Platelet function testing in clinical diagnostics

A. R. Rechner

doi:10.5482/ha-1133

Hämostaseologie, Table of Contents

Hamostaseologie 2011; 31(02): 79-87
DOI: 10.5482/ha-1133

Review

Schattauer GmbH

Platelet function testing in clinical diagnostics

Plättchenfunktionstests in der klinischen Routine

Authors

A. R. Rechner

¹Assay Development Hemostasis, Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany

Abstract

Summary

Although the utility of platelet function testing is still under debate, the necessity to inhibit platelets in patients suffering from cardiovascular and cerebrovascular disease is undoubted and well proven. The wide variety of available platelet function tests often using different methodologies, the apparent lack of standardization, and finally the emerging evidence on the clinical value of platelet function testing are resulting in a considerable uncertainty in the clinical practice, how to deal with the issue of platelet function testing. Platelet function testing might not only yield clinical benefits for the patients but also economical advantages by identifying the right drug at the right dose for the right patient.

This article intends to provide an overview of the current platelet function tests such as light transmittance aggregometry, whole blood impedance aggregometry, the PFA-100¹ system, the VerifyNow² system, flow cytometry, as well as other promising technologies like Plateletworks³, IMPACT-R⁴, PADA, thromboelastography, and the mean platelet component (MPC), briefly addressing strengths, weaknesses and clinical utility of these tests.

Zusammenfassung

Auch wenn die Nützlichkeit von Thrombozytenfunktionsuntersuchungen weiterhin debattiert wird, ist die Notwendigkeit der Thrombozyteninhibierung bei Patienten, die an kardio- und/ oder zerebrovaskulären Erkrankungen leiden, unzweifelhaft und eindeutig nachgewiesen. Die große Variabilität der erhältlichen Thrombozytenfunktionstests, die oft unterschiedliche Methodologien verwenden, das offensichtliche Fehlen von Standardisierung und letztlich der aufkommende Beweis für den klinischen Wert von Thrombozytenfunktionsuntersuchungen führen zu einer gewissen Unsicherheit in der klinischen Praxis, wie mit dem Thema Thrombozytenfunktionsuntersuchungen umgegangen werden soll. Durch die Identifikation des richtigen antithrombotischen Medikaments in der richtigen Dosis für den richtigen Patienten könnten Thrombozytenfunktionsuntersuchungen nicht nur einen klinischen, sondern auch ökonomischen Gewinn erbringen.

Dieser Artikel soll einen Überblick über Thrombozytenfunktionstests Lichttransmissionsaggregometrie, Vollblutimpedanzaggrego- metrie, PFA-100-System¹, VerifyNow-System², Durchflusszytometrie, aber auch andere vielsprechende Technologien wie Plateletworks³, IMPACT-R⁴, PADA, Thromboelasto- graphie und die Thrombozytendichte (MPC), bieten. Stärken, Schwächen und klinische Nützlichkeit der Tests werden kurz beschrieben.

Keywords

Platelet function testing - clinical application - anti-platelet drugs - bleeding risk assessment

