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Hamostaseologie 2011; 31(01): 41-51
DOI: 10.5482/ha-1146
Review
Schattauer GmbH

Monitoring of antiplatelet therapy

Current limitations, challenges, and perspectivesPlättchenfunktionstestung unter antithrombozytärer TherapieDerzeitige Grenzen, Heraus-forderungen und Perspektiven
H. Seidel
1   Department of Experimental and Clinical Haemostasis, Haemotherapy and Transfusion Medicine, and Haemophilia Comprehensive Care Center, Heinrich Heine University Medical Center, Düsseldorf, Germany
,
M. M. Rahman
1   Department of Experimental and Clinical Haemostasis, Haemotherapy and Transfusion Medicine, and Haemophilia Comprehensive Care Center, Heinrich Heine University Medical Center, Düsseldorf, Germany
2   Division of Haematology, Dhaka Medical College Hospital, Dhaka, Bangladesh
,
R. E. Scharf
1   Department of Experimental and Clinical Haemostasis, Haemotherapy and Transfusion Medicine, and Haemophilia Comprehensive Care Center, Heinrich Heine University Medical Center, Düsseldorf, Germany
› Author AffiliationsThis work was supported in part by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 612 „Molecular analysis of cardiovascular functions and dysfunctions”, TPB2 „Modulation of platelet thrombogenicity through genetically determined variants of platelet integrins”). Additional support was provided by the Biological Medical Research Center, Heinrich Heine University, Düsseldorf. We also express our gratitude to Dr. Till Hoffmann, Dr. Houssain Makhloufi and other staff members for their work in the haemostasis lab. The technical assistance of Elisabeth Kirchhoff, Beate Maruhn-Debwoski, Uta Vandercappelle, Bianca Weingart, and Ursula Morgenrot is also acknowledged. Dr. M. Mizanur Rahman is recipient of a fellowship (“Reach the World Education Program”) from the International Society on Thrombosis and Haemostasis.
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Publication History

Publication Date:
27 December 2017 (online)

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Summary

Screening of platelet function can be performed by point-of-care testing followed by platelet aggregometry in response to agonists such as collagen, adenosine diphosphate, epinephrine, and arachidonic acid. Despite in use for decades, this technique is not well standardized. Monitoring of antiplatelet therapy is increasingly applied in patients at high risk for re-thrombosis or bleeding. To assess pharmacological inhibition of platelet function, agonist-induced platelet aggregation, thromboxane B2 (TxB2) and vasodilator-stimulated protein phosphorylation (VASP) are being measured. While serum TxB2 levels of < 2 ng/ml reflect aspirin-induced inhibition of cyclo-oxygenase-1 activity with high sensitivity, VASP exhibits a wide variability upon treatment with clopidogrel or prasugrel. Multiple studies reveal an association between high residual platelet reactivity and adverse cardiovascular events in patients on antiplatelet therapy. However, despite the plethora of platelet function assays currently under investigation, their use in daily practice cannot be recommended. This is due to several reasons: (i) there is no consensus on the method and a respective cut-off value associated with clinical adverse outcome, and (ii) data demonstrating any benefit of tailored antiplatelet therapy and its monitoring (based on assessment of platelet functions) are still limited. Thus, appropriate identification of ‘resistant’ or ‘poor responders’ to antiplatelet agents remains challenging in clinical practice.

