Semin Thromb Hemost 2021; 47(07): 843-854
DOI: 10.1055/s-0041-1728786
Review Article

The Current Role of Platelet Function Testing in Clinical Practice

George A. Mason
1   Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia
,
David J. Rabbolini
2   Lismore Cancer and Haematology Unit, Lismore Base Hospital, Lismore, New South Wales, Australia
3   The University of Sydney Northern Clinical School and the Rural Clinical School, Sydney, Australia
› Author Affiliations

Abstract

Platelet dysfunction, whether hereditary or acquired, may increase an individual's risk of spontaneous, posttraumatic, or postoperative bleeding. Conversely, increased platelet reactivity on antiplatelet agents following vascular (in particular, coronary vascular) intervention may increase the risk of thrombosis and adverse vascular events. The aim of platelet function testing is to identify and characterize platelet dysfunction in these settings to inform bleeding/ thrombosis risk and guide perioperative prophylactic management strategies. A vast array of screening and diagnostic tests is available for this purpose. The successful clinical application of platelet function tests depends on the knowledge of their analytical strengths and limitations and the correct extrapolation of derived results to a particular clinical scenario. This review critically appraises traditional and contemporary platelet function testing focusing on their role in clinical practice.



Publication History

Article published online:
15 June 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Nurden AT. The biology of the platelet with special reference to inflammation, wound healing and immunity. Front Biosci 2018; 23: 726-751
  • 2 Steinhubl SR. Historical observations on the discovery of platelets, platelet function testing and the first antiplatelet agent. Curr Drug Targets 2011; 12 (12) 1792-1804
  • 3 Dovlatova N. Current status and future prospects for platelet function testing in the diagnosis of inherited bleeding disorders. Br J Haematol 2015; 170 (02) 150-161
  • 4 Born GV, Cross MJ. The aggregation of blood platelets. J Physiol 1963; 168: 178-195
  • 5 Hechler B, Dupuis A, Mangin PH, Gachet C. Platelet preparation for function testing in the laboratory and clinic: historical and practical aspects. Res Pract Thromb Haemost 2019; 3 (04) 615-625
  • 6 Gresele P, Harrison P, Bury L. et al. Diagnosis of suspected inherited platelet function disorders: results of a worldwide survey. J Thromb Haemost 2014; 12 (09) 1562-1569
  • 7 Hayward CP, Pai M, Liu Y. et al. Diagnostic utility of light transmission platelet aggregometry: results from a prospective study of individuals referred for bleeding disorder assessments. J Thromb Haemost 2009; 7 (04) 676-684
  • 8 Mumford AD. How useful is light transmission platelet aggregometry for the diagnosis of bleeding disorders?. J Thromb Haemost 2009; 7 (04) 673-675
  • 9 Gresele P. Subcommittee on Platelet Physiology of the International Society on Thrombosis and Hemostasis. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost 2015; 13 (02) 314-322
  • 10 Lawrie AS, Kobayashi K, Lane PJ, Mackie IJ, Machin SJ. The automation of routine light transmission platelet aggregation. Int J Lab Hematol 2014; 36 (04) 431-438
  • 11 Bret VE, Pougault B, Guy A. et al. Assessment of light transmission aggregometry on the routine coagulation analyzer Sysmex CS-2500 using CE-marked agonists from Hyphen Biomed. Platelets 2019; 30 (04) 540-542
  • 12 Stratmann J, Karmal L, Zwinge B, Miesbach W. Platelet aggregation testing on a routine coagulation analyzer: a method comparison study. Clin Appl Thromb Hemost 2019; 25: 1076029619885184
  • 13 Sun P, McMillan-Ward E, Mian R, Israels SJ. Comparison of light transmission aggregometry and multiple electrode aggregometry for the evaluation of patients with mucocutaneous bleeding. Int J Lab Hematol 2019; 41 (01) 133-140
  • 14 Chan MV, Armstrong PC, Papalia F, Kirkby NS, Warner TD. Optical multichannel (optimul) platelet aggregometry in 96-well plates as an additional method of platelet reactivity testing. Platelets 2011; 22 (07) 485-494
