- Email: [email protected]
Evaluation of the Platelet Function Analyzer (PFA-100®) vs. the Thromboelastogram (TEG®) in the Clinical Setting
Acta Anaesthesiol Taiwan 2009;47(3):107−109
EDITO R IAL VIEW
Evaluation of the Platelet Function Analyzer (PFA-100®) vs. the Thromboelastogram (TEG®) in the Clinical Setting Although major surgeries such as liver transplantation now use less blood than previously, more could be done to conserve blood products. There are risks and benefits associated with the transfusion of blood products. Overall, transfusion safety has improved dramatically over the past 20 years, but there is evidence to suggest that transfusion to various subgroups of surgical patients, including liver transplantation recipients, is associated with decreased survival and increased number of perioperative complications. Thus, it is important to minimize the exposure of patients to transfused blood products. The marked variability in blood use can partly be explained by differences in the characteristics of patient populations or differences in perioperative blood loss. The discrepancy in the amount of blood transfusion between similar procedures also points to a lack of objective standards that direct the use of blood transfusion. Not only is this a risk to the patient, but the unnecessary use of blood components increases health care costs and contributes to blood shortages. The consequences of unnecessary blood transfusion make it important to question the rationale for giving some blood components and to refine the methods by which we determine if a transfusion is actually necessary. Optimal intraoperative coagulation management is probably one of the greatest challenges in this field.1 Blood coagulation monitoring offers the best objective evidence to guide hemostatic therapies, predict the risk of bleeding, reduce health care costs, and improve transfusion safety and patient outcome in liver transplantation and other surgical procedures.2 Recent published data have compared the use of two popular coagulation monitors: the Platelet Function Analyzer (PFA-100®) and the Thromboelastogram (TEG®) or modified TEG® (mTEG® or PlateletMappingTM).3−7 Nevertheless, controversies still exist with regard to using different reagents in the clinical setting. ©2009 Taiwan Society of Anesthesiologists
The PFA-100® measures the time taken for a platelet plug to occlude an aperture in a membrane that is impregnated with collagen and epinephrine or adenosine diphosphate (ADP). The time to occlude the aperture is called the closure time. Aspirin has been shown to increase the epinephrine closure time (C-EPI CT),8 while in some studies, clopidogrel has been shown to increase the ADP closure time (C-ADP CT).9−13 A recent review of the PFA-l00® concluded that it “provides a rapid, simple and reliable measure of platelet function”.14 The TEG® is a point-of-care coagulation monitor that measures some platelet aggregation defects including post-cardiopulmonary bypass-induced platelet dysfunction related to glycoprotein IIb/IIIa receptors.15 However, conventional TEG®, because of the overwhelming presence of thrombin generation, cannot often capture the platelet adhesion defects that occur with aspirin16−18 or demonstrate ADP receptor blockade with clopidogrel. Patients using clopidogrel who have definitive platelet inhibition as measured by aggregometry (and an 80% increase in the need for platelet transfusion after cardiac surgery) have been shown to have a normal maximum amplitude on conventional TEG®.18 However, a recent modification of the TEG® (mTEG®) assay19 generates clot without thrombin generation using reptilase and factor XIIIa. The new TEG® assay overcomes this limitation. The addition of platelet agonists such as arachidonic acid or ADP facilitates measurement of platelet inhibition resulting from aspirin or clopidogrel, respectively. These new assays show that mTEG® has good agreement with aggregometry.19 In 2006, Agarwal et al4 reconfirmed that there was good agreement between the results of aggregometry and mTEG® in patients taking clopidogrel. In this issue of Acta Anaesthesiologica Taiwanica, Chang et al compare the sensitivity and specificity of the PFA-100® and TEG®.3 They use two agents
