Measures of Platelet Activation and Aggregation

  • Jean-Philippe Collet
  • Gilles Montalescot
Part of the Contemporary Cardiology book series (CONCARD)


Platelets play a key role in the pathophysiology of cardiovascular disease. Disrupting platelet activation and aggregation with antiplatelet agents is effective both for primary and secondary prevention of atherothrombotic events, and has become a cornerstone of cardiovascular disease management nowadays. Identifying hyperactive platelets as predictors of a thrombotic tendency and monitoring the response to antiplatelet agents have become the key objectives of platelet function monitoring. We have learned more about the variable response to antiplatelet drugs as more accurate and reliable platelet function assays have been developed. However, there are currently no data establishing a cause-and-effect relationship or allowing for the establishment of an algorithm for treatment in response to measured platelet function inhibition.

Key Words

Platelet thrombus aggregation atherothrombosis antiplatelet agents 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Braunwald E, Antman EM, Califf RM, et al. ACC/AHA Guideline Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction—2002: Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Circulation 2002;106:1893–1900.CrossRefPubMedGoogle Scholar
  2. 2.
    Michelson AD. How platelets work: platelet function and dysfunction. J Thromb Thrombolysis 2004;16: 7–12.CrossRefGoogle Scholar
  3. 3.
    Woulfe D, Yang J, Prevost N, O’Brien PJ, Brass LF. Signal transduction during the initiation, extension, and perpetuation of platelet plug formation. In: Michelson AD, ed. Platelets. Academic/Elsevier Science, New York, 2002, pp.197–213.Google Scholar
  4. 4.
    Packham MA, Rand ML, Kinlough-Rathbone RL. Aggregation. In: Gresele P, Page CP, Fuster V, Vermylen J, eds. Platelets in Thrombotic and Non-Thrombotic Disorders. Cambridge University Press; Cambridge, UK, 2002, pp. 338–356.Google Scholar
  5. 5.
    Tsuji S, Sugimoto M, Miyata S, et al. Real-time analysis of mural thrombus formation in various platelet aggregation disorders: distinct shear-dependent roles of platelet receptors and adhesive proteins under flow. Blood 1999;94:968–975.PubMedGoogle Scholar
  6. 6.
    Nieuwland R, Sturk A. Platelet-derived microparticles. In: Michelson AD, ed. Platelets. Academic/Elsevier Science, New York, 2002, pp. 255–265.Google Scholar
  7. 7.
    Bouchard BA, Butenas S, Mann KG, Tracy PB. Interactions between platelets and the coagulation system. In: Michelson AD, ed. Platelets. Academic/Elsevier Science New York, 2002, pp. 229–253.Google Scholar
  8. 8.
    Du X, Ginsberg MH. Integrin aIIbb3 and platelet function. Thromb Haemost 1997;78:96–100.PubMedGoogle Scholar
  9. 9.
    Zwaal RFA, Comfurius P, Bevers EM. Lipid-protein interactions in blood coagulation. Biochim Biophys Acta 1998;1376:433–453.PubMedGoogle Scholar
  10. 10.
    Coughlin SR. Protease activated receptors and platelet function. Thromb Haemost 1999;82:353–356.PubMedGoogle Scholar
  11. 11.
    Patrignani P, Sciulli G. Amplification loops: thromboxane generation. In: Gresele P, Page CP, Fuster V, Vermylen J, eds. Platelets in Thrombotic and Non-Thrombotic Disorders. Cambridge University Press, Cambridge, UK, 2002, pp. 369–380.Google Scholar
  12. 12.
    Thiagarajan P, Wu KK. In vitro assays for evaluating platelet function. In: Gresele P, Page CP, Fuster V, Vermylen J, eds. Platelets in Thrombotic and Non-Thrombotic Disorders. Cambridge University Press, Cambridge, UK, 2002, pp. 459–470.Google Scholar
  13. 13.
    Rodgers RP, Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemost 1990;16:1–20.CrossRefPubMedGoogle Scholar
  14. 14.
    Kundu SK, Heilmann EJ, Sio R, et al. Description of an in vitro platelet function analyzer PFA-100TM. Semin Thromb Hemost 1995;21(Suppl 2):106–112.PubMedGoogle Scholar
  15. 15.
    Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction. J Lab Clin Med 2001;138:152–163.CrossRefPubMedGoogle Scholar
  16. 16.
    Fressinaud E, Veyradier A, Truchaud F, et al. Screening for von Willebrand disease with a new analyzer using high shear stress: a study of 60 cases. Blood 1998;91:1325–1331.PubMedGoogle Scholar
  17. 17.
    Hezard N, Metz D, Nazeyrollas P, et al. Use of the PFA-100TM apparatus to assess platelet function in patients undergoing PTCA during and after infusion of cE3 Fab in the presence of other antiplatelet agents. Thromb Haemost 2000;83:540–544.PubMedGoogle Scholar
  18. 18.
    Gum PA, Kottke-Marchant K, Poggio ED, et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001;88:230–235.CrossRefPubMedGoogle Scholar