Schlüsselwörter

Thrombozytenfunktion - klinische Anwendung - Antithrombotika - Blutungsrisiko

Full Text

References

References
1 Ahnadi CE, Boughrassa FF, Chapman-Montgomery ES. et al. Comparison of two methods to assess variability of platelet response to anti-platelet therapies in patients with acute coronary syndrome undergoing angioplasty. Thromb Haemost 2004; 92: 1207-1213.
2 Ahnadi CE, Sabrinah EChapman, Lépine M. et al. Assessment of platelet activation in several different anticoagulants by the Advia 120 Hematology System, fluorescence flow cytometry, and electron microscopy. Thromb Haemost 2003; 90: 940-948.
3 Aleil B, Ravanat C, Cazenave JP. et al. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost 2005; 03: 85-92.
4 Alström U, Granath F, Oldgren J. et al. Platelet inhibition assessed with VerifyNow, flow cytometry and platelet mapping in patients undergoing heart surgery. Thromb Res 2009; 124: 572-577.
5 Blindt R, Stellbrink K, de Taeye A. et al. The significance of vasodilator-stimulated phosphoprotein for risk stratification of stent thrombosis. Thromb Haemost 2007; 98: 1329-1334.
6 Bonello L, Camoin-Jau L, Arques S. et al. Adjusted clopidogrel loading doses according to vasodilatorstimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance. J Am Coll Cardiol 2008; 51: 1404-1411.
7 Bonello L, Paganelli F, Arpin-Bornet M. et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007; 05: 1630-1636.
8 Born GV. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962; 194: 927-929.
9 Breet NJ, van Werkum JW, Bouman HJ. et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010; 303: 754-762.
10 Buonamici P, Marcucci R, Migliorini A. et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49: 2312-2317.
11 Cannon CP, Harrington RA, James S. et al. PLATelet inhibition and patient Outcomes Investigators. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO). Lancet 2010; 375: 283-293.
12 Cattaneo M, Hayward CP, Moffat KA. et al. Results of a worldwide survey on the assessment of platelet function by light transmission aggregometry. J Thromb Haemost 2009; 07: 1029.
13 Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007; 05 (Suppl. 01) 230-237.
14 Chapman ES, Sorette M, Hetherington E. et al. A rapid, automated flow cytometric method to measure activated degranulated platelets by density determination. Thromb Haemost 2003; 89: 1004-1015.
15 Chen WH, Cheng X, Lee PY. et al. Aspirin resistance and adverse clinical events in patients with coronary artery disease. Am J Med 2007; 120: 631-635.
16 Christie DJ, Kottke-Marchant K, Gorman RT. Hypersensitivity of platelets to adenosine diphosphate in patients with stable cardiovascular disease predicts major adverse events despite antiplatelet therapy. Platelets 2008; 19: 104-110.
17 Collyer TC, Gray DJ, Sandhu R. et al. Assessment of platelet inhibition secondary to clopidogrel and as-pirin therapy in preoperative acute surgical patients measured by thrombelastography platelet mapping. Br J Anaesth 2009; 102: 492-498.
18 Cooke J, Murphy T, McFadden E. et al. Can mean platelet component be used as an index of platelet activity in stable coronary artery disease?. Hematology 2009; 14: 111-114.
19 Craft RM, Chavez JJ, Snider CC. et al. Comparison of modified thrombelastograph and Plateletworks whole blood assays to optical platelet aggregation for monitoring reversal of clopidogrel inhibition in elective surgery patients. J Lab Clin Med 2005; 145: 309-315.
20 Crescente M, Di Castelnuovo A, Iacoviello L. et al. PFA-100 closure time to predict cardiovascular events in aspirin-treated cardiovascular patients. Thromb Haemost 2008; 99: 1129-1131.
21 Crescente M, Di Castelnuovo A, Iacoviello L. et al. Response variability to aspirin as assessed by the platelet function analyzer (PFA)-100. Thromb Haemost 2008; 99: 14-26.
22 Elsenberg EH, van Werkum JW, van de Wal RM. et al. The influence of clinical characteristics, laboratory and inflammatory markers on ‘high on-treatment platelet reactivity’ as measured with different platelet function tests. Thromb Haemost 2009; 102: 719-727.