108 (levobupivacaine and CGS21680) to induce platelet dysfunction as detection target in an ex vivo experimental model. The starting platelet counts, platelet aggregation, closure time of PFA-100®, and the parameters of TEG® were examined. Their results showed that platelet aggregation was suppressed by levobupivacaine (10 μg/mL, 50 μg/mL, 200 μg/mL) and CGS21680 (100 nM, 500 nM, 1 μM) in a dose-dependent manner. Using the same doses, levobupivacaine and CGS21680 at the maximal dose of testing had no significant effect on each parameter in the TEG® assay, but both levobupivacaine and CGS21680 showed significantly prolonged closure time in the PFA-100® assay. The authors concluded that PFA-100® has higher sensitivity and specificity than TEG® for the detection of platelet dysfunction.3 However, a direct comparison of these tests is not simple. This is because the design principles, the reagents used, the testing profiles/functions, the scope of clinical application and data display of PFA-100® and TEG® are significantly different. Thus, it is difficult to do a one-sided comparison. The current clinical literature suggests that when using the PFA-100® analyzer to measure aspirinmediated platelet inhibition, there are increased event rates in patients with a profile of aspirin resistance.6 This method has several limitations, however, including a poor correlation with other measures of platelet performance. In addition, this method relies on the von Willebrand factor level and its activity, and platelet count. The PFA-100® method also uses collagen and epinephrine as agonists, neither of which is specific for cyclooxygenase-1 activity, the target of aspirin. A major limitation of all the published studies of aspirin resistance is a lack of serial platelet function measurements, because the degree of aspirin resistance can fluctuate over time and can be affected by aspirin dose.6 The main issue of controversy raised from previous studies was that TEG® could use five different reagents for detection: TEG-Kaolin, TEG-Heparinase, PlateletMapping™ (mTEG®), Rapid TEG® and functional fibrinogen test. After 2004, the mTEG® assay has been used to measure platelet function.4,6,20−23 In the mTEG® technique, the contribution of arachidonic acid-induced platelet aggregation and ADPinduced aggregation to the overall tensile strength of a platelet-fibrin clot can be quantified and correlated with turbidimetric aggregometry.24 The mTEG® assay can measure the contribution of ADP and TXA2 receptors to clot formation by adding the appropriate agonists.5,20,23 Because Chang et al3 only used the TEG-Kaolin assay, just as some other researchers did, they might not be able to determine significant changes in platelet dysfunction.
M.Y. Tsou In conclusion, different study designs and TEG® reagents may result in different findings during PFA-100® and TEG® studies. In clinical anesthesia practice, coagulation monitoring is very important in certain types of surgery. The PFA-100® can offer good information about platelet function. But TEG® with appropriate reagents may produce more information about platelet function, coagulation factors, fibrin and fibrinolysis, which are vital in clinical blood transfusion therapy. Mei-Yung Tsou, MD, PhD Associate Editor, Acta Anaesthesiologica Taiwanica Division Chief of Neuroanesthesia, Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine
References 1.
