Methoden zur Messung der Azetylsalizylsäure- bzw. Clopidogrelresistenz

 

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Zusammenfassung

Basierend auf der Prämisse, wonach eine so genannte Resistenz gegenüber Thrombozytenfunktionshemmern vorliegt, wenn das Pharmakon den für die klinische Wirksamkeit entscheidenden pharmakodynamischen Effekt nicht ausübt, sollten zur Evaluation der Wirkung von Thrombozytenfunktionshemmern Laborteste eingesetzt werden, die den pharmakodynamischen Effekt möglichst direkt erfassen.

Für die Evaluation von Azetylsalizylsäurewirkungen scheint die Messung von Thromboxan B2 oder die der Arachidonsäure- induzierten Aggregation (Turbidimetrie oder Vollblutaggregometrie) angebracht. Für die Evaluation von Clopidogrelwirkungen scheint die Messung der VASP-Phosphorylierung (Durchflusszytometrie) oder die der ADPinduzierten Thrombozytenaggregation (Turbidimetrie oder Vollblutaggregometrie) sinnvoll.

Summary

Based on the concept that the so-called resistance to antiplatelet drugs is meant to describe a phenomenon where the drug does not hit its direct pharmacodynamic target, assays, used to evaluated the effects of anti-platelet drugs, should as closely as possible measure the direct pharmacodynamic effect of a particular drug.

Thus, for the detection of aspirin effects, thromboxane concentrations or arachidonic acid-induced responses (light aggregometry, whole-blood aggregometry) should be measured. For the detection of clopidogrel actions, VASP phosphorylation (flow cytometry) or ADP-induced responses (light aggregometry, whole blood aggregometry) should be analysed.

