CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Armen Yuri Gasparyan, MD, PhD and
Gregory Y.H. Lip, MD, FRCP*
* University Department of Medicine, City Hospital, Dudley Road, Birmingham, B18 7QH, United Kingdom (Email: g.y.h.lip{at}bham.ac.uk).
We thank the 2 authors for their interest in our review (1), in which a number of issues were raised regarding definition, possible causes, detection, and treatment of "aspirin resistance." The emergence of the latter requires, first of all, the selection of specific, reproducible, simple, and standardized platelet function tests that could distinguish patients responding to COX-1–related aspirin effects from those patients in whom the administration of aspirin fails to inhibit production of thromboxane A2 through COX-1–related pathway(s). The latter is viewed by us as a true incident of "laboratory aspirin resistance."
The most specific test for the assessment of aspirin effects is light transmission platelet aggregometry with low concentrations of arachidonic acid and adenosine diphosphate. This method is widely used in almost all large prospective studies of aspirin resistance and is closely associated with occurrence of cardiovascular events. Its use allows the clinician to assess platelet function by forming macroaggregates of platelets and is characterized by more serious limitations. First and foremost, platelet aggregometry requires the use of different agonists at different concentrations and their (ex vivo) addition to platelet-rich plasma. A frequently used agonist, arachidonic acid, has been criticized for its possible lytic effects on platelets, resulting in an increase of the light transmission through platelets suspension without an increase in the level of macroaggregates (2). Another frequently used agonist, adenosine diphosphate at low concentrations, can partly activate the arachidonic acid cascade, but its main effect is not specific for the COX-1 pathway. Also, the adjustment of platelet count in platelet-rich plasma by adding autologous platelet-poor plasma, which is mandatory for platelet aggregometry, can itself suppress platelet function (3). Thus, laboratory preparation and the use of agonists for platelet aggregometry can cause unpredictable results, far from reflecting true platelet function per se in cardiovascular disease patients taking aspirin.
Thus, we would agree with the comments that we should avoid the use of agonists for the "ideal test" of aspirin resistance, but this suggestion probably requires the revision of the current definition of "laboratory aspirin resistance." From the physiological point of view, platelet aggregometry in platelet-rich plasma is also an in vitro time-consuming test that neglects interactions of platelets with leucocytes and erythrocytes at the time of blood sampling. This problem is partly overcome with the use of whole blood aggregometry and semiautomated point-of-care platelet function assays that use whole blood (e.g., the PFA-100 test, Siemens Health Diagnostics, Newark, Delaware), which again exhibits a number of other limitations.
It was thought that the use of light transmission aggregometry in combination with other platelet function tests could avoid the limitations of different tests and provide a comprehensive assessment of platelet function. However, this alternative approach raises another important question as to how interpret different, and sometimes polarized, results of different tests. One of the latest studies (4) assessing the prevalence of aspirin resistance with several major platelet function tests (e.g., light transmission aggregometry, whole blood aggregometry, PFA-100, VerifyNow-Aspirin [Accumetrics, San Diego, California], and urinary 11-dehydrothromboxane B2) yielded a prevalence ranging from 6.7% (by VerifyNow-Aspirin) to 59.5% (by PFA-100). These results again confirm the lack of correlation between laboratory tests of aspirin resistance.
We would agree with the comments that flow cytometry is an in vivo quantitative test for the detection of activated platelets and release of microparticles with the surface markers specific for thromboxane A2 pathway at an early stage of platelet activation, and that it may be viewed as an important tool for future studies on true prevalence of "laboratory aspirin resistance." Nonetheless, the expense of flow cytometry and the need to assay samples in highly-specialized laboratory centers would make it difficult to employ flow cytometry in large-scale prospective studies.
Finally, we agree with Kapoor on the suggestion that there is incomplete suppression of platelet aggregation with enteric-coated aspirin. Nonetheless, we should not lose sight of the fact that one common explanation for aspirin resistance, whether defined as laboratory resistance or clinical resistance (i.e., increased thrombotic events), is noncompliance (5).
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1. Gasparyan AY, Watson T, Lip GY. The role of aspirin in cardiovascular prevention: implications of aspirin resistance J Am Coll Cardiol 2008;51:1829-1843.[Abstract/Free Full Text]2. Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance Arterioscler Thromb Vasc Biol 2004;24:1980-1987.[Abstract/Free Full Text] 3. Cattaneo M, Lecchi A, Zighetti ML, Lussana F. Platelet aggregation studies: autologous platelet-poor plasma inhibits platelet aggregation when added to platelet-rich plasma to normalize platelet count Haematologica 2007;92:694-697.[Abstract/Free Full Text] 4. Lordkipanidzé M, Pharand C, Schampaert E, Turgeon J, Palisaitis DA, Diodati JG. 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.[Abstract/Free Full Text] 5. Dalen JE. Aspirin resistance: is it real?. Is it clinically significant?. Am J Med 2007;120:1-4.[Web of Science][Medline]
Related Article
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Enteric Coating Is a Possible Cause of Aspirin Resistance
- John R. Kapoor
J. Am. Coll. Cardiol. 2008 52: 1276-1277.
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