  • 15 Ge S, Woo E, White JG, Haynes CL. Electrochemical measurement of endogenous serotonin release from human blood platelets. Anal Chem 2011; 83 (07) 2598-2604
  • 16 Feinman RD, Lubowsky J, Charo I, Zabinski MP. The lumi-aggregometer: a new instrument for simultaneous measurement of secretion and aggregation by platelets. J Lab Clin Med 1977; 90 (01) 125-129
  • 17 Brunet JG, Iyer JK, Badin MS. et al. Electron microscopy examination of platelet whole mount preparations to quantitate platelet dense granule numbers: Implications for diagnosing suspected platelet function disorders due to dense granule deficiency. Int J Lab Hematol 2018; 40 (04) 400-407
  • 18 Rabbolini D, Connor D, Morel-Kopp M-C. et al; Sydney Platelet Group. An integrated approach to inherited platelet disorders: results from a research collaborative, the Sydney Platelet Group. Pathology 2020; 52 (02) 243-255
  • 19 Mumford AD, Frelinger III AL, Gachet C. et al. A review of platelet secretion assays for the diagnosis of inherited platelet secretion disorders. Thromb Haemost 2015; 114 (01) 14-25
  • 20 Fox SC, Sasae R, Janson S, May JA, Heptinstall S. Quantitation of platelet aggregation and microaggregate formation in whole blood by flow cytometry. Platelets 2004; 15 (02) 85-93
  • 21 Pasalic L, Pennings GJ, Connor D, Campbell H, Kritharides L, Chen VM. Flow cytometry protocols for assessment of platelet function in whole blood. Methods Mol Biol 2017; 1646: 369-389
  • 22 Pasalic L. Assessment of platelet function in whole blood by flow cytometry. Methods Mol Biol 2017; 1646: 349-367
  • 23 Fritsma GA, McGlasson DL. Whole blood platelet aggregometry. Methods Mol Biol 2017; 1646: 333-347
  • 24 Hvas AM, Favaloro EJ. Platelet function analyzed by light transmission aggregometry. Methods Mol Biol 2017; 1646: 321-331
  • 25 Hvas AM, Grove EL. Platelet function tests: preanalytical variables, clinical utility, advantages, and disadvantages. Methods Mol Biol 2017; 1646: 305-320
  • 26 Sibbing D, Aradi D, Alexopoulos D. et al. Updated Expert Consensus Statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv 2019; 12 (16) 1521-1537
  • 27 Shen YM, Frenkel EP. Acquired platelet dysfunction. Hematol Oncol Clin North Am 2007; 21 (04) 647-661 , vi
  • 28 Zhang S, Zhou X, Liu S. et al. MYH9-related disease: description of a large Chinese pedigree and a survey of reported mutations. Acta Haematol 2014; 132 (02) 193-198
  • 29 Orsini S, Noris P, Bury L. et al; European Hematology Association - Scientific Working Group (EHA-SWG) on Thrombocytopenias and Platelet Function Disorders. Bleeding risk of surgery and its prevention in patients with inherited platelet disorders. Haematologica 2017; 102 (07) 1192-1203
  • 30 Kundu SK, Heilmann EJ, Sio R, Garcia C, Davidson RM, Ostgaard RA. Description of an in vitro platelet function analyzer--PFA-100. Semin Thromb Hemost 1995; 21 (Suppl. 02) 106-112
  • 31 Podda GM, Bucciarelli P, Lussana F, Lecchi A, Cattaneo M. Usefulness of PFA-100 testing in the diagnostic screening of patients with suspected abnormalities of hemostasis: comparison with the bleeding time. J Thromb Haemost 2007; 5 (12) 2393-2398
  • 32 Favaloro EJ. Clinical utility of closure times using the platelet function analyzer-100/200. Am J Hematol 2017; 92 (04) 398-404
  • 33 Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008; 34 (08) 709-733
  • 34 Dovlatova N, Lordkipanidzé M, Lowe GC. et al; UK GAPP Study Group. Evaluation of a whole blood remote platelet function test for the diagnosis of mild bleeding disorders. J Thromb Haemost 2014; 12 (05) 660-665
  • 35 Tóth O, Calatzis A, Penz S, Losonczy H, Siess W. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006; 96 (06) 781-788
  • 36 Calatzis A, Rahe-Meyer N, Theisen F, Spannagl M. Detection of aspirin and clopidogrel using multiple electrode aggregometry: 6AP1–10. Eur J Anaesth. 2007; 24: 67