• References

• 1 Asai F, Jakubowski JA, Naganuma H. et al. Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y₁₂ inhibitor: a single ascending dose study in healthy humans. Platelets 2006; 17: 209-217.
  CrossrefPubMedGoogle Scholar
• 2 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: 295-302.
  CrossrefPubMedGoogle Scholar
• 3 Bonello L, Paganelli F, Arpin-Bornet M. et al. Vasodilator- stimulated phosphoprotein phosphorylation analysis prior to percutanecous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost 2007; 5: 1630-1636.
  CrossrefPubMedGoogle Scholar
• 4 Bretschneider E, Glusa E, Schrör K. ADP-, PAFand adrenaline-induced platelet aggregation and thromboxane formation are not affected by a thromboxane receptor antagonist at physiological external Ca++ concentrations. Thromb Res 1994; 75: 233-242.
  CrossrefPubMedGoogle Scholar
• 5 Cattaneo M. Laboratory detection of ‘aspirin resistance’: what test should we use (if any)?. Eur Heart J 2007; 28: 1673-1675.
  CrossrefPubMedGoogle Scholar
• 6 Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007; 5 (Suppl. 01) 230-237.
  CrossrefPubMedGoogle Scholar
• 7 Censarek P, Freidel K, Udelhoven M. et al. Cyclooxygenase (COX)-2a, a novel COX-2 mRNA variant, in platelets from patients after coronary artery bypass grafting. Thromb Haemost 2004; 92: 925-928.
  Article in Thieme ConnectPubMedGoogle Scholar
• 8 Censarek P, Steger G, Paolini C. et al. Alternative splicing of platelet cyclooxygenase-2 mRNA in patients after coronary artery bypass grafting. Thromb Haemost 2007; 98: 1309-1315.
  Article in Thieme ConnectPubMedGoogle Scholar
• 9 Cuisset T, Frere C, Quilici J. et al. Lack of association between the 807 C/T polymorphism of glycoprotein Ia gene and post-treatment platelet reactivity after aspirin and clopidogrel in patients with acute coronary syndrome. Thromb Haemost 2007; 97: 212-217.
  Article in Thieme ConnectPubMedGoogle Scholar
• 10 Cuisset T, Frere C, Quilici J. et al. High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non- ST elevation acute coronary syndromes. Thromb Haemost 2007; 97: 282-287.
  Article in Thieme ConnectPubMedGoogle Scholar
• 11 Dichiara J, Bliden KP, Tantry US. et al. Platelet function measured by VerifyNowTM identifies generalized high platelet reactivity in aspirin treated patients. Platelets 2007; 18: 414-423.
  CrossrefPubMedGoogle Scholar
• 12 Dropinski J, Musial J, Jakiela B. et al. Anti-thrombotic action of clopidogrel and P1(A1/A2) polymorphism of beta3 integrin in patients with coronary artery disease not being treated with aspirin. Thromb Haemost 2005; 94: 1300-1305.
  Article in Thieme ConnectPubMedGoogle Scholar
• 13 Dropinski J, Jakiela B, Sanak M. et al. The additive antiplatelet action of clopidogrel in patients with coronary artery disease treated with aspirin. Thromb Haemost 2007; 98: 201-209.
  Article in Thieme ConnectPubMedGoogle Scholar
• 14 Fefer P, Hod H, Matetzky S. Clopidogrel resistance – the cardiologist’s perspective. Platelets 2007; 18: 175-181.
  CrossrefPubMedGoogle Scholar
• 15 Geiger J, Teichmann L, Grossmann R. et al. Monitoring of clopidogrel action: comparison of methods. Clin Chem 2005; 51: 957-965.
  CrossrefPubMedGoogle Scholar
• 16 Geisler T, Gawaz M. Variable response to clopidogrel in patients with coronary artery disease. Semin Thromb Haemost 2007; 33: 196-202.
  Article in Thieme ConnectPubMedGoogle Scholar
• 17 Görlinger K, Jambor C, Hanke AA. et al. Perioperative coagulation management and control of platelet transfusion by point-of-care function analysis. Transf Med Hemother 2007; 34: 396-411.
  PubMedGoogle Scholar
• 18 Grossmann R, Sokolova O, Schnurr A. et al. Variable extent of clopidogrel responsiveness in patients after coronary stenting. Thromb Haemost 2004; 92: 1201-1206.
  Article in Thieme ConnectPubMedGoogle Scholar
• 19 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: 3156-3164.
  CrossrefPubMedGoogle Scholar
• 20 Gurbel PA, Bliden KP, Etherington A. et al. Assessment of clopidogrel responsiveness: measurements of maximum platelet aggregation, final platelet aggregtation and their correlation with vasodilator- stimulated phosphoprotein in resistant patients. Thromb Res 2007; 121: 107-115.
  CrossrefPubMedGoogle Scholar
• 21 Hermann A, Rauch BH, Braun M. et al. Platelet CD40 ligand (CD40L) -subcellular localization, regulation of expression, and inhibition by clopidogrel. Platelets 2001; 12: 74-82.
  CrossrefPubMedGoogle Scholar
• 22 Hezard N, Metz D, Garnotel R. et al. Platelet VASP phosphorylation assessment in clopidogrel-treated patients: lack of agreement between Western blot and flow cytometry. Platelets 2005; 16: 474-481.
  CrossrefPubMedGoogle Scholar
• 23 Hochholzer W, Trenk W, Frundi D. et al. Whole blood aggregometry for evaluation of the antiplatelet effects of clopidogrel. Thromb Res 2007; 119: 285-291.
  CrossrefPubMedGoogle Scholar
• 24 Hohlfeld T. Aspirin resistance. J Lab Med 2006; 30: 302-309.
  PubMedGoogle Scholar
• 25 Hohlfeld T, Zimmermann N, Weber A-A. et al. Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. J Thromb Haemost. 2007 (doi: 10.1111/j.1538–7836.2007.02800.x).
  PubMedGoogle Scholar
• 26 Hübl W, Assadian A, Lax J. et al. Assessing aspirininduced attenuation of platelet reactivity by flow cytometry. Thromb Res 2007; 121: 135-143.