Ozier Y, Tsou MY. Changing trends in transfusion practice in liver transplantation. Curr Opin Org Transpl 2008;13:304−9. 2. Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 2008;106:1366−75. 3. Chang YW, Liao CH, Day YJ. Platelet Function Analyzer (PFA-100®) offers higher sensitivity and specificity than Thromboelastography (TEG®) in detection of platelet dysfunction. Acta Anaesthesiol Taiwan 2009;47:110−7. 4. Agarwal S, Coakely M, Reddy K, Riddell A, Mallett S. Quantifying the effect of antiplatelet therapy. Anesthesiology 2006;105:676−83. 5. Alström U, Tydén H, Oldgren J, Siegbahn A, Ståhle E. The platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment. Thromb Res 2007;120:353−9. 6. Gurbel PA, Becker RC, Mann KG, Steinhubl SR, Michelson AD. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007;50:1822−34. 7. Davies JR, Fernando R, Hallworth SP. Hemostatic function in healthy pregnant and preeclamptic women: an assessment using the Platelet Function Analyzer (PFA-100®) and Thromboelastograph®. Anesth Analg 2007;104:416−20. 8. Homoncik M, Jilma B, Hergovich N, Stohlawetz P, Panzer S, Speiser W. Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyser PFA-100®. Thromb Haemost 2000;83:316−21. 9. Kretschmer V, Middelbeck T, Sohngen D. In vitro bleeding test: a simple method for the detection of aspirin effects on platelet function. Thromb Res 1989;56:593−602. 10. Fischetti D, Sciahbasi A, Leone AM, Niccoli G, Schiavoni G, Trani C, Mazzari MA, et al. Ticlopidine and aspirin fail to suppress the increased platelet aggregability that follows percutaneous coronary interventions. J Thromb Thrombolysis 2000;10:265−9. 11. Kottke-Marchant K, Powers JB, Brooks L, Kundu S, Christie DJ. The effect of anti-platelet drugs, heparin, and preanalytical variables on platelet function detected by the platelet function analyzer (PFA-100®). Clin Appl Thromb Hemost 1999;5:122−30. 12. Hezard N, Metz D, Nazeyrollas P, Droulle C, Elaerts J, Potron G, Nguyen P. Use of the PFA-100® apparatus to assess platelet function in patients undergoing PTCA during and after infusion of c7E3 Fab in the presence of other antiplatelet agents. Thromb Haemost 2000;83:540−4.
Evaluation of the PFA-100® vs. TEG® in the clinical setting 13. Hezard N, Metz D, Nazeyrollas P, Droulle C, Potron G, Nguyen P. PFA-100® and flow cytometry: can they challenge aggregometry to assess antiplatelet agents, other than GPIIbIIIa blockers, in coronary angioplasty? Thromb Res 2003;108:43−7. 14. Harrison P. The role of PEA-100® testing in the investigation and management of haemostatic defects in children and adults. Br J Haematol 2005;130:3−10. 15. Katori N, Szlam F, Levy J, Tanaka K. A novel method to assess platelet inhibition by eptifibatide with TEG®. Anesth Analg 2004;6:1784−9. 16. Trentalange MJ, Walts LFA. Comparison of thromboelastogram and template bleeding time for the evaluation of platelet function after ingestion. J Clin Anaesth 1991;3:377−81. 17. Orlikowski CE, Payne AJ, Moodley J, Rocke DA. Thromboelastography after aspirin ingestion in pregnant and non pregnant subjects. Br J Anaesth 1992;69:159−61. 18. Tanaka KA, Szlam F, Kelly AB, Vega JD, Levy JH. Clopidogrel (Plavix) and cardiac surgical patients: implications for platelet function monitoring and postoperative bleeding. Platelets 2004;15:325−32. 19. Craft RM, Chavez JJ, Snider CC, Muenchen RA, Carroll RC. Comparison of Thrombelastograph and Plateletworks whole blood assays to optical platelet aggregation for monitoring
20.
21.
22.
23.
24.
109 reversal of clopidogrel inhibition in elective surgery patients. J Lab Clin Med 2005;145:309−15. Bochsen L, Wiinberg B, Kjelgaard-Hansen M, Steinbrüchel DA, Johansson PI. Evaluation of the TEG® platelet mapping™ assay in blood donors. Thromb J 2007;5:3. Gurbel PA, Bliden KP, Guyer K, Aggarwal N, Tantry US. Delayed thrombin-induced platelet-fibrin clot generation by clopidogrel: a new dose-related effect demonstrated by thrombelastography in patients undergoing coronary artery stenting. Thromb Res 2007;119:563−70. 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 platelet aggregation. J Lab Clin Med 2004;143:301−9. Gwozdziewicz M, Němec P, Zezula R, Novotny J. Platelet mapping in postoperative management of acute aortocoronary bypass thrombosis. Kardiochlurgiai Torakochirurgia Polska 2006;3:214−6. Tantry US, Bliden KP, Gurbel PA. Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol 2005; 46:1705−9.
