Semin Thromb Hemost 2017; 43(03): 311-319
DOI: 10.1055/s-0036-1597298
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Monitoring Antiplatelet Therapy

Rachel Orme
1   Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
,
Heather M. Judge
1   Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
,
Robert F. Storey
1   Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
06 March 2017 (online)

Abstract

The increasing use of antiplatelet therapy, particularly aspirin and oral P2Y12 inhibitors, in the prevention and management of arterial thrombosis, has stimulated extensive pharmacodynamic studies and research into tailored antiplatelet regimens. Many different methodologies have been studied for monitoring antiplatelet drugs and some are now well validated and used in clinical practice. However, clinical studies of tailored antiplatelet therapy have not convincingly demonstrated a benefit of this approach in patients treated with aspirin and clopidogrel, coupled with the fact that more potent antiplatelet therapies have more consistent effects compared with clopidogrel and so may reduce the rationale for monitoring. On the other hand, the optimum timing of urgent surgery after cession of oral antiplatelet therapy may be informed by platelet function testing. This review discusses the different methodologies that have been used to monitor the effects of antiplatelet therapy and highlights the current position of platelet function testing in clinical practice.

 
  • References

  • 1 Fintel DJ. Oral antiplatelet therapy for atherothrombotic disease: overview of current and emerging treatment options. Vasc Health Risk Manag 2012; 8: 77-89
  • 2 Reejhsinghani R, Lotfi AS. Prevention of stent thrombosis: challenges and solutions. Vasc Health Risk Manag 2015; 11: 93-106
  • 3 Hamm CW, Bassand JP, Agewall S , et al; European Society of Cardiology. [ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC)]. G Ital Cardiol (Rome) 2012; 13 (3) 171-228
  • 4 Abbate R, Cioni G, Ricci I, Miranda M, Gori AM. Thrombosis and acute coronary syndrome. Thromb Res 2012; 129 (3) 235-240
  • 5 Held C, Asenblad N, Bassand JP , et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol 2011; 57 (6) 672-684
  • 6 Sousa-Uva M, Storey R, Huber K , et al; ESC Working Group on Cardiovascular Surgery and ESC Working Group on Thrombosis. Expert position paper on the management of antiplatelet therapy in patients undergoing coronary artery bypass graft surgery. Eur Heart J 2014; 35 (23) 1510-1514
  • 7 Roffi M, Patrono C, Collet JP , et al; Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37 (3) 267-315
  • 8 Grove EL, Storey RF, Würtz M. Platelet function testing in atherothrombotic disease. Curr Pharm Des 2012; 18 (33) 5379-5391
  • 9 Aradi D, Storey RF, Komócsi A , et al; Working Group on Thrombosis of the European Society of Cardiology. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J 2014; 35 (4) 209-215
  • 10 Schultze M. Ein heizbarer Objecttisch und seine Verwendung bei Untersuchungen des Blutes. Arch Mikrosc Anat 1865; 1: 1-42
  • 11 Brewer DB. Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet. Br J Haematol 2006; 133 (3) 251-258
  • 12 Bizzozero J. Ueber einen neuen Formbestandtheil des Blutes und dessen Rolle bei der Thrombose und der Blutgerinnung. Arch Pathol Anat Physiol Klin Med 1882; 90: 261-332
  • 13 Lee RE, Young RH, Castleman B. James Homer Wright: a biography of the enigmatic creator of the Wright stain on the occasion of its centennial. Am J Surg Pathol 2002; 26 (1) 88-96
  • 14 Steg PG, Dorman SH, Amarenco P. Atherothrombosis and the role of antiplatelet therapy. J Thromb Haemost 2011; 9 (Suppl. 01) 325-332
  • 15 Mozaffarian D, Benjamin EJ, Go AS , et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation 2015; 131 (4) e29-e322
  • 16 Duke WW. The relation of blood platelets to hemorrhagic disease. Description of a method for determining the bleeding time and coagulation time and report of three cases of hemorrhagic disease relieved by blood transfusion. JAMA 1910; 55 (14) 1185-1192
  • 17 Storey RF, Heptinstall S. Laboratory investigation of platelet function. Clin Lab Haematol 1999; 21 (5) 317-329
  • 18 Collet JP, Montalescot G. Platelet function testing and implications for clinical practice. J Cardiovasc Pharmacol Ther 2009; 14 (3) 157-169
  • 19 Joshi RR, Hossain R, Morton AC , et al. Evolving pattern of platelet P2Y12 inhibition in patients with acute coronary syndromes. Platelets 2014; 25 (6) 416-422