  • 37 Awidi A, Maqablah A, Dweik M, Bsoul N, Abu-Khader A. Comparison of platelet aggregation using light transmission and multiple electrode aggregometry in Glanzmann thrombasthenia. Platelets 2009; 20 (05) 297-301
  • 38 Albanyan A, Al-Musa A, AlNounou R. et al. Diagnosis of Glanzmann thrombasthenia by whole blood impedance analyzer (MEA) vs. light transmission aggregometry. Int J Lab Hematol 2015; 37 (04) 503-508
  • 39 Al Ghaithi R, Drake S, Watson SP, Morgan NV, Harrison P. Comparison of multiple electrode aggregometry with lumi-aggregometry for the diagnosis of patients with mild bleeding disorders. J Thromb Haemost 2017; 15 (10) 2045-2052
  • 40 Dawood BB, Lowe GC, Lordkipanidzé M. et al. Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel. Blood 2012; 120 (25) 5041-5049
  • 41 Quiroga T, Goycoolea M, Panes O. et al. High prevalence of bleeders of unknown cause among patients with inherited mucocutaneous bleeding. A prospective study of 280 patients and 299 controls. Haematologica 2007; 92 (03) 357-365
  • 42 Quiroga T, Goycoolea M, Matus V. et al. Diagnosis of mild platelet function disorders. Reliability and usefulness of light transmission platelet aggregation and serotonin secretion assays. Br J Haematol 2009; 147 (05) 729-736
  • 43 Nieuwenhuis HK, Akkerman JW, Sixma JJ. Patients with a prolonged bleeding time and normal aggregation tests may have storage pool deficiency: studies on one hundred six patients. Blood 1987; 70 (03) 620-623
  • 44 Israels SJ, McNicol A, Robertson C, Gerrard JM. Platelet storage pool deficiency: diagnosis in patients with prolonged bleeding times and normal platelet aggregation. Br J Haematol 1990; 75 (01) 118-121
  • 45 van Asten I, Blaauwgeers M, Granneman L. et al. Flow cytometric mepacrine fluorescence can be used for the exclusion of platelet dense granule deficiency. J Thromb Haemost 2020; 18 (03) 706-713
  • 46 Chan MV, Warner TD. Standardised optical multichannel (optimul) platelet aggregometry using high-speed shaking and fixed time point readings. Platelets 2012; 23 (05) 404-408
  • 47 Chan MV, Leadbeater PD, Watson SP, Warner TD. Not all light transmission aggregation assays are created equal: qualitative differences between light transmission and 96-well plate aggregometry. Platelets 2018; 29 (07) 686-689
  • 48 Chan MV, Armstrong PC, Warner TD. 96-well plate-based aggregometry. Platelets 2018; 29 (07) 650-655
  • 49 Lordkipanidzé M, Lowe GC, Kirkby NS. et al; UK Genotyping and Phenotyping of Platelets Study Group. Characterization of multiple platelet activation pathways in patients with bleeding as a high-throughput screening option: use of 96-well Optimul assay. Blood 2014; 123 (08) e11-e22
  • 50 de Witt SM, Swieringa F, Cavill R. et al. Identification of platelet function defects by multi-parameter assessment of thrombus formation. Nat Commun 2014; 5: 4257
  • 51 Nagy M, Heemskerk JWM, Swieringa F. Use of microfluidics to assess the platelet-based control of coagulation. Platelets 2017; 28 (05) 441-448
  • 52 Michelson AD, Bhatt DL. How I use laboratory monitoring of antiplatelet therapy. Blood 2017; 130 (06) 713-721
  • 53 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 (23) 2908-2913
  • 54 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48 (09) 1742-1750
  • 55 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 (25) 3171-3175
  • 56 Sibbing D, Steinhubl SR, Schulz S, Schömig A, Kastrati A. Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window. J Am Coll Cardiol 2010; 56 (04) 317-318
  • 57 Racine-Brzostek SE, Asmis LM. Assessment of platelet function utilizing viscoelastic testing. Transfusion 2020; 60 (Suppl. 06) S10-S20
  • 58 Gurbel PA, Bliden KP, Navickas IA. et al. Adenosine diphosphate-induced platelet-fibrin clot strength: a new thrombelastographic indicator of long-term poststenting ischemic events. Am Heart J 2010; 160 (02) 346-354
  • 59 Mangiacapra F, Patti G, Barbato E. et al. A therapeutic window for platelet reactivity for patients undergoing elective percutaneous coronary intervention: results of the ARMYDA-PROVE (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity for Outcome Validation Effort) study. JACC Cardiovasc Interv 2012; 5 (03) 281-289