Zusammenfassung

Zum Screening der Plättchenfunktion werden Point-of-Care-Techniken, anschließend die Aggregometrie nach Stimulation mit Agonisten wie Kollagen, Adenosindiphosphat, Adrenalin und Arachidonsäure eingesetzt. Zunehmend erfolgt ein Monitoring der antithrombozytären Therapie bei Patienten mit hohem Rethrombose- oder Blutungsrisiko. Als Nachweis der pharmakologischen Plättchenfunktionshemmung dienen neben Aggregometrie, die trotz ihres jahrzehntelangen Einsatzes nur unzureichend standardisiert ist, Messung der Thromboxan-B2 (TxB2)-Spiegel und Bestimmung der Vasodilator-stimulierten Proteinphosphorylierung (VASP). Serum-TxB2-Konzentrationen < 2 ng/ml spiegeln die Aspirin-induzierte Hemmung der Zyklooxygenase-1-Aktivität mit hoher Empfindlichkeit wider. Hingegen zeigen VASP-Spiegel eine große Streubreite unter Behandlung mit Clopidogrel bzw. Prasugrel. Zahlreiche Studien belegen eine Assoziation zwischen erhöhter residueller Plättchenreaktivität und kardiovaskulären Ereignissen bei Patien-ten unter antithrombozytärer Therapie. Trotz der Fülle an Messmethoden, die derzeit untersucht werden, kann ihr Routine-Einsatz gegenwärtig nicht empfohlen werden. Gründe hierfür sind: (i) Es besteht bislang kein Konsens über Methode und jeweils anzulegende Grenzwerte, die mit unerwünschten Ereignissen assoziiert sind und (ii) ist die Datenlage über den Nutzen einer maßgeschneiderten antithrom-bozytären Therapie und ihrem Monitoring (basierend auf Plättchenfunktionsuntersuchungen) noch begrenzt. Somit bleibt die Identifizierung individueller Patienten mit ‚Resistenz’ bzw. „unzureichender Antwort’ auf Behandlung mit plättchenfunktionshemmenden Substanzen eine Herausforderung im klinischen Alltag.

Keywords

Assessment of platelet function(s) - point-of-care testing - drug resistance - clinical resistance - high on-treatment residual platelet reactivity

Schlüsselwörter

Plättchenfunktionsprüfungen - patientennahe Testung - Arzneimittel-Resistenz - klinische Resistenz - hohe residuelle Plättchenreaktivität unter Behandlung
 