23 Eshtehardi P, Windecker S, Cook S. et al. Dual low response to acetylsalicylic acid and clopidogrel is associated with myonecrosis and stent thrombosis after coronary stent implantation. Am Heart J 2010; 159: 891-898.
24 Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008; 34: 709-733.
25 Frelinger 3^rd AL, Li Y, Linden MD. et al. Association of cyclooxygenase-1-dependent and -independent platelet function assays with adverse clinical outcomes in aspirin-treated patients presenting for cardiac catheterization. Circulation 2009; 120: 2586-2596.
26 Frelinger AL, Li Y, Linden MD. et al. Aspirin ‘resistance’: role of pre-existent platelet reactivity and correlation between tests. J Thromb Haemost 2008; 06: 2035-2044.
27 Frere C, Cuisset T, Quilici J. et al. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome. Thromb Haemost 2007; 98: 838-843.
28 Fressinaud E, Veyradier A, Sigaud M. et al. Therapeutic monitoring of von Willebrand disease. Brit J Haematol 1999; 106: 777-783.
29 Frossard M, Fuchs I, Leitner JM. et al. Platelet function predicts myocardial damage in patients with acute myocardial infarction. Circulation 2004; 110: 1392-1397.
30 Fuchs I, Frossard M, Spiel A. et al. Platelet function in patients with acute coronary syndrome (ACS) predicts recurrent ACS. J Thromb Haemost 2006; 04: 2547-2552.
31 Gadisseur A, Hermans C, Berneman Z. et al. Laboratory diagnosis and molecular classification of von Willebrand disease.Acta Haematol 2009; 121: 71-84.
32 Gasparyan AY, Watson T, Lip GY. The role of aspirin in cardiovascular prevention: implications of aspirin resistance. J Am Coll Cardiol 2008; 51: 1829-1843.
33 Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest 2005; 115: 3378-3384.
34 Gianetti J, Parri MS, Sbrana S. et al. Platelet activation predicts recurrent ischemic events after percutaneous coronary angioplasty. Thromb Res 2006; 118: 487-493.
35 Godeneche G, Sorel N, Ragot S. et al. Stroke and aspirin non-responder patients. Platelets 2009; 20: 471-477.
36 Grove EL, Hvas AM, Johnsen HL. et al. A comparison of platelet function tests and thromboxane metabolites to evaluate aspirin response in healthy individuals and patients with coronary artery disease. Thromb Haemost 2010; 103: 1245-1253.
37 Gum PA, Kottke-Marchant K, Welsh PA. et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003; 41: 961-965.
38 Gurbel PA, Bliden KP, Butler K. et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 2010; 121: 1188-1199.
39 Hankey GJ, Eikelboom JW. Antithrombotic drugs for patients with ischaemic stroke and transient ischaemic attack to prevent recurrent major vascular events. Lancet Neurol 2010; 09: 273-284.
40 Harrison P, Keeling D. Clinical tests of platelet function. In: Michelson AD. (ed). Platelets. Boston: Academic Press; 2007: 445-474.
41 Harrison P, Segal H, Silver L. et al. Lack of reproducibility of assessment of aspirin responsiveness by optical aggregometry and two platelet function tests. Platelets 2008; 19: 119-124.
42 Hayward CP, Moffat KA, Pai M. et al. An evaluation of methods for determining reference intervals for light transmission platelet aggregation tests on samples with normal or reduced platelet counts. Thromb Haemost 2008; 100: 134-145.
43 Ivandic BT, Sausemuth M, Ibrahim H. et al. Dual antiplatelet drug resistance is a risk factor for cardiovascular events after percutaneous coronary intervention. Clin Chem 2009; 55: 1171-1176.
44 Jámbor C, Weber CF, Gerhardt K. et al. Whole blood multiple electrode aggregometry is a reliable pointof-care test of aspirin-induced platelet dysfunction. Anesth Analg 2009; 109: 25-31.
45 Jennings LK, McCabe MWhite. Platelet aggregation. In: Michelson AD. (ed). Platelets. Boston: Academic Press; 2007: 495-507.
46 Koscielny J, von Tempelhoff GF, Ziemer S. et al. A practical concept for preoperative management of patients with impaired primary hemostasis. Clin Appl Thromb Hemost 2004; 10: 155-166.
47 Koscielny J, Ziemer S, Radtke H. et al. A practical concept for preoperative identification of patients with impaired primary hemostasis. Clin Appl Thromb Hemost 2004; 10: 195-204.
