Plättchenfunktionstests zum Monitoring der Azetylsalizylsäuretherapie

H. Haubelt; M. Simon; Ch. Anders; P. Hellstern

doi:10.1055/s-0037-1619621

Hämostaseologie, Table of Contents

Hamostaseologie 2004; 24(03): 196-202
DOI: 10.1055/s-0037-1619621

In eigener Sache

Schattauer GmbH

Plättchenfunktionstests zum Monitoring der Azetylsalizylsäuretherapie

Klinische Wertigkeit bei plättchenfunktionshemmender BehandlungPlatelet function tests for monitoring of acetylsalicylic acidclinical significance in antiplatelet treatment

Authors

H. Haubelt

¹Institut für Hämostaseologie und Transfusionsmedizin (Direktor: Prof. Dr. med. Peter Hellstern), Klinikum der Stadt Ludwigshafen gGmbH
M. Simon

¹Institut für Hämostaseologie und Transfusionsmedizin (Direktor: Prof. Dr. med. Peter Hellstern), Klinikum der Stadt Ludwigshafen gGmbH
Ch. Anders

¹Institut für Hämostaseologie und Transfusionsmedizin (Direktor: Prof. Dr. med. Peter Hellstern), Klinikum der Stadt Ludwigshafen gGmbH
P. Hellstern

¹Institut für Hämostaseologie und Transfusionsmedizin (Direktor: Prof. Dr. med. Peter Hellstern), Klinikum der Stadt Ludwigshafen gGmbH

Abstract

Zusammenfassung

Mehrere Studien mit verschiedenen Plättchenfunktionstests (PFT) zeigten, dass Subgruppen von Patienten unter Azetylsalizylsäure(ASS)-Therapie den erwarteten plättchenfunktionshemmenden Effekt vermissen lassen. Dieses Phänomen wird ebenso wie das klinische Versagen einer ASS-Prophylaxe als ASS-Resistenz (AR) oder Nichtansprechen (nonresponsiveness) auf ASS bezeichnet. Mithilfe von PFT lassen sich mehrere Subtypen unterscheiden. Zur Charakterisierung einer AR wurden bislang folgende PFT herangezogen: optische Aggregometrie, Vollblut-Aggregometrie, Plättchenfunktionsanalyzer PFA-100, Plättchenreaktivitätsindex, Durchflusszytometrie und die Ausscheidung von Metaboliten des Thromboxans B₂ im Urin oder die Thromboxan-B₂-Generation in plättchenreichem Plasma. Eine komplizierte Präanalytik und Analytik sowie unspezifische Störeinflüsse und schlechte Reproduzierbarkeit schränken ihre Anwendung in der klinischen Routine erheblich ein. Darüber hinaus sind unterschiedliche PFT offenbar nicht austauschbar im Hinblick auf die Beurteilung einer AR. Drei prospektive klinische Studien wiesen eine Assoziation zwischen einer vermeintlichen, laboranalytisch festgestellten AR und kardiovaskulären Ereignissen nach. Daher besteht dringender Bedarf an einem einfachen und reproduzierbaren Test, der zuverlässig die individuelle klinische Wirksamkeit einer Therapie mit Plättchenfunktionshemmern anzeigt. Keiner der aktuell verfügbaren PFT einschließlich des PFA-100-Systems wird gegenwärtig diesem Anspruch gerecht.

Summary

Several studies have demonstrated with the use platelet function tests (PFT) that subgroups of patients under acetylsalicylic acid (ASA) fail to produce the anticipated antiplatelet effect. This phenomenon as well as the clinical failure of ASA to protect patients from thromboembolic complications has been termed ASA resistance (AR) or ASA nonresponsiveness. Several subtypes of AR can be distinguished by PFT. The following PFT were used to characterize AR: optical aggregometry, platelet aggregation in whole blood, platelet function analyzer (PFA-100), platelet reactivity test or platelet aggregate ratio, flow cytometry and thromboxane B₂ generation. All PFT have in common that their widespread clinical use is substantially limited due to complex preanalytic factors, reduced specificity and poor reproducibility. PFT are not interchangeable for monitoring antiplatelet treatment. Three prospective clinical trials revealed a possible relationship between AR and subsequent cardiovascular events. There is a need for a simple and reliable assay for predicting the clinical efficacy of antiplatelet therapy. Recent data demonstrate that none of the currently available assays including the PFA-100 system are capable to accomplish these objectives.