  • References

  • 1 Patrono C. Aspirin resistance: definition, mechanisms and clinical read-outs. J Thromb Haemost 2003; 01: 1710-1723.
    CrossrefPubMedGoogle Scholar
  • 2 Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance. Arterioscler Thromb Vasc Biol 2004; 24: 1980-1987.
    CrossrefPubMedGoogle Scholar
  • 3 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.
    CrossrefPubMedGoogle Scholar
  • 4 Sibbing D, Schulz S, Braun S. et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 2010; 08: 250-256.
    CrossrefPubMedGoogle Scholar
  • 5 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007; 05 (Suppl. 01) 230-237.
    CrossrefPubMedGoogle Scholar
  • 7 Patrono C, Rocca B. Aspirin, 110 years later. J Thromb Haemost 2009; 07 (Suppl. 01) 258-261.
    CrossrefPubMedGoogle Scholar
  • 8 Bonello L, Tantry US, Marcucci R. et al. Consensus and future directions on the definition of high ontreatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
    CrossrefPubMedGoogle Scholar
  • 9 Schömig A. Ticagrelor – is there need for a new player in the antiplatelet-therapy field?. N Engl J Med 2009; 361: 1108-1111.
    CrossrefPubMedGoogle Scholar
  • 10 Kost GJ. Goals, guidelines and princliples for pointof-care testing. In: Hagerstwon MD. (ed). Principles & Practice of Point-of-Care Testing. Philadelphia: Lippincott Williams & Wilkins; 2002: 3-12.
    Google Scholar
  • 11 Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008; 34: 709-733.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 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.
    CrossrefPubMedGoogle Scholar
  • 13 Favaloro EJ. The utility of the PFA-100 in the identification of von Willebrand disease: a concise review. Semin Thromb Hemost 2006; 32: 537-545.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Acharya S, Barraclough J, Ibrahim MS. et al. The usefulness of the platelet function analyser (PFA-100) in screening for underlying bleeding disorders in women with menorrhagia. J Obstet Gynaecol 2008; 28: 310-314.
    CrossrefPubMedGoogle Scholar
  • 15 Quiroga T, Goycoolea M, Munoz B. et al. Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients. J Thromb Haemost 2004; 02: 892-898.
    CrossrefPubMedGoogle Scholar
  • 16 Cammerer U, Dietrich W, Rampf T. et al. The predictive value of modified computerized thromboelastography and platelet function analysis for postoperative blood loss in routine cardiac surgery. Anesth Analg 2003; 96: 51-57.
    PubMedGoogle Scholar
  • 17 Mani H, Linnemann B, Luxembourg B. et al. Response to aspirin and clopidogrel monitored with different platelet function methods. Platelets 2006; 17: 303-310.
    CrossrefPubMedGoogle Scholar
  • 18 Paniccia R, Antonucci E, Gori AM. et al. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost 2007; 05: 1839-1847.
    CrossrefPubMedGoogle Scholar
  • 19 Rahe-Meyer N, Winterhalter M, Hartmann J. et al. An evaluation of cyclooxygenase-1 inhibition before coronary artery surgery: aggregometry versus patient self-reporting. Anesth Analg 2008; 107: 1791-1797.
    CrossrefPubMedGoogle Scholar
  • 20 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.
    CrossrefPubMedGoogle Scholar
  • 21 Mengistu AM, Wolf MW, Boldt J. et al. Evaluation of a new platelet function analyzer in cardiac surgery: a comparison of modified thromboelastography and whole-blood aggregometry. J Cardiothorac Vasc Anesth 2008; 22: 40-46.
    CrossrefPubMedGoogle Scholar
  • 22 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.
    CrossrefPubMedGoogle Scholar
  • 23 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.
    CrossrefPubMedGoogle Scholar
  • 24 Sibbing D, Braun S, Jawansky S. et al. Assessment of ADP-induced platelet aggregation with light transmission aggregometry and multiple electrode platelet aggregometry before and after clopidogrel treatment. Thromb Haemost 2008; 99: 121-126.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Gurbel PA, Antonino MJ, Bliden KP. et al. Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target. Platelets 2008; 19: 595-604.
    CrossrefPubMedGoogle Scholar
  • 26 von Beckerath N, Pogatsa-Murray G, Wieczorek A. et al. Correlation of a new point-of-care test with conventional optical aggregometry for the assessment of clopidogrel responsiveness. Thromb Haemost 2006; 95: 910-911.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Shah U, Ma AD. Tests of platelet function. Curr Opin Hematol 2007; 14: 432-437.
    CrossrefPubMedGoogle Scholar
  • 28 van Werkum JW, Bouman HJ, Breet NJ. et al. The Cone-and-Plate(let) analyzer is not suitable to monitor clopidogrel therapy: a comparison with the flowcytometric VASP assay and optical aggregometry. Thromb Res 2010; 126: 44-49.
    CrossrefPubMedGoogle Scholar
  • 29 Born GV. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962; 194: 927-929.
    PubMedGoogle Scholar