EDITO R IAL VIEW
Evaluation of the Platelet Function Analyzer (PFA-100®) vs. the Thromboelastogram (TEG®) in the Clinical Setting Although major surgeries such as liver transplantation now use less blood than previously, more could be done to conserve blood products. There are risks and benefits associated with the transfusion of blood products. Overall, transfusion safety has improved dramatically over the past 20 years, but there is evidence to suggest that transfusion to various subgroups of surgical patients, including liver transplantation recipients, is associated with decreased survival and increased number of perioperative complications. Thus, it is important to minimize the exposure of patients to transfused blood products. The marked variability in blood use can partly be explained by differences in the characteristics of patient populations or differences in perioperative blood loss. The discrepancy in the amount of blood transfusion between similar procedures also points to a lack of objective standards that direct the use of blood transfusion. Not only is this a risk to the patient, but the unnecessary use of blood components increases health care costs and contributes to blood shortages. The consequences of unnecessary blood transfusion make it important to question the rationale for giving some blood components and to refine the methods by which we determine if a transfusion is actually necessary. Optimal intraoperative coagulation management is probably one of the greatest challenges in this field.1 Blood coagulation monitoring offers the best objective evidence to guide hemostatic therapies, predict the risk of bleeding, reduce health care costs, and improve transfusion safety and patient outcome in liver transplantation and other surgical procedures.2 Recent published data have compared the use of two popular coagulation monitors: the Platelet Function Analyzer (PFA-100®) and the Thromboelastogram (TEG®) or modified TEG® (mTEG® or PlateletMappingTM).3−7 Nevertheless, controversies still exist with regard to using different reagents in the clinical setting. ©2009 Taiwan Society of Anesthesiologists
The PFA-100® measures the time taken for a platelet plug to occlude an aperture in a membrane that is impregnated with collagen and epinephrine or adenosine diphosphate (ADP). The time to occlude the aperture is called the closure time. Aspirin has been shown to increase the epinephrine closure time (C-EPI CT),8 while in some studies, clopidogrel has been shown to increase the ADP closure time (C-ADP CT).9−13 A recent review of the PFA-l00® concluded that it “provides a rapid, simple and reliable measure of platelet function”.14 The TEG® is a point-of-care coagulation monitor that measures some platelet aggregation defects including post-cardiopulmonary bypass-induced platelet dysfunction related to glycoprotein IIb/IIIa receptors.15 However, conventional TEG®, because of the overwhelming presence of thrombin generation, cannot often capture the platelet adhesion defects that occur with aspirin16−18 or demonstrate ADP receptor blockade with clopidogrel. Patients using clopidogrel who have definitive platelet inhibition as measured by aggregometry (and an 80% increase in the need for platelet transfusion after cardiac surgery) have been shown to have a normal maximum amplitude on conventional TEG®.18 However, a recent modification of the TEG® (mTEG®) assay19 generates clot without thrombin generation using reptilase and factor XIIIa. The new TEG® assay overcomes this limitation. The addition of platelet agonists such as arachidonic acid or ADP facilitates measurement of platelet inhibition resulting from aspirin or clopidogrel, respectively. These new assays show that mTEG® has good agreement with aggregometry.19 In 2006, Agarwal et al4 reconfirmed that there was good agreement between the results of aggregometry and mTEG® in patients taking clopidogrel. In this issue of Acta Anaesthesiologica Taiwanica, Chang et al compare the sensitivity and specificity of the PFA-100® and TEG®.3 They use two agents
