[HTML][HTML] Are Immature Platelets Growing Up? Toward a New Marker of Antiplatelet Drug Resistance

NS Kleiman - Journal of the American College of Cardiology, 2016 - jacc.org
NS Kleiman
Journal of the American College of Cardiology, 2016jacc.org
In 2003, Gurbel et al.(1) observed that the response of platelets to the P2Y12 inhibitor
clopidogrel was nonuniform and suggested that patients who have persistently high ex vivo
platelet reactivity while receiving clopidogrel might be prone to stent thrombosis and
myocardial infarction. This hypothesis has subsequently been confirmed, most notably in the
ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) study (2),
although randomized clinical trials have thus far failed to demonstrate a clinical benefit for …
In 2003, Gurbel et al.(1) observed that the response of platelets to the P2Y12 inhibitor clopidogrel was nonuniform and suggested that patients who have persistently high ex vivo platelet reactivity while receiving clopidogrel might be prone to stent thrombosis and myocardial infarction. This hypothesis has subsequently been confirmed, most notably in the ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) study (2), although randomized clinical trials have thus far failed to demonstrate a clinical benefit for strategies that are based on such findings (3–5). The utility of platelet function testing may be diminished in patients treated with the newer P2Y12 antagonists prasugrel and ticagrelor; however, the fact remains that most patients, even among the highest risk strata, are still discharged on clopidogrel, and platelet function testing is not commonly performed (6). As the mechanical and device-related aspects of stent implantation continue to improve, the proportional contribution of the pharmacological response to platelet-inhibiting drugs increases. These considerations become particularly important in an era of high consumer expectations and public reporting of percutaneous coronary intervention (PCI) outcomes. Most of the techniques currently used to assess platelet activity are inconvenient and resource intensive. The original report by Gurbel et al.(1) measured light transmittance aggregometry in response to different concentrations of adenosine diphosphate (ADP). Subsequent studies have used devices such as electronic impedance aggregometry, platelet shear through a tiny aperture (PFA-100 System, Siemens Medical Solutions USA, Malvern, Pennsylvania), and point-of-care platelet agglutination (VerifyNow System, Accriva Diagnostics, San Diego, California). Each of the latter 3 tests require blood specimens be transported to a testing area and have varying degrees of operator dependence, whereas all 4 require reagents to stimulate platelets, adding further variability to the assessment. Genetic testing, most notably for polymorphisms of cytochrome (CYP) P450 2C19, explains a small proportion of the variability observed in the response to clopidogrel (7) and has the advantage of being state independent (ie, not subject to the influence of concomitant medications or illnesses). However, it is also resource intensive, and with current commercial technology, the results are not immediately available.
In this issue of the Journal, Stratz et al.(8) report the use of a greatly simplified and relatively inexpensive surrogate for platelet reactivity: measurement of immature platelet count using an automated cell counter. Understanding this measurement requires knowing a bit about platelet physiology. Its potential utility is based on an observation made by Karpatkin (9) in 1969 that platelets newly released into the circulation are more likely to participate in thrombosis than “older” cells. But the cumbersome technique used by Karpatkin required separation of platelets according to density, then measurement of high-energy phosphate and platelet factor 4 release from the platelets after agonist stimulation. The later development of thiazole orange (10), a fluorescent dye that forms high-intensity bonds with nucleotides, allowed use of flow cytometry to identify platelets with high ribonucleic acid (RNA) content in a reticulated pattern, hence the name “reticulated platelets”(11).
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