  • 30 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
  • 31 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-1425.
    CrossrefPubMedGoogle Scholar
  • 32 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: 1742-1750.
    CrossrefPubMedGoogle Scholar
  • 33 El Ghannudi S, Ohlmann P, Meyer N. et al. Impact of P2Y12 inhibition by clopidogrel on cardiovascular mortality in unselected patients treated by percutaneous coronary angioplasty: a prospective registry. JACC Cardiovasc Interv 2010; 03: 648-656.
    CrossrefPubMedGoogle Scholar
  • 34 Scharf RE. Thrombozyten und Mikrozirkulationsstörungen. Klinische und experimentelle Untersuchungen zum Sekretionsverhalten und Arachidonsäurestoffwechsel der Blutplättchen. Stuttgart, New York: Schattauer; 1986: 47-51.
    Google Scholar
  • 35 Fontana P, Berdague P, Castelli C. et al. Clinical predictors of dual aspirin and clopidogrel poor responsiveness in stable cardiovascular patients from the ADRIE study. J Thromb Haemost. 2010 Sep 22. doi: 10.1111/j.1538–7836.2010.04063.x. [Epub ahead of print]..
    PubMedGoogle Scholar
  • 36 Hedegaard SS, Hvas AM, Grove EL. et al Optical platelet aggregation versus thromboxane metabolites in healthy individuals and patients with stable coronary artery disease after low-dose aspirin administration. Thromb Res 2009; 124: 96-100.
    CrossrefPubMedGoogle Scholar
  • 37 Gurbel PA, Bliden KP, Hayes KM. et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005; 45: 1392-1396.
    CrossrefPubMedGoogle Scholar
  • 38 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: 237-242.
    CrossrefPubMedGoogle Scholar
  • 39 Bassand J. Unmet needs in antiplatelet therapy. Eur Heart Journal 2008; 10 (Suppl) D3-D11.
    PubMedGoogle Scholar
  • 40 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
  • 41 Müller I, Besta F, Schulz C. et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89: 783-787.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Jakubowski JA, Li YG, Small DS. et al. A comparison of the VerifyNow P2Y12 point-of-care device and light transmission aggregometry to monitor platelet function with prasugrel and clopidogrel: an integrated analysis. J Cardiovasc Pharmacol 2010; 56: 29-37.
    CrossrefPubMedGoogle Scholar
  • 43 Mangiacapra F, Patti G, Peace A. et al. Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. Am J Cardiol 2010; 106: 619-23.
    CrossrefPubMedGoogle Scholar
  • 44 Godino C, Mendolicchio L, Figini F. et al. Comparison of VerifyNow-P2Y12 test and Flow cytometry for monitoring individual platelet response to clopidogrel. What is the cut-off value for identifying patients who are low responders to clopidogrel therapy? Thromb J 2009; 07: 4.
    PubMedGoogle Scholar
  • 45 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 46 Geisler T, Schaeffeler E, Dippon J. et al. CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics 2008; 09: 1251-1259.
    CrossrefPubMedGoogle Scholar
  • 47 Pare G, Mehta SR, Yusuf S. et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010; 363: 1704-1714.
    CrossrefPubMedGoogle Scholar
  • 48 Feit F, Voeltz MD, Attubato MJ. et al. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 Trial. Am J Cardiol 2007; 100: 1364-1369.
    CrossrefPubMedGoogle Scholar
  • 49 Rao SV, O’Grady K, Pieper KS. et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005; 96: 1200-1206.
    CrossrefPubMedGoogle Scholar
  • 50 Smith Jr SC, Feldman TE, Hirshfeld Jr JW. et al. ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention – summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006; 113: 156-175.
    CrossrefPubMedGoogle Scholar
  • 51 Bhatt DL. Intensifying platelet inhibition – navigating between Scylla and Charybdis. N Engl J Med 2007; 357: 2078-2081.
    CrossrefPubMedGoogle Scholar
  • 52 Gurbel PA, Becker RC, Mann KG. et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007; 50: 1822-1834.
    CrossrefPubMedGoogle Scholar
  • 53 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 54 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.
    CrossrefPubMedGoogle Scholar
  • 55 Price MJ, Berger PB, Angiolillo DJ. et al. Evaluation of individualized clopidogrel therapy after drugeluting stent implantation in patients with high residual platelet reactivity: design and rationale of the GRAVITAS trial. Am Heart J 2009; 157: 818-24 24 e1..
    CrossrefPubMedGoogle Scholar
  • 56 Cuisset T, Frere C, Quilici J. et al. Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients. Am J Cardiol 2009; 104: 1078-1082.
    CrossrefPubMedGoogle Scholar
  • 57 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 58 Pettersen AA, Seljeflot I, Abdelnoor M. et al. Unstable angina, stroke, myocardial infarction and death in aspirin non-responders. A prospective, randomized trial. The ASCET (ASpirin non-responsiveness and Clopidogrel Endpoint Trial) design. Scand Cardiovasc J 2004; 38: 353-356.
    CrossrefPubMedGoogle Scholar