108 (levobupivacaine and CGS21680) to induce platelet dysfunction as detection target in an ex vivo experimental model. The starting platelet counts, platelet aggregation, closure time of PFA-100®, and the parameters of TEG® were examined. Their results showed that platelet aggregation was suppressed by levobupivacaine (10 μg/mL, 50 μg/mL, 200 μg/mL) and CGS21680 (100 nM, 500 nM, 1 μM) in a dose-dependent manner. Using the same doses, levobupivacaine and CGS21680 at the maximal dose of testing had no significant effect on each parameter in the TEG® assay, but both levobupivacaine and CGS21680 showed significantly prolonged closure time in the PFA-100® assay. The authors concluded that PFA-100® has higher sensitivity and specificity than TEG® for the detection of platelet dysfunction.3 However, a direct comparison of these tests is not simple. This is because the design principles, the reagents used, the testing profiles/functions, the scope of clinical application and data display of PFA-100® and TEG® are significantly different. Thus, it is difficult to do a one-sided comparison. The current clinical literature suggests that when using the PFA-100® analyzer to measure aspirinmediated platelet inhibition, there are increased event rates in patients with a profile of aspirin resistance.6 This method has several limitations, however, including a poor correlation with other measures of platelet performance. In addition, this method relies on the von Willebrand factor level and its activity, and platelet count. The PFA-100® method also uses collagen and epinephrine as agonists, neither of which is specific for cyclooxygenase-1 activity, the target of aspirin. A major limitation of all the published studies of aspirin resistance is a lack of serial platelet function measurements, because the degree of aspirin resistance can fluctuate over time and can be affected by aspirin dose.6 The main issue of controversy raised from previous studies was that TEG® could use five different reagents for detection: TEG-Kaolin, TEG-Heparinase, PlateletMapping™ (mTEG®), Rapid TEG® and functional fibrinogen test. After 2004, the mTEG® assay has been used to measure platelet function.4,6,20−23 In the mTEG® technique, the contribution of arachidonic acid-induced platelet aggregation and ADPinduced aggregation to the overall tensile strength of a platelet-fibrin clot can be quantified and correlated with turbidimetric aggregometry.24 The mTEG® assay can measure the contribution of ADP and TXA2 receptors to clot formation by adding the appropriate agonists.5,20,23 Because Chang et al3 only used the TEG-Kaolin assay, just as some other researchers did, they might not be able to determine significant changes in platelet dysfunction.
M.Y. Tsou In conclusion, different study designs and TEG® reagents may result in different findings during PFA-100® and TEG® studies. In clinical anesthesia practice, coagulation monitoring is very important in certain types of surgery. The PFA-100® can offer good information about platelet function. But TEG® with appropriate reagents may produce more information about platelet function, coagulation factors, fibrin and fibrinolysis, which are vital in clinical blood transfusion therapy. Mei-Yung Tsou, MD, PhD Associate Editor, Acta Anaesthesiologica Taiwanica Division Chief of Neuroanesthesia, Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine
References 1.