  CrossrefPubMedGoogle Scholar
• 27 Hulot J-S, Bura A, Villard E. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-2247.
  CrossrefPubMedGoogle Scholar
• 28 Lepantalo A, Mikkelsson J, Resendiz JC. et al. Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients. Thromb Haemost 2006; 95: 253-259.
  Article in Thieme ConnectPubMedGoogle Scholar
• 29 Lordkipanidzé M, Pharand C, Schampaert E. et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 2007; 28: 1702-1708.
  CrossrefPubMedGoogle Scholar
• 30 Malinin A, Pokov A, Spergling M. et al. Monitoring platelet inhibition after clopidogrel with the VerfyNow-P2Y₁₂R rapid analyzer: the VERIfy Thrombosis rik Assessment (VERITAS) study. Thromb Res 2007; 119: 277-284.
  CrossrefPubMedGoogle Scholar
• 31 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
• 32 Mueller T, Dieplinger B, Poelz W. et al. Utility of whole blood impedance aggregometry for the assessment of clopidogrel action using the novel Multiplate R analyzer – comparison with two flow cytometric methods. Thromb Res 2007; 121: 249-258.
  CrossrefPubMedGoogle Scholar
• 33 Pampuch A, Cerletti C, de Gaetano G. Comparison of VASP-phosphorylation assay to light-transmission aggregometry in assessing inhibition of the platelet ADP P2Y₁₂ receptor. Thromb Haemost 2006; 96: 767-773.
  Article in Thieme ConnectPubMedGoogle Scholar
• 34 Schafer A, Bonz AW, Eigenthaler M. et al. Late thrombosis of a drug-eluting stent during combined anti-platelet therapy in a clopidogrel nonresponsive diabetic patient: shall we routinely test platelet function?. Thromb Haemost 2007; 97: 862-865.
  Article in Thieme ConnectPubMedGoogle Scholar
• 35 Schrör K, Seidel H. Blood-vessel wall arachidonate metabolism and its pharmacological modification in a new in vitro assay system. Naunyn Schmiedeberg’s Arch Pharmacol 1988; 337: 177-182.
  PubMedGoogle Scholar
• 36 Schror K, Weber AA, Hohlfeld T. Clopidogrel ˶resistance“. Thromb Haemost 2004; 92: 229-231.
  Article in Thieme ConnectPubMedGoogle Scholar
• 37 Schrör K, Weber A-A, Hohlfeld T. Clopidogrel ˶resistance“ and statin cotreatment – significant for cardiocoronary prevention in real life?. Thromb Haemost 2005; 94: 235-237.
  Article in Thieme ConnectPubMedGoogle Scholar
• 38 Schwarz UR, Geiger J, Walter U. et al. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets – definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost 1999; 82: 1145-1152.
  Article in Thieme ConnectPubMedGoogle Scholar
• 39 Siller-Matula J, Schrör K, Wojta J. et al. Thienopyridines in cardiovascular disease: focus on clopidogrel resistance. Thromb Haemost 2007; 97: 385-393.
  Article in Thieme ConnectPubMedGoogle Scholar
• 40 Snoep JD, Hovens M, Eikelboom JCJ. et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007; 154: 221-231.
  CrossrefPubMedGoogle Scholar
• 41 Snoep JD, Hovens M, Eikelboom 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.
  CrossrefPubMedGoogle Scholar
• 42 Toth 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.
  Article in Thieme ConnectPubMedGoogle Scholar
• 43 Undas A, Placzkiewicz-Jankowska E, Zielinski L. et al. Lack of aspirin-induced decrease in thrombin formation in subjects resistant to aspirin. Thromb Haemost 2007; 97: 1056-1058.
  Article in Thieme ConnectPubMedGoogle Scholar
• 44 Valles J, Santos MT, Fuset MP. et al. Partial inhibition of platelet thromboxane A2 synthesis by aspirin is associated with myonecrosis in patients with ST-segment elevation myocardial infarction. Am J Cardiol 2007; 99: 19-25.
  CrossrefPubMedGoogle Scholar
• 45 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
• 46 Weber A-A, Zimmermann KC, Meyer-Kirchrath J. et al. Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet 1999; 353: 900.
  PubMedGoogle Scholar
• 47 Weber A-A, Reimann S, Schrör K. Specific inhibition of ADP-induced platelet aggregation by clopidogrel in vitro. Br J Pharmacol 1999; 126: 415-420.
  CrossrefPubMedGoogle Scholar
• 48 Weber A-A, Hohlfeld T, Schrör K. CAMP is an important messenger for ADP-induced platelet aggregation. Platelets 1999; 10: 238-241.
  CrossrefPubMedGoogle Scholar
• 49 Weber A-A, Liesener S, Hohlfeld T. et al. 40 mg of aspirin are not sufficient to inhibit platelet function under conditions of limited compliance. Thromb Res 2000; 97: 365-367.
  CrossrefPubMedGoogle Scholar
• 50 Weber A-A, Braun M, Hohlfeld T. et al. Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers. Br J Clin Pharmacol 2001; 52: 333-336.
  CrossrefPubMedGoogle Scholar
• 51 Weber A-A, Przytulski B, Schanz A. et al. Towards a definition of aspirin resistance: a typological approach. Platelets 2002; 13: 37-40.
  CrossrefPubMedGoogle Scholar
• 52 Weerakkody GJ, Brandt JT, Payne CD. et al. Clopidogrel poor responders: An objective definition based on Bayesian classification. Platelets 2007; 18: 428-435.
  CrossrefPubMedGoogle Scholar
• 53 Zimmermann N, Kienzle P, Weber A-A. et al. Aspirin resistance after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2001; 121: 982-984.
  CrossrefPubMedGoogle Scholar
• 54 Zimmermann N, Wenk A, Kim U. et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 2003; 108: 542-547.
  CrossrefPubMedGoogle Scholar