New direct and indirect methods for the detection of cyclooxygenase 1 acetylation by aspirin; the lack of aspirin resistance among healthy individuals

Kovács, Emese; Katona, Éva; Bereczky, Zsuzsanna; Homoródi, Nóra; Balogh, László; Tóth, Eszter; Péterfy, Hajna; Kiss, Róbert Gábor; Édes, István; Muszbek, László

doi:10.1016/j.thromres.2013.01.033

Cited by 26 publications

(19 citation statements)

References 27 publications

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“…Recently, an assay using the Western blot technique to evaluate AceCOX-1 levels in aspirin-treated individuals has been reported [29]. It allows the obtaining of only a qualitative assessment of protein levels, is characterized by lower sensitivity, specificity and reproducibility, and uses monoclonal antibodies, which are not commercially available.…”

Section: Discussionmentioning

confidence: 99%

Reappraisal of the clinical pharmacology of low‐dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action

Patrignani

Tacconelli

Piazuelo

et al. 2014

Journal of Thrombosis and Haemostasis

102

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Summary. Background: Even though the acetylation of platelet cyclooxygenase (COX)-1 at serine-529 is the direct mechanism of action of low-dose aspirin, its antiplatelet effect has been characterized using indirect indexes of COX-1 activity. Objectives: We performed a clinical study with enteric-coated low-dose aspirin (EC-aspirin), in healthy subjects, to evaluate the effects on the extent and duration of platelet COX-1 acetylation, using a novel proteomic strategy for absolute protein quantification (termed AQUA), as compared with traditional pharmacokinetic and pharmacodynamic parameters. Subjects and methods: In a phase I, single-arm, open-label study of EC aspirin (100 mg day À1 ) administered to 24 healthy subjects, we compared, over a 24 h-period on day 1 and 7, % platelet acetylated COX-1 (AceCOX-1) with traditional pharmacokinetic and pharmacodynamics [i.e. serum thromboxane (TX) B 2 , platelet function by monitoring CEPI(collagen/epinephrine) closure time (CT) using whole-blood PFA-100 and urinary excretion of 11-dehydro-TXB 2 ] parameters. Results: Acetylation of platelet COX-1 was measurable before detection of aspirin levels in the systemic circulation and increased in a cumulative fashion upon repeated dosing. After the last dose of EC-aspirin, %AceCOX-1, serum TXB 2 and CEPI-CT values were maximally and persistently modified throughout 24 h; they averaged 76 AE 2%, 99.0 AE 0.4% and 271 AE 5 s, respectively. EC-aspirin caused 75% reduction in urinary 11-dehydro-TXB 2 excretion. After chronic dosing with aspirin, the pharmacokinetics of acetylsalicylic acid was completely dissociated from pharmacodynamics. Conclusions: The demonstrated feasibility of quantifying the extent and duration of platelet COX-1 acetylation will allow characterizing the genetic, pharmacokinetic and pharmacodynamic determinants of the inter-individual variability in the antiplatelet response to low-dose aspirin as well as identifying extraplatelet sites of drug action.

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Section: Discussionmentioning

confidence: 99%

Reappraisal of the clinical pharmacology of low‐dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action

Patrignani

Tacconelli

Piazuelo

et al. 2014

Journal of Thrombosis and Haemostasis

102

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“…It is detected more commonly in East Asian populations only [13,14]. Another author supports this statement and proposes to use a new method to evaluate the effect of aspirin in vivo by measuring acetylation of COX [17]. Unlike clopidogrel, aspirin is not a pro-drug.…”

Section: Introductionmentioning

confidence: 94%

The role of clinical parameters and of CYP2C19 G681 and CYP4F2 G1347A polymorphisms on platelet reactivity during dual antiplatelet therapy

