Platelet Function Tests: Why They Fail to Guide Personalized Antithrombotic Medication

Gorog, Diana A.; Jeong, Young‐Hoon

doi:10.1161/jaha.115.002094

Cited by 20 publications

(22 citation statements)

References 67 publications

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“…The present study is limited by the small sample size; however, a study population calculation was done to ensure that a sample size of 12 for each treatment group was adequate to produce a type 1 error of less than 5% and a type 2 error of less than 20%. Furthermore, we acknowledge the limitations with platelet function testing, and because there is no universally accepted method, we feel as though our method was suitable for the study presented . Last, this study did not look at multiple daily doses or concurrent administration of aspirin and diclofenac; however, platelet aggregation studies were carried out until platelet function returned to baseline, and the results would predict that no interaction would occur with daily aspirin.…”

Section: Discussionmentioning

confidence: 99%

Topical diclofenac does not affect the antiplatelet properties of aspirin as compared to the intermediate effects of oral diclofenac: A prospective, randomized, complete crossover study

Rowcliffe

Nezami

Westphal

et al. 2015

The Journal of Clinical Pharma

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Nonsteroidal anti-inflammatory drugs (NSAIDs) adversely interact with aspirin, diminishing its antiplatelet effect and potentially placing patients at an increased risk for recurrent thrombotic events. This crossover study aimed to determine whether the topical NSAID diclofenac epolamine 1.3% patch or oral diclofenac 50 mg interfered with the antiplatelet effects of aspirin 325 mg. Twelve healthy men and women aged 18-50 were included. Participants were randomized into 5 treatment arms: aspirin, diclofenac potassium 50 mg, diclofenac patch, diclofenac potassium plus ASA 325 mg, and diclofenac patch plus aspirin. Platelet responsiveness was determined using whole-blood impedance aggregation (WBA) to collagen 1 μg/mL and arachidonic acid (AA) 0.5 mM and was sampled every 2 hours. No significant difference in platelet function was observed following the diclofenac patch and aspirin vs aspirin alone. Oral diclofenac produced a mixed effect with significant reduction in platelet inhibition at hour 2 and hour 8 following aspirin administration. Topical diclofenac does not significantly interfere with the antiplatelet effects of aspirin and may be a safer alternative to the oral formulation.

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Section: Discussionmentioning

confidence: 99%

Topical diclofenac does not affect the antiplatelet properties of aspirin as compared to the intermediate effects of oral diclofenac: A prospective, randomized, complete crossover study

Rowcliffe

Nezami

Westphal

et al. 2015

The Journal of Clinical Pharma

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“…Frelinger commented that the PK and PD of clopidogrel vary widely despite efforts to exclude or control for polymorphisms, diet, smoking, and noncompliance . He concluded that “it remains unclear whether these factors fully explain the variability observed in clopidogrel pharmacokinetics and pharmacodynamics, or if a significant portion of the variability is due to still unknown factors.” There has developed a more generalized view that platelet aggregation studies are of limited clinical value . Individual platelet reactivity varies over time in patients treated with clopidogrel based on data from the ELEVATE‐TIMI 56 trial .…”

Section: From Cyp2c19 Back To Cyp3amentioning

confidence: 99%

The Metabolism of Clopidogrel: CYP2C19 Is a Minor Pathway

Ford

2016

The Journal of Clinical Pharma

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The major metabolic pathway of clopidogrel is conversion to carboxylic acid by an esterase (CES1), forming clopidogrelic acid (SR26334) that is inactive. There is agreement on the structure of the active metabolite; however, there are differing views about the mechanism of its formation. Sanofi studied the conversion of clopidogrel to the active metabolite using human liver microsomes. It was concluded that 2-oxo-clopidogrel was formed via CYP3A oxidation. From a subsequent in vitro study by Sankyo of the metabolism of clopidogrel using recombinant DNA CYPs, it was concluded that CYP2C19 was the major oxidative pathway. Such CYPs can give false-negative results particularly with drugs such as clopidogrel that have high first-pass metabolism in the enterocyte. CYP3A is present in the enterocyte but not CYP2C19. However, the view that clopidogrel is a CYP2C19 substrate was reinforced by a finding that omeprazole, a CYP2C19 inhibitor, reduced the ability of clopidogrel to inhibit platelet aggregation. The drug-drug interaction study of clopidogrel with omeprazole had the effect of reducing the area under the curve (AUC) of the clopidogrel active metabolite by 45%. However, a drug interaction study with a CYP3A inhibitor, grapefruit juice, caused a 6-fold reduction in the AUC of the active metabolite. Clopidogrel is therefore now considered to be primarily a CYP3A4/5 substrate. CYP2C19 has a minor role whose effect can be detected using a sensitive methodology such as platelet aggregometry.

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“…Thus, platelets flowing through capillaries would be subjected to non-homogeneous shear stress profiles, which may result in incomplete activation of the platelets. Furthermore, a recent study 18 raised an issue that insufficient shear rate generation might be the cause of failure of platelet function tests to guide personalized antithrombotic medication.…”

Section: Introductionmentioning

confidence: 99%

A simple method for activating the platelets used in microfluidic platelet aggregation tests: Stirring-induced platelet activation

et al. 2016

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High-shear stimulation is well known as one of the key factors affecting platelet activation and aggregation, which can lead to the formation of a thrombus. In one of our previous studies, we introduced migration distance-based platelet function analysis in a microfluidic system. In this study, we set out to examine the effects of stirring on shear-induced platelet activation and aggregation in a chamber system by using a rotating stirrer. We found that the rotating stirrer caused not only rotational shear flow but also a strong radial secondary flow. The latter flow led to efficient mixing in the chamber. Moreover, the rotational flow led to the generation of shear stress, the magnitude of which can be controlled to activate the platelets. Activated platelets tend to aggregate themselves. The maximum platelet aggregation was observed at a critical shear rate of 3100 s−1, regardless of the stirrer shape. Furthermore, the time taken to attain maximum aggregation was significantly shortened when using a wide stirrer (30 s) instead of a narrow one (180 s). When using a flat stirrer, the non-uniform shear field in the chamber system was resolved with the radial secondary flow-induced mixing; thus, most of the platelets were homogenously activated. The stirring-induced platelet activation mechanism was experimentally confirmed in a microfluidic system for a platelet aggregation test while monitoring the migration distance until the microfluidic channel is occluded. Our findings indicate that the present system, consisting of a rotating stirrer and a confined chamber, provides effective shear stimulation for activating platelets and inducing platelet aggregates.

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Platelet Function Tests: Why They Fail to Guide Personalized Antithrombotic Medication

Cited by 20 publications

References 67 publications

Topical diclofenac does not affect the antiplatelet properties of aspirin as compared to the intermediate effects of oral diclofenac: A prospective, randomized, complete crossover study

Topical diclofenac does not affect the antiplatelet properties of aspirin as compared to the intermediate effects of oral diclofenac: A prospective, randomized, complete crossover study

The Metabolism of Clopidogrel: CYP2C19 Is a Minor Pathway

A simple method for activating the platelets used in microfluidic platelet aggregation tests: Stirring-induced platelet activation

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