  19. 19.
    Jarvis GE. Platelet aggregation: turbidimetric measurements. Methods Mol Biol 2004;272:65–76.PubMedGoogle Scholar
  20. 20.
    White MM, Jennings LK. Platelet Protocols: Research and Clinical Laboratory Procedures. Academic, San Diego, 1999.Google Scholar
  21. 21.
    Coller BS. Monitoring of platelet GP IIb/IIIa antagonist therapy. Circulation 1997;96:3828–3832.PubMedGoogle Scholar
  22. 22.
    Ingerman-Wojenski C, Smith JB, Silver MJ. Evaluation of electrical aggregometry: comparison with optical aggregometry, secretion of ATP, and accumulation of radiolabeled platelets. J Lab Clin Med 1983; 101:44–52.PubMedGoogle Scholar
  23. 23.
    Steinhubl SR, Kereiakes DJ. Ultegra rapid platelet function analyzer. In: Michelson A, ed. Platelets. Academic, San Diego, 2002, pp. 317–323.Google Scholar
  24. 24.
    Smith JW, Steinhubl SR, Lincoff AM, et al. The rapid platelet function assay: an automated and quantitative cartridge-based method. Circulation 1999;99:620–625.PubMedGoogle Scholar
  25. 25.
    Kereiakes DJ, Mueller M, Howard W, et al. Efficacy of abciximab induced platelet blockade using a rapid point of care assay. J Thromb Thrombolysis 1999;7:265–275.CrossRefPubMedGoogle Scholar
  26. 26.
    Steinbhubl SR, Talley JB, Braden GA, et al. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-assessing Ultegra) multi-center study. Circulation 2001;103:2572–2578.Google Scholar
  27. 27.
    Kulkarni S, Nesbitt WS, Dopheide SM, et al. Techniques to examine platelet adhesive interactions under flow. Methods Mol Biol 2004;272:165–186.PubMedGoogle Scholar
  28. 28.
    Varon D, Savion N. Cone and plate(let) analyzer. In: Michelson A, ed. Platelets. Academic, San Diego, 2002, pp. 337–345.Google Scholar
  29. 29.
    Goodall AH, Appleby J. Flow-cytometric analysis of platelet-membrane glycoprotein expression and platelet activation. Methods Mol Biol 2004;272:225–254.PubMedGoogle Scholar
  30. 30.
    Michelson AD, Barnard MR, Krueger LA, Frelinger III AL, Furman MI. Flow cytometry. In: Michelson AD, ed. Platelets. Academic, San Diego, 2002, pp. 297–315.Google Scholar
  31. 31.
    Dachary-Prigent J, Freyssinet J-M, Pasquet J-M, Carron JC, Nurden AT. Annexin V as a probe of aminophospholipid exposure and platelet membrane vesiculation: a flow cytometry study showing a role for free sulfhydryl groups. Blood 1993;81:2554–2565.PubMedGoogle Scholar
  32. 32.
    Schultheiss HP, Tschoepe D, Esser J, et al. Large platelets continue to circulate in an activated state after myocardial infarction. Eur J Clin Invest 1994;24:243–247.CrossRefPubMedGoogle Scholar
  33. 33.
    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;31:325–328.CrossRefGoogle Scholar
  34. 34.
    Scharf RE, Tomer A, Marzec UM, et al. Activation of platelets in blood perfusing angioplasty-damaged coronary arteries: flow cytometric detection. Arterioscl Thromb 1992;12:475–487.Google Scholar
  35. 35.
    Montalescot G, Bal-dit-Solier C, Chibedit D, et al. Comparison of effects on markers of blood cell activation of enoxaparin, dalteparin, and unfractionated heparin in patients with unstable angina pectoris or non-ST-segment elevation acute myocardial infarction (the ARMADA study). Am J Cardiol 2003;91: 925–930.CrossRefPubMedGoogle Scholar
  36. 36.
    Carr ME. Development of platelet contractile force as a research and clinical measure of platelet function. Cell Biochem Biophys 2003;38:55–78.CrossRefPubMedGoogle Scholar
  37. 37.
    Collet JP, Montalescot G, Lesty C, et al. Disaggregation of in vitro pre-formed platelet-rich clots by abciximab increases fibrin exposure and promotes fibrinolysis. Arterioscl Thromb Vasc Biol 2001;21: 142–148.PubMedGoogle Scholar
  38. 38.
    Collet JPH, Montalescot G, Lesty C, Weisel JW. A structural and dynamic investigation of the facilitating effect of glycoprotein IIb/IIIa inhibitors in dissolving platelet-rich clots. Circ Res 2002;90:428–434.CrossRefPubMedGoogle Scholar
  39. 39.
    Collet JPH, Montalescot G, Lesty Cl, et al. Effects of abciximab on the architecture of platelet-rich clot in patients with acute myocardial infarction undergoing primary coronary intervention. Circulation 2001; 103:2328–2331.PubMedGoogle Scholar
  40. 40.
    Bevers EM, Comfurius P, Reutelingsperger CPM, Zwaal RFA. Platelet procoagulant activity and its measurement. In: Watson SP, Authi KS, eds. Platelets: A Practical Approach. Oxford University Press, New York, 1996, pp. 319–340.Google Scholar
  41. 41.