Tatarūnas¹,

Jankauskienė²,

Kupstytė

et al. 2014

Blood Coagulation &Amp; Fibrinolysis

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Dual antiplatelet therapy with aspirin and clopidogrel is used to lower the risk of arterial thrombosis. However, this strategy is not always successful owing to high interindividual variability in response to antiplatelet therapy. To evaluate an impact of CYP2C19 G681A and CYP4F2 G1347A polymorphisms and clinical factors on dual antiplatelet effect of clopidogrel and aspirin. Totally 89 patients who continued dual aspirin and clopidogrel antiplatelet therapy for at least of 14 days were included into the further study. Test for platelet aggregation was performed according to the classical Born method. Genotyping of CYP2C19*2 and CYP2C19*3 and CYP4F2*3 was done by using commercial probes from Applied Biosystems (UK). Patient age, weight and body weight index did not correlate significantly with platelet aggregation level both induced by ADP and epinephrine (P > 0.05). Serum concentration of creatinine, diabetes, angiotensin II receptor blockers, B-blockers, statin or omeprazole use had no significant effect on platelet aggregation. The users of angiotensin-converting enzyme inhibitors had lower platelet aggregation levels with epinephrine vs. nonusers: 28.80 ± 13.25 vs. 51.15 ± 23.50, P < 0.03, respectively. Platelet aggregation with ADP was higher in CYP2C19*1*2 genotype carriers than in CYP2C19*1*1 carriers (P = 0.01). Platelet aggregation with epinephrine was higher in CYP4F2 GA genotype carriers than in GG (P = 0.04) or AA (P = 0.01) carriers. Our study confirms that CYP2C19 G681A genotype has an impact on antiplatelet effect of clopidogrel. The novelty is that the platelet aggregation after induction with epinephrine is influenced by CYP4F2 G1347A genotype.

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“…The methods utilize two monoclonal antibodies, one of which reacts only with acetylated COX-1, while the other antibody only recognizes the nonacetylated form. 29,30 Although this method is too laborious for a routine laboratory, it is the most specific assay so far available to detect "true" aspirin resistance. As a result, the authors found no patients in whom lowdose aspirin would not acetylate COX-1, reflecting uniform action of aspirin on platelets without any true aspirin-resistant subjects in 108 healthy volunteers.…”

Section: Methods For Platelet Function Testing Aspirinmentioning

confidence: 99%

Platelet Function Testing in Patients on Antiplatelet Medications

Groß

Aradi

Sibbing

2016

Semin Thromb Hemost

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Guidelines provide a Class IA recommendation for the use of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI). However, there is interindividual variability in the pharmacodynamic response to antiplatelet medications. Some patients present with a status of high on-treatment platelet reactivity (HPR) during platelet function testing after standard doses of antiplatelet drugs, reflecting a failure to achieve adequate platelet inhibition. As an example, patients with HPR on clopidogrel are at increased risk for thrombotic events, particularly for stent thrombosis and myocardial infarction, but cardiovascular mortality is also elevated. On the contrary, low on-treatment platelet reactivity or an enhanced response to antiplatelet medications has been linked to a higher risk for bleeding. Although both thrombotic and bleeding events are multifactorial in origin, there is supportive evidence for the prognostic value of platelet function testing for risk prediction of both sides of the coin. However, although small studies have provided evidence that treatment adjustments based on platelet function testing results may improve clinical outcomes, the available randomized controlled trials showed no benefit of modifying antiplatelet treatment based on platelet function testing. This review presents the current evidence regarding platelet function testing in patients undergoing PCI. The prognostic value of platelet function testing regarding ischemic and bleeding events is highlighted. Furthermore, the value of platelet function testing for guiding treatment and possible explanations for the so-far negative trial results are presented. The possible future role of platelet function testing for individualized antiplatelet treatment regimens in high-risk patients will be also discussed.

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New direct and indirect methods for the detection of cyclooxygenase 1 acetylation by aspirin; the lack of aspirin resistance among healthy individuals

Cited by 26 publications

References 27 publications

Reappraisal of the clinical pharmacology of low‐dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action

Reappraisal of the clinical pharmacology of low‐dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action

The role of clinical parameters and of CYP2C19 G681 and CYP4F2 G1347A polymorphisms on platelet reactivity during dual antiplatelet therapy

Platelet Function Testing in Patients on Antiplatelet Medications

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