richter A. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002;252: 233–238. 55. Colwell JA, Nair RM, Halushka PV, Rogers C, Whetsell A, Sagel J. Platelet adhesion and aggregation in diabetes mellitus. Metabolism 1979;28(4 Suppl 1):394–400. 56. Tamminen M, Lassila R, Westerbacka J, Vehkavaara S, Yki-Jarvinen H. Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects. Int J Obes Relat Metab Disord 2003;27:907–911. 57. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171–3175. 58. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, Investigators FT. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with

518

A. R. Hobson et al.

aspirin after coronary stenting: The clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000;102:624–629. 59. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic GA, Airoldi F, Chieffo A, Montorfano M, Carlino M, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126–2130. 60. Ong ATL, McFadden EP, Regar E, de Jaegere PPT, van Domburg RT, Serruys PW. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol 2005;45:2088–2092.

61. Wenaweser P, Dorffler MJ, Imboden K, Windecker S, Togni M, Meier B, Haeberli A, Hess OM. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol 2005;45:1748–1752. 62. Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ, Tantry US. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: Results of the CREST Study. J Am Coll Cardiol 2005;46:1827–1832. 63. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: Response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908–2913.

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