Schlüsselwörter

Azetylsalizylsäure - Azetylsalizylsäureresistenz - Plättchenfunktionstests

Keywords

Acetylsalicylic acid - acetylsalicylic acid resistance - platelet function tests

Full Text

References

Literatur
1 Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Brit Med J 2002; 324: 71-86.
2 Berglund U, Wallentin L. Persistent inhibition of platelet function during long-term treatment with 75 mg acetylsalicylic acid daily in men with unstable coronary artery disease. Eur Heart J 1991; 12: 428-33.
3 Böck M, de Haan J, Beck KH. et al. Standardization of the PFA-100 platelet function test in 105 mmol/l buffered citrate: effect of gender, smoking, and oral contraceptives. Brit J Haematol 1999; 106: 898-904.
4 Born GV, Dearnley R, Foulks JG. et al. Quantification of the morphological reaction of platelets to aggregating agents and of its reversal by aggregation inhibitors. J Physiol 1978; 280: 193-212.
5 Born GVR. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 194 1962; 927-9.
6 Breddin K, Ziemen M, Bauer O. et al. Time and temperature dependent changes of ADP- and collagen-induced and »spontaneous« aggregation. Thromb Res 1980; 19: 621-38.
7 Cambria-Kiely JA, Gandhi PJ. Aspirin resistance and genetic polymorphisms. J Thromb Thrombol 2002; 14: 51-8.
8 Cardinal DC, Flower RJ. The electronic aggregometer: a novel device for assessing platelet behaviour in blood. J Pharmacol Methods. 1980; 3: 135-58.
9 Chakroun T, Gerotziafas G, Robert F. et al. In vitro aspirin resistance detected by PFA-100 closure time: pivotal role of plasma von Willebrand factor. Brit J Haematol 2004; 124: 80-5.
10 Cotter G, Shemesh E, Zehavi M. et al. Lack of aspirin effect: aspirin resistance or resistance to taking aspirin?. Am Heart J 2004; 147: 293-300.
11 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: 1650-5.
12 FitzGerald GA, Pedersen AK, Patrono C. Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. Circulation 1983; 67: 1174-7.
13 Fressinaud E, Veyradier A, Truchoud I. et al. Screening for von Willebrand disease with a new analyzer using high shear stress: a study of 60 cases. Blood 1998; 91: 1325-31.
14 Granström E. Methodology in prostaglandin and thromboxane assay. Prog Lipid Res 1986; 25: 119-27.
15 Grotemeyer KH, Scharafinski HW, Husstedt IW. 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.
16 Grotemeyer KH. Effects of acetylsalicylic acid in stroke patients – evidence of nonresponders in a subpopulation of treated patients. Thromb Res 1991; 63: 587-93.
17 Grotemeyer KH. The platelet reactivity test. A useful by-product of the blood sampling procedure?. Thromb Res 1991; 61: 423-31.
18 Grundmann K, Jaschonek K, Kleine B. et al. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks. J Neurol 2003; 250: 63-6.
19 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: 230-5.
20 Gum PA, Kottke-Marchant K, Welsh PA. et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003; 41: 961-5.
21 Halushka MK, Walker LP, Halushka PV. Genetic variation in cyclooxygenase 1: effects on response to aspirin. Clin Pharmacol Ther 2003; 73: 122-30.
22 Harrison P. Progress in the assessment of platelet function. Br J Haematol 2000; 111: 733-44.
23 Helgason CM, Bolin KM, Hoff JA. et al. Development of aspirin resistance in persons with previous ischemic stroke. Stroke 1994; 25: 2331-6.
24 Helgason CM, Tortorice KL, Winkler SR. et al. Aspirin response and failure in cerebral infarction. Stroke 1993; 24: 345-50.
25 Hézard N, Metz D, Nazeyrollas P. et al. PFA-100 and flow cytometry: can they challenge aggregometry to assess antiplatelet agents, other than GPIIbIIIa blockers, in coronary angioplasty?. Thromb Res 2003; 108: 43-7.
26 Homoncik M, Jilma B, Hergovich N. et al. Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyzer PFA-100. Thromb Haemost 2000; 83: 316-21.
27 Howard PA. Aspirin resistance. Ann Pharmacother 2002; 36: 1620-4.
28 Hurlen M, Seljeflot I, Arnesen H. The effect of different antithrombotic regimens on platelet aggregation after myocardial infarction. Scand Cardiovasc J 1998; 233-7.
29 Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital and acquired platelet dysfunction. J Lab Clin Med 2001; 138: 152-63.
30 Kratzer MA, Born GV. Simulation of primary haemostasis in vitro. Haemostasis 1985; 15: 357-62.
31 Kundu SK, Heilmann EJ, Sio R. et al. Characterization of an in vitro platelet function analyzer, PFA-100. Clin Appl Thromb Haemost 1996; 2: 241-9.
32 Macchi L, Christiaens L, Brabant S. et al. Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. Thromb Res 2002; 107: 45-9.
33 Mammen EF, Comp PC, Gosselin R. et al. PFA-100 system: a new method for assessment of platelet dysfunction. Semin Thromb Hemost 1998; 24: 195-202.
34 McKee SA, Sane DC, Deliagyris N. Aspirin resistance in cardiovascular disease: a review of prevalence, mechanisms, and clinical significance. Thromb Haemost 2002; 88: 711-5.
35 Mueller MR, Salat A, Stangl P. et al. Variable platelet response to low-dose ASA and the link of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost 1997; 78: 1003-7.
36 Nicholson NS, Panzer-Knodle SG, Haas NF. et al. Assessment of platelet function assays. Am Heart J 1998; 135: 170-8.
37 Patrono C, Coller B, Dalen JE. et al. Platelet active drugs. The relationships among dose, effectiveness, and side effects. Chest 2001; 119: 39S-63S.
38 Sane DC, McKee SA, Malinin AI. et al. Frequency of aspirin resistance in patients with congestive heart failure treated with antecedent aspirin. Am J Cardiol 2002; 90: 893-5.
39 Schör K. Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis. Semin Thromb Hemost 1997; 23: 349-56.
40 Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing physicians’ health study. N Engl J Med 1989; 321: 129-35.
41 ten Berg JM, Gerritsen WBM, Haas FJLM. et al. High-dose aspirin in addition to daily low-dose aspirin decreases platelet activation in patients before and after percutaneous coronary intervention. Thromb Res 2002; 105: 385-90.
42 Weber AA, Przytulski B, Schanz A. et al. Towards a definition of aspirin resistance: a typological approach. Platelets 2002; 13: 37-40.
43 Weksler BB, Kent JL, Rudolph D. et al. Effects of low dose aspirin on platelet function in patients with recent cerebral ischemia. Stroke 1985; 16: 5-9.
44 Wu KK, Hoak JC. A new method for quantitative detection of platelet aggregates in patients with arterial insufficiency. Lancet 1974; II: 924-6.