  • 20 Kutcher ME, Redick BJ, McCreery RC , et al. Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg 2012; 73 (1) 13-19
  • 21 E Kehrel B, F Brodde M. State of the art in platelet function testing. Transfus Med Hemother 2013; 40 (2) 73-86
  • 22 Gurbel PA, Bliden KP, DiChiara J , et al. Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation 2007; 115 (25) 3156-3164
  • 23 Frelinger III 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 (25) 2586-2596
  • 24 Bonello L, Tantry US, Marcucci R , et al; Working Group on High On-Treatment Platelet Reactivity. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56 (12) 919-933
  • 25 Storey RF, Angiolillo DJ, Bonaca MP , et al. Platelet inhibition with Ticagrelor 60.  mg versus 90 mg twice daily in the PEGASUS-TIMI 54 trial. J Am Coll Cardiol 2016; 67 (10) 1145-1154
  • 26 Blann AD, Nadar SK, Lip GY. The adhesion molecule P-selectin and cardiovascular disease. Eur Heart J 2003; 24 (24) 2166-2179
  • 27 Minamino T, Kitakaze M, Sanada S , et al. Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide. Circulation 1998; 98 (17) 1721-1727
  • 28 Ikeda H, Takajo Y, Ichiki K , et al. Increased soluble form of P-selectin in patients with unstable angina. Circulation 1995; 92 (7) 1693-1696
  • 29 Furman MI, Benoit SE, Barnard MR , et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 1998; 31 (2) 352-358
  • 30 O'Connor CM, Gurbel PA, Serebruany VL. Usefulness of soluble and surface-bound P-selectin in detecting heightened platelet activity in patients with congestive heart failure. Am J Cardiol 1999; 83 (9) 1345-1349
  • 31 Chong BH, Murray B, Berndt MC, Dunlop LC, Brighton T, Chesterman CN. Plasma P-selectin is increased in thrombotic consumptive platelet disorders. Blood 1994; 83 (6) 1535-1541
  • 32 Briggs C, Kunka S, Hart D, Oguni S, Machin SJ. Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia. Br J Haematol 2004; 126 (1) 93-99
  • 33 Michelson AD, Barnard MR, Krueger LA, Valeri CR, Furman MI. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001; 104 (13) 1533-1537
  • 34 Furman MI, Barnard MR, Krueger LA , et al. Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. J Am Coll Cardiol 2001; 38 (4) 1002-1006
  • 35 Judge HM, Buckland RJ, Sugidachi A, Jakubowski JA, Storey RF. Relationship between degree of P2Y12 receptor blockade and inhibition of P2Y12-mediated platelet function. Thromb Haemost 2010; 103 (6) 1210-1217
  • 36 Dovlatova N, May JA, Fox SC. Remote platelet function testing--Significant progress towards widespread testing in clinical practice. Platelets 2015; 26 (5) 399-401
  • 37 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 (14) 1650-1655
  • 38 Storey RF. Biology and pharmacology of the platelet P2Y12 receptor. Curr Pharm Des 2006; 12 (10) 1255-1259
  • 39 Cattaneo M. Letter by Cattaneo regarding article, “incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk”. Circulation 2009; 119 (24) e594 , author reply e595–e596
  • 40 Grove EL, Hvas AM, Mortensen SB, Larsen SB, Kristensen SD. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost 2011; 9 (1) 185-191
  • 41 Thompson CB, Eaton KA, Princiotta SM, Rushin CA, Valeri CR. Size dependent platelet subpopulations: relationship of platelet volume to ultrastructure, enzymatic activity, and function. Br J Haematol 1982; 50 (3) 509-519
  • 42 Martin JF, Trowbridge EA, Salmon G, Plumb J. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb Res 1983; 32 (5) 443-460
  • 43 Brown AS, Martin JF. The megakaryocyte platelet system and vascular disease. Eur J Clin Invest 1994; 24 (Suppl. 01) 9-15
  • 44 Grove EL, Würtz M, Hvas AM, Kristensen SD. Increased platelet turnover in patients with previous definite stent thrombosis. J Thromb Haemost 2011; 9 (7) 1418-1419
  • 45 Lakkis N, Dokainish H, Abuzahra M , et al. Reticulated platelets in acute coronary syndrome: a marker of platelet activity. J Am Coll Cardiol 2004; 44 (10) 2091-2093
  • 46 Martin JF, Kristensen SD, Mathur A, Grove EL, Choudry FA. The causal role of megakaryocyte–platelet hyperactivity in acute coronary syndromes. Nat Rev Cardiol 2012; 9 (11) 658-670
  • 47 Grove EL, Hvas AM, Kristensen SD. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009; 101 (1) 151-156
  • 48 Rocca B, Secchiero P, Ciabattoni G , et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci U S A 2002; 99 (11) 7634-7639
  • 49 Born GV. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962; 194: 927-929
  • 50 O'Brien. Platelet aggregation: Part II Some results from a new method of study. J Clin Pathol 1962; 15 (5) 452-455