48 Kozek-Langenecker SA. Perioperative coagulation monitoring. Best Pract Res Clin Anaesthesiol 2010; 24: 27-40.
49 Kundu SK, Heilmann EJ, Sio R. et al. Characterization of an in vitro platelet function analyzer, PFA-100. Clin Appl Thromb Hemost 1996; 02: 241-249.
50 Kunicki TJ, Williams SA, Salomon DR. et al. Genetics of platelet reactivity in normal, healthy individuals. J Thromb Haemost 2009; 07: 2116-2122.
51 Linnemann B, Schwonberg J, Mani H. et al. Standardization of light transmittance aggregometry for monitoring antiplatelet therapy. J Thromb Haemost 2008; 06: 677-683.
52 Linnemann B, Schwonberg J, Rechner AR. et al. Assessment of clopidogrel non-response by the PFA-100 system using the new test cartridge INNOVANCE PFA P2Y. Ann Hematol 2010; 89: 597-605.
53 Malinin A, Pokov A, Spergling M. et al. Monitoring platelet inhibition after clopidogrel with the Verify Now-P2Y12(R) rapid analyzer. Thromb Res 2007; 119: 277-284.
54 Malinin AI, Atar D, Callahan KP. et al. Effect of a single dose aspirin on platelets in humans with multiple risk factors for coronary artery disease. Eur J Pharmacol 2003; 462: 139-143.
55 Marcucci R, Gori AM, Paniccia R. et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay. Circulation 2009; 119: 237-242.
56 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.
57 Matzdorff AC, Kühnel G, Kemkes-Matthes B, Voss R. Comparison of GP IIB/IIIA inhibitors and their activity as measured by aggregometry, flow cytometry, single platelet counting, and the rapid platelet function analyzer. J Thromb Thrombolysis 2001; 12: 129-139.
58 McGlasson DL, Fritsma GA. Comparison of four laboratory methods to assess aspirin sensitivity. Blood Coagul Fibrinolysis 2008; 19: 120-123.
59 McGlasson DL, Fritsma GA. Whole blood platelet aggregometry and platelet function testing. Semin Thromb Hemost 2009; 35: 168-180.
60 Michelson AD. (ed). Platelets. Boston: Academic Press; 2007
61 Michelson AD, Barnard MR, Krueger LA. et al. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin. Circulation 2001; 104: 1533-1537.
62 Michelson AD, Linden MD, Barnard MR. et al. Flow cytometry. In: Michelson AD. (ed.) Platelets. Boston: Academic Press; 2007: 545-563
63 Michelson AD. Flow cytometry: a clinical test of platelet function. Blood 1996; 87: 4925-4936.
64 Michelson AD. P2Y12 antagonism: promises and challenges. Arterioscler Thromb Vasc Biol 2008; 28: 33-38.
65 Michiels JJ, Gawaz M. Preface: platelets in inflammation and atherothrombosis. Semin Thromb Hemost 2007; 33: 119-122.
66 Moffat KA, Ledford-Kraemer MR, Nichols WL, Hayward CP. North American Specialized Coagulation Laboratory Association. Variability in clinical laboratory practice in testing for disorders of platelet function. Thromb Haemost 2005; 93: 549-553.
67 Mueller T, Dieplinger B, Poelz W, Haltmayer M. Utility of the PFA-100 instrument and the novel Multiplate analyzer for the assessment of aspirin and clopidogrel effects on platelet function in patients with cardiovascular disease. Clin Appl Thromb Hemost 2008; 15: 652-659.
68 Nielsen HL, Kristensen SD, Thygesen SS. et al. Aspirin response evaluated by the VerifyNow Aspirin System and light transmission aggregometry. Thromb Res 2008; 123: 267-273.
69 Nowak G, Wiesenburg A, Schumann A, Bucha E. Platelet adhesion assay--a new quantitative whole blood test to measure platelet function. Semin Thromb Hemost 2005; 31: 470-475.
70 Nowak G. From aspirin to aspirin resistance – History, biochemical background, diagnostics and clinical relevance. Transfus Med Hemother 2007; 34: 413-419.
71 Nowak G. Heparin-induced thrombocytopenia (HIT II) – a drug-associated autoimmune disease. Thromb Haemost 2009; 102: 887-891.
72 Paniccia R, Antonucci E, Gori AM. et al. Comparison of different methods to evaluate the effect of aspirin on platelet function in high-risk patients with ischemic heart disease receiving dual antiplatelet treatment. Am J Clin Pathol 2007; 128: 143-149.
73 Paniccia R, Antonucci E, Maggini N. et al. Comparison of methods for monitoring residual platelet reactivity after clopidogrel by point-of-care tests on whole blood in high-risk patients. Thromb Haemost 2010; 104: 287-292.