Ozier Y, Tsou MY. Changing trends in transfusion practice in liver transplantation. Curr Opin Org Transpl 2008;13:304−9. 2. Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 2008;106:1366−75. 3. Chang YW, Liao CH, Day YJ. Platelet Function Analyzer (PFA-100®) offers higher sensitivity and specificity than Thromboelastography (TEG®) in detection of platelet dysfunction. Acta Anaesthesiol Taiwan 2009;47:110−7. 4. Agarwal S, Coakely M, Reddy K, Riddell A, Mallett S. Quantifying the effect of antiplatelet therapy. Anesthesiology 2006;105:676−83. 5. Alström U, Tydén H, Oldgren J, Siegbahn A, Ståhle E. The platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment. Thromb Res 2007;120:353−9. 6. Gurbel PA, Becker RC, Mann KG, Steinhubl SR, Michelson AD. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007;50:1822−34. 7. Davies JR, Fernando R, Hallworth SP. Hemostatic function in healthy pregnant and preeclamptic women: an assessment using the Platelet Function Analyzer (PFA-100®) and Thromboelastograph®. Anesth Analg 2007;104:416−20. 8. Homoncik M, Jilma B, Hergovich N, Stohlawetz P, Panzer S, Speiser W. Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyser PFA-100®. Thromb Haemost 2000;83:316−21. 9. Kretschmer V, Middelbeck T, Sohngen D. In vitro bleeding test: a simple method for the detection of aspirin effects on platelet function. Thromb Res 1989;56:593−602. 10. Fischetti D, Sciahbasi A, Leone AM, Niccoli G, Schiavoni G, Trani C, Mazzari MA, et al. Ticlopidine and aspirin fail to suppress the increased platelet aggregability that follows percutaneous coronary interventions. J Thromb Thrombolysis 2000;10:265−9. 11. Kottke-Marchant K, Powers JB, Brooks L, Kundu S, Christie DJ. The effect of anti-platelet drugs, heparin, and preanalytical variables on platelet function detected by the platelet function analyzer (PFA-100®). Clin Appl Thromb Hemost 1999;5:122−30. 12. Hezard N, Metz D, Nazeyrollas P, Droulle C, Elaerts J, Potron G, Nguyen P. Use of the PFA-100® apparatus to assess platelet function in patients undergoing PTCA during and after infusion of c7E3 Fab in the presence of other antiplatelet agents. Thromb Haemost 2000;83:540−4.
Evaluation of the PFA-100® vs. TEG® in the clinical setting 13. Hezard N, Metz D, Nazeyrollas P, Droulle C, Potron G, Nguyen P. PFA-100® and flow cytometry: can they challenge aggregometry to assess antiplatelet agents, other than GPIIbIIIa blockers, in coronary angioplasty? Thromb Res 2003;108:43−7. 14. Harrison P. The role of PEA-100® testing in the investigation and management of haemostatic defects in children and adults. Br J Haematol 2005;130:3−10. 15. Katori N, Szlam F, Levy J, Tanaka K. A novel method to assess platelet inhibition by eptifibatide with TEG®. Anesth Analg 2004;6:1784−9. 16. Trentalange MJ, Walts LFA. Comparison of thromboelastogram and template bleeding time for the evaluation of platelet function after ingestion. J Clin Anaesth 1991;3:377−81. 17. Orlikowski CE, Payne AJ, Moodley J, Rocke DA. Thromboelastography after aspirin ingestion in pregnant and non pregnant subjects. Br J Anaesth 1992;69:159−61. 18. Tanaka KA, Szlam F, Kelly AB, Vega JD, Levy JH. Clopidogrel (Plavix) and cardiac surgical patients: implications for platelet function monitoring and postoperative bleeding. Platelets 2004;15:325−32. 19. Craft RM, Chavez JJ, Snider CC, Muenchen RA, Carroll RC. Comparison of Thrombelastograph and Plateletworks whole blood assays to optical platelet aggregation for monitoring
20.
21.
22.
23.
24.
109 reversal of clopidogrel inhibition in elective surgery patients. J Lab Clin Med 2005;145:309−15. Bochsen L, Wiinberg B, Kjelgaard-Hansen M, Steinbrüchel DA, Johansson PI. Evaluation of the TEG® platelet mapping™ assay in blood donors. Thromb J 2007;5:3. Gurbel PA, Bliden KP, Guyer K, Aggarwal N, Tantry US. Delayed thrombin-induced platelet-fibrin clot generation by clopidogrel: a new dose-related effect demonstrated by thrombelastography in patients undergoing coronary artery stenting. Thromb Res 2007;119:563−70. 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 platelet aggregation. J Lab Clin Med 2004;143:301−9. Gwozdziewicz M, Němec P, Zezula R, Novotny J. Platelet mapping in postoperative management of acute aortocoronary bypass thrombosis. Kardiochlurgiai Torakochirurgia Polska 2006;3:214−6. Tantry US, Bliden KP, Gurbel PA. Overestimation of platelet aspirin resistance detection by thrombelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol 2005; 46:1705−9.