  • 51 Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995; 332 (23) 1553-1559
  • 52 Gachet C, Aleil B. Testing antiplatelet therapy. Eur Heart J 2008; 10 (Suppl A): A28-A234
  • 53 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. J Am Coll Cardiol 2003; 41 (6) 961-965
  • 54 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
  • 55 Gurbel PA, Bliden KP, Guyer K , et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005; 46 (10) 1820-1826
  • 56 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 (8) 754-762
  • 57 Accumetrics Inc. 2011. Interpreting VerifyNow Aspirin Test Results. . Available at: http://www.accriva.com/uploads/literature/mvn_0003_-_verifynow_interpretingresults-aspirin_1 . Accessed May 2016
  • 58 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 (8) 992-1000
  • 59 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: a 12-month follow-up. Circulation 2009; 119 (2) 237-242
  • 60 Patti G, Nusca A, Mangiacapra F, Gatto L, D'Ambrosio A, Di Sciascio G. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study. J Am Coll Cardiol 2008; 52 (14) 1128-1133
  • 61 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
  • 62 Valgimigli M, Campo G, de Cesare N , et al. Tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel (3T/2R). Rationale for the study and protocol design. Cardiovasc Drugs Ther 2008; 22 (4) 313-320
  • 63 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
  • 64 Cardinal DC, Flower RJ. The electronic aggregometer: a novel device for assessing platelet behavior in blood. J Pharmacol Methods 1980; 3 (2) 135-158
  • 65 Sibbing D, Braun S, Morath T , et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53 (10) 849-856
  • 66 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 (5) 891-898.e1
  • 67 Gianetti J, Parri MS, Sbrana S , et al. Platelet activation predicts recurrent ischemic events after percutaneous coronary angioplasty: a 6 months prospective study. Thromb Res 2006; 118 (4) 487-493
  • 68 Castaman G, Tosetto A, Goodeve A , et al. The impact of bleeding history, von Willebrand factor and PFA-100(®) on the diagnosis of type 1 von Willebrand disease: results from the European study MCMDM-1VWD. Br J Haematol 2010; 151 (3) 245-251
  • 69 Campbell J, Ridgway H, Carville D. Plateletworks: a novel point of care platelet function screen. Mol Diagn Ther 2008; 12 (4) 253-258
  • 70 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; 5 (8) 1630-1636
  • 71 Barragan P, Bouvier JL, Roquebert PO , et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003; 59 (3) 295-302
  • 72 Shenkman B, Matetzky S, Fefer P , et al. Variable responsiveness to clopidogrel and aspirin among patients with acute coronary syndrome as assessed by platelet function tests. Thromb Res 2008; 122 (3) 336-345
  • 73 Hartert H. Blutgerinnungsstudien mit der Thrombelastographie; einem neuen Untersuchungs verfahren. Klin Wochenschr 1948; 26 (37-38): 577-583
  • 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 (2) 261-269
  • 75 Weitzel NS, Weitzel LB, Epperson LE, Karimpour-Ford A, Tran ZV, Seres T. Platelet mapping as part of modified thromboelastography (TEG®) in patients undergoing cardiac surgery and cardiopulmonary bypass. Anaesthesia 2012; 67 (10) 1158-1165
  • 76 Blais N, Pharand C, Lordkipanidzé M, Sia YK, Merhi Y, Diodati JG. Response to aspirin in healthy individuals. Cross-comparison of light transmission aggregometry, VerifyNow system, platelet count drop, thromboelastography (TEG) and urinary 11-dehydrothromboxane B(2). Thromb Haemost 2009; 102 (2) 404-411
  • 77 Ramakers BP, Pickkers P, Deussen A , et al. Measurement of the endogenous adenosine concentration in humans in vivo: methodological considerations. Curr Drug Metab 2008; 9 (8) 679-685
  • 78 Bonello L, Laine M, Kipson N , et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014; 63 (9) 872-877
  • 79 Storey RF, Angiolillo DJ, Patil SB , et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol 2010; 56 (18) 1456-1462
  • 80 Aradi D, Kirtane A, Bonello L , et al. Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention. Eur Heart J 2015; 36 (27) 1762-1771
  • 81 Storey RF. More transparency for a therapeutic window in platelet P2Y12 inhibition?. Eur Heart J 2015; 36 (27) 1714-1717
  • 82 Kaudewitz D, Skroblin P, Bender LH , et al. Association of microRNAs and YRNAs with platelet function. Circ Res 2016; 118 (3) 420-432
  • 83 McManus DD, Freedman JE. MicroRNAs in platelet function and cardiovascular disease. Nat Rev Cardiol 2015; 12 (12) 711-717