74 Paniccia R, Antonucci E, Maggini N. et al. Assessment of platelet function on whole blood by multiple electrode aggregometry in high-risk patients with coronary artery disease receiving antiplatelet therapy. Am J Clin Pathol 2009; 131: 834-842.
75 Pfanner G, Koscielny J, Pernerstorfer T. et al. Resuscitation and intensive care. Preoperative evaluation of the bleeding history. Recommendations of the working group on perioperative coagulation of the Austrian Society for Anaesthesia, Resuscitation and Intensive Care. Anaesthesist 2007; 56: 604-611.
76 Price MJ, Endemann S, Gollapudi RR. et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000.
77 Rahe-Meyer N, Winterhalter M, Boden A. et al. Platelet concentrates transfusion in cardiac surgery and platelet function assessment by multiple electrode aggregometry. Acta Anaesthesiol Scand 2009; 53: 168-175.
78 Ranucci M, Baryshnikova E, Soro G. et al. Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients receiving thienopyridines. Ann Thorac Surg 2011; 91: 123-129.
79 Reny JL, De Moerloose P, Dauzat M, Fontana P. Use of the PFA-100 closure time to predict cardiovascular events in aspirin-treated cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost 2008; 06: 444-450.
80 Scharbert G, Auer A, Kozek-Langenecker S. Evaluation of the platelet mapping assay on rotational thromboelastometry ROTEM. Platelets 2009; 20: 125-130.
81 Schwarz UR, Geiger J, Walter U, Eigenthaler M. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets. Thromb Haemost 1999; 82: 1145-1152.
82 Shenkman B, Einav Y, Salomon O. et al. Testing agonist-induced platelet aggregation by the Impact-R. Platelets 2008; 19: 440-446.
83 Sibbing D, Braun S, Morath T. et al. Platelet reactivity after clopidogrel treatment assessed with pointof-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.
84 Sibbing D, Morath T, Braun S. et al. Clopidogrel response status assessed with Multiplate point-ofcare analysis and the incidence and timing of stent thrombosis over six months following coronary stenting. Thromb Haemost 2010; 103: 151-159.
85 Siller-Matula JM, Christ G, Lang IM. et al. Multiple electrode aggregometry predicts stent thrombosis better than the vasodilator-stimulated phosphoprotein phosphorylation assay. J Thromb Haemost 2010; 08: 351-359.
86 Snoep JD, Hovens MM, Eikenboom 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 2007; 167: 1593-1599.
87 Sofi F, Marcucci R, Gori AM. et al. Clopidogrel nonresponsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost 2010; 103: 841-848.
88 Steinhubl SR, Talley JD, Braden GA. et al. Point-ofcare measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study. Circulation 2001; 103: 2572-2578.
89 Thielmann M, Bunschkowski M, Tossios P. et al. Perioperative thrombocytopenia in cardiac surgical patients – incidence of heparin-induced thrombocytopenia, morbidities and mortality. Eur J Cardiothorac Surg 2010; 37: 1391-1395.
90 Tóth O, Calatzis A, Penz S. et al. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006; 96: 781-788.
91 Van Werkum JW, Bouman HJ, Breet NJ. et al. The Cone-and-Plate(let) analyzer is not suitable to monitor clopidogrel therapy. Thromb Res 2010; 126: 44-49.
92 Van Werkum JW, Harmsze AM, Elsenberg EH. et al. The use of the VerifyNow system to monitor antiplatelet therapy. Platelets 2008; 19: 479-488.
93 Van Werkum JW, Kleibeuker M, Postma S. et al. A comparison between the Plateletworks-assay and light transmittance aggregometry for monitoring the inhibitory effects of clopidogrel. Int J Cardiol 2010; 140: 123-126.
94 Von Beckerath N, Sibbing D, Jawansky S. et al. Assessment of platelet response to clopidogrel with multiple electrode aggregometry, the VerifyNow P2Y12 analyzer and platelet Vasodilator-Stimulated Phosphoprotein flow cytometry. Blood Coagul Fibrinolysis 2010; 21: 46-52.
95 Wiviott SD, Braunwald E, McCabe CH. et al. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
96 Yee DL, Bergeron AL, Sun CW. et al. Platelet hyperreactivity generalizes to multiple forms of stimulation. J Thromb Haemost 2006; 04: 2043-2050.