  • 60 Price MJ, Angiolillo DJ, Teirstein PS. et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation 2011; 124 (10) 1132-1137
  • 61 Stone GW, Witzenbichler B, Weisz G. et al; ADAPT-DES Investigators. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013; 382 (9892): 614-623
  • 62 Price MJ, Berger PB, Teirstein PS. et al; GRAVITAS Investigators. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011; 305 (11) 1097-1105
  • 63 Trenk D, Stone GW, Gawaz M. et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012; 59 (24) 2159-2164
  • 64 Collet JP, Cuisset T, Rangé G. et al; ARCTIC Investigators. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012; 367 (22) 2100-2109
  • 65 Cayla G, Cuisset T, Silvain J. et al; ANTARCTIC Investigators. Platelet function monitoring in elderly patients on prasugrel after stenting for an acute coronary syndrome: design of the randomized Antarctic study. Am Heart J 2014; 168 (05) 674-681
  • 66 Aradi D, Gross L, Trenk D. et al. Platelet reactivity and clinical outcomes in acute coronary syndrome patients treated with prasugrel and clopidogrel: a pre-specified exploratory analysis from the TROPICAL-ACS trial. Eur Heart J 2019; 40 (24) 1942-1951
  • 67 Spahn DR, Bouillon B, Cerny V. et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care 2019; 23 (01) 98
  • 68 Gonzalez E, Moore EE, Moore HB. et al. Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays. Ann Surg 2016; 263 (06) 1051-1059
  • 69 Connelly CR, Yonge JD, McCully SP. et al. Assessment of three point-of-care platelet function assays in adult trauma patients. J Surg Res 2017; 212: 260-269
  • 70 Moore HB, Moore EE, Chin TL. et al. Activated clotting time of thrombelastography (T-ACT) predicts early postinjury blood component transfusion beyond plasma. Surgery 2014; 156 (03) 564-569
  • 71 George MJ, Burchfield J, MacFarlane B. et al. Multiplate and TEG platelet mapping in a population of severely injured trauma patients. Transfus Med 2018; 28 (03) 224-230
  • 72 Lindblad C, Thelin EP, Nekludov M. et al. Assessment of platelet function in traumatic brain injury-a retrospective observational study in the neuro-critical care setting. Front Neurol 2018; 9: 15
  • 73 Godier A, Garrigue D, Lasne D. et al. Management of antiplatelet therapy for non elective invasive procedures of bleeding complications: proposals from the French working group on perioperative haemostasis (GIHP), in collaboration with the French Society of Anaesthesia and Intensive Care Medicine (SFAR). Anaesth Crit Care Pain Med 2019; 38 (03) 289-302
  • 74 Mahla E, Suarez TA, Bliden KP. et al. Platelet function measurement-based strategy to reduce bleeding and waiting time in clopidogrel-treated patients undergoing coronary artery bypass graft surgery: the timing based on platelet function strategy to reduce clopidogrel-associated bleeding related to CABG (TARGET-CABG) study. Circ Cardiovasc Interv 2012; 5 (02) 261-269
  • 75 Agarwal S, Johnson RI, Shaw M. Preoperative point-of-care platelet function testing in cardiac surgery. J Cardiothorac Vasc Anesth 2015; 29 (02) 333-341
  • 76 Vlot EA, Willemsen LM, Van Dongen EPA. et al. Perioperative point of care platelet function testing and postoperative blood loss in high-risk cardiac surgery patients. Platelets 2019; 30 (08) 982-988
  • 77 Mahla E, Metzler H, Bornemann-Cimenti H. et al. Platelet inhibition and bleeding in patients undergoing non-cardiac surgery—the BIANCA observational study. Thromb Haemost 2018; 118 (05) 864-872
  • 78 Cattaneo M, Cerletti C, Harrison P. et al. Recommendations for the standardization of light transmission aggregometry: a consensus of the working party from the platelet physiology subcommittee of SSC/ISTH. J Thromb Haemost 2013; 11: 1183-1189
  • 79 Tantry US, Bonello L, Aradi D. et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013; 62 (24) 2261-2273