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Aspirin resistance, PFA-100, and variation
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Søren R Kristensen, Dept. Clin. Biochem., Centre of Cardiovasc. Res. Aalborg Hosp., Aarhus Univ. Hosp., Aalborg, Denmark, Esben H. Madsen, Dept. Clin. Biochem., Centre of Cardiovasc. Res., Aalborg Hosp., Aarhus Univ. Hosp., Aalborg, Denmark
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srk{at}rn.dk Søren R Kristensen, et al.
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Karon et al. (1) recently published an interesting comparison of various methods to detect “aspirin (ASA) resistance”. Although still debated, the presence of “ASA resistance” may be an important cause of arterial thrombosis in spite of treatment with ASA. Since no consensus about method and/or criteria to detect this problem exists, there is a need for experimental work illuminating possibilities and problems regarding high residual platelet reactivity during ASA therapy. Karon et al. (1) tested four frequently used methods, including the platelet function analyzer 100 (PFA-100), on volunteers given ASA, and concluded that all methods were able to detect the effect of ASA with high confidence. The results obtained with PFA-100 are surprising and contradictory to other findings including our own (2-4). The authors found none of the volunteers to have a low response to ASA defined as a closure time (CT) < 193 s at any occasion. Furthermore, they found a mean value close to 300 s (which is the maximal value measured by this equipment) and a coefficient of variance (CV) of 3.5 – 5.0 %. Fontana et al. (3) and Gonzalez-Conejero et al. (4) found several low responders among healthy volunteers - Karon et al (1) discuss these contradictive results, but find no explanation. The low CV indicates that apparently no duplicates with a high and a low value (e.g. > 300 s and 120 s) was found, which in our experience seems peculiar. We recently published results showing a wide variation between the two results in a considerable part of duplicate measurements (2). The examined population consisted of patients with peripheral arterial disease (PAD), and they may differ in this respect compared to a normal population. However, we observed the same problem among healthy volunteers (5). Although the variation at baseline was rather low it increased considerably during therapy with ASA because of frequently occurring duplicates with a very high and a completely normal result, and the results deemed 9 of 20 participants “ASA resistant” at 1-3 occasions out of four measurements on each. Therefore, the results reported by Karon et al. are surprising, and we wonder whether the technicians perhaps have expelled some unexpected low results as they might have believed them to be technical faults and simply repeated the test? By doing so, you will often get a high result at repetition which seems more reasonable during ASA therapy. Our suggestion is pure speculation, but we know from other centres investigating the effect of ASA that all have got results like ours, and we want to stress that the results presented by Karon et al. are not the usual finding using PFA-100. Several investigators use single determinations because of a rather low CV in healthy individuals, but since the variation is much larger during ASA treatment, we have suggested to use duplicate determination (2). A high and a low result of a duplicate might indicate an intermediate responsiveness between ASA-sensitive and ASA-low-responders (2). Further clinical studies may shed light on this question. Grant/ funding support: The studies were supported by the Danish Heart Foundation Financial disclosures: Nothing to declare Acknowledgements: n/a References (1) Karon BS, Wockenfus A, Scott R, Hartman SJ, McConnell JP, Santrach PJ, et al. Aspirin responsiveness in healthy volunteers measured with multiple assay platforms. Clin.Chem. 2008;54(6):1060-1065. (2) Madsen EH, Schmidt EB, Gehr N, Johannesen NL, Kristensen SR. Test of Aspirin resistance by PFA-100: some methodological caveats and considerations. J.Thromb.Haemost. 2008;6:386-8. (3) Fontana P, Nolli S, Reber G, de MP. Biological effects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers. J.Thromb.Haemost. 2006;4:813-819. (4) Gonzalez-Conejero R, Rivera J, Corral J, Acuna C, Guerrero JA, Vicente V. Biological assessment of aspirin efficacy on healthy individuals: heterogeneous response or aspirin failure? Stroke 2005;36:276 -280. (5) Madsen E, Schmidt E, Maurer–Spurej E, Kristensen SR. Effects of aspirin and clopidogrel in healthy men measured by platelet aggregation and PFA–100. Platelets, in press. |
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Bradley S. Karon
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Karon.Bradley{at}mayo.edu Bradley S. Karon
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Response to Madsen et al., We read with interest the comments of Dr. Kristensen who found discrepant results with the PFA-100 in patients with peripheral vascular disease1. As pointed out in our manuscript, we have no good explanation for the lack of non-response found in our study relative to some others. However the strength of our study was the consistency of the findings across multiple platforms rather than relying on only one approach. Patient population studied is likely to be one important variable since patients with co-morbidities may have other reasons for procoagulant activity (for example poorer reproducibility could be due to thrombin activation). The data presented in our manuscript represents all tests performed, there were no repeat tests done or results excluded from analysis. As pointed out in our paper, we took great care to minimize pre-analytic or analytic errors that can result in poor performance of coagulation tests. Two experienced laboratory technologists drew all blood samples in the same room where the instrument was located (to minimize time between blood draw and analysis). Because the PFA-100 requires manual dosing of cartridges, these same two experienced technologists performed all testing. Although our methods do not differ significantly from those published previously1,2, it is possible that the smaller group of experienced laboratory technologists employed in our study resulted in more consistent results. Blood samples collected for research studies that are drawn outside the laboratory may also be particularly prone to over-filling, under-filling, improper mixing, and other variables likely to impact coagulation results. Most errors in coagulation testing are due to pre-analytic errors, and thus this is likely another variable to consider. In addition other investigators have observed consistent results with the PFA-100 when healthy volunteers were dosed aspirin3, so our findings are not unique in that regard. We did specifically point out in the manuscript the high inter-lab CV reported on “inhibited” specimens distributed as part of proficiency testing efforts in the US, so we would not object to the idea of duplicate testing for research use of the device. We simply did not observe poor reproducibility in normal volunteers in our study. Regards, Brad Karon References 1. Madsen EH, Schmidt EB, Gehr N, Johannesen NL, Kristensen SR. Testing aspirin resistance using the platelet function analyzer-100: some methodological caveats and considerations. J Thromb Haemost 2008;6:386-8. 2. Fontana P, Nolli S, Reber G, De Moerloose P. Biological effects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers. J Thromb Haemost 2006;4:813-9. 3. Homoncik M, Jilma B, Hergovich N, Stohlawetz P, Panzer S, Speiser W. Monitoring of aspirin pharmacodynamics with the platelet function analyzer PFA-100. Thromb Haemost 2000;83:316-21. |
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