    Wagner CL, Mascelli MA, Neblock DS, et al. Analysis of GPIIb/IIIa receptor number by quantification of 7E3 binding to human platelets. Blood 1996;88:907–914.PubMedGoogle Scholar
  42. 42.
    Phillips DR, Teng W, Arfsten A, et al. Effect of Ca2+ on GP IIb/IIIa interactions with integrilin: enhanced GP IIb/IIIa binding and inhibition of platelet aggregation by reduction in the concentration of ionized calcium in plasma anticoagulated with citrate. Circulation 1997;96:1488–1494.PubMedGoogle Scholar
  43. 43.
    The IMPACT-II investigators. Randomized placebo controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet 1997;349:1422–1428.CrossRefGoogle Scholar
  44. 44.
    The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998;339:436–443.CrossRefGoogle Scholar
  45. 45.
    Tcheng JE, Ellis SG, George BS, et al. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 1994;90:1757–1764.PubMedGoogle Scholar
  46. 46.
    Steinhubl SR, Talley J, Braden G, et al. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event following percutaneous coronary intervention: results of the GOLD (AU-assessing Ultegra) multicenter study. Circulation 2001;103:2572–2578.PubMedGoogle Scholar
  47. 47.
    Kini AS, Richard M, Suleman J, et al. Effectiveness of tirofiban, eptifibatide, and abciximab in minimizing myocardial necrosis during percutaneous coronary intervention (TEAM pilot study). Am J Cardiol 2002;90:999–1002.CrossRefGoogle Scholar
  48. 48.
    Dalby M, Montalescot G, Bal dit Sollier C, et al. Eptifibatide provides additional platelet inhibition in non-ST-elevation myocardial infarction patients already treated with aspirin and clopidogrel: results of the platelet activity extinction in non-Q-wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE study). J Am Coll Cardiol 2004;43:162–168.CrossRefPubMedGoogle Scholar
  49. 49.
    Antiplatelet trialists’ collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324: 71–86.CrossRefGoogle Scholar
  50. 50.
    McKee SA, Sane DC, Deliargyris EN. Aspirin resistance in cardiovascular disease: a review of prevalence, mechanisms, and clinical significance. Thromb Haemost 2002;88:711–715.PubMedGoogle Scholar
  51. 51.
    Grotemeyer KH, Scharafinski HW, Hussted JW. Two-year follow-up of aspirin responder and aspirin non responder: a pilot study including 180 post-stroke patients. Thromb Res 1993;71:397–403.CrossRefPubMedGoogle Scholar
  52. 52.
    Mueller MR, Salat A, Stangl P, et al. Variable platelet response to low-dose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost 1997;78:1003–1007.PubMedGoogle Scholar
  53. 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;41:961–965.CrossRefPubMedGoogle Scholar
  54. 54.
    Eikelboom JW, Hirsh J, Weitz JI, et al. 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.CrossRefPubMedGoogle Scholar
  55. 55.
    Chen WH, Lee PY, Ng W, Tse HF, Lau CP. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol 2004;43:1122–1126.CrossRefPubMedGoogle Scholar
  56. 56.
    Steinhubl SR, Varinasi JS, Goldberg L. Determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2004;42:1336–1337.CrossRefGoogle Scholar
  57. 57.
    Feuring M, Haseroth K, Janson CP, et al. Inhibition of platelet aggregation after intake of acetylsalicylic acid detected by a platelet function analyzer (PFA-100). Int J Clin Pharmacol Ther 1999;37:584–588.PubMedGoogle Scholar
  58. 58.
    Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908–2913.CrossRefPubMedGoogle Scholar
  59. 59.
    Muller I, Besta F, Schulz C, et al. Prevalence of clopidogrel nonresponders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003;89:783–787.PubMedGoogle Scholar
  60. 60.
    Jaremo P, Lindahl TL, Fransson SG, et al. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002;252:233–238.CrossRefPubMedGoogle Scholar
  61. 61.
    Gurbel PA, Bliden KP. Durability of platelet inhibition by clopidogrel. Am J Cardiol 2003;91:1123–1125.CrossRefPubMedGoogle Scholar
  62. 62.
    Soffer D, Moussa I, Harjai KJ, et al. Impact of angina class on inhibition of platelet aggregation following clopidogrel loading in patients undergoing coronary intervention: do we need more aggressive dosing regimens in unstable angina? Catheter Cardiovasc Intervent 2003;59:21–25.CrossRefGoogle Scholar
  63. 63.
    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.CrossRefPubMedGoogle Scholar
  64. 64.
    Heeschen C, Dimmeler S, Hamm CW, et al. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003;348:1104–1111.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Jean-Philippe Collet
    • 1
  • Gilles Montalescot
    • 1
  1. 1.Institut de CardiologieHôpital Pitié-SalpêtriéreParisFrance

Personalised recommendations