scholarly journals Genetic Polymorphisms Impact Response to Clopidogrel in Feline Hypertrophic Cardiomyopathy

2021 ◽  
Author(s):  
Yu Ueda ◽  
Ronald Li ◽  
Nghi Nguyen ◽  
Eric Ontiveros ◽  
Samantha Fousse ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Hypertrophic Cardiomyopathy ◽  
Whole Blood ◽  
Plasma Concentrations ◽  
Blood Platelet ◽  
Platelet Inhibition ◽  
Platelet Aggregometry ◽  
Clopidogrel Therapy ◽  
Adp Receptor ◽  
The Impact

Abstract Clopidogrel is converted to its active metabolite by cytochrome P450 isoenzymes and irreversibly inhibits platelet activation by antagonizing the adenosine-diphosphate (ADP) receptor. It is frequently used in cats with hypertrophic cardiomyopathy (HCM) to prevent thromboembolic complications. However, significant interpatient variability of the response to clopidogrel therapy has been suspected. In this study, we assessed the impact of single nucleotide polymorphisms (SNPs) within ADP receptor (P2RY1, P2RY12) and cytochrome P450 isoenzyme (CYP2C41) genes on platelet inhibition by clopidogrel administration in cats with HCM. Forty-nine cats completed the study, and blood samples were obtained before and after clopidogrel therapy to assess the degree of platelet inhibition based on flow cytometry and whole blood platelet aggregometry. Plasma concentrations of clopidogrel metabolites were measured after the last dose of clopidogrel. Whole blood platelet aggregometry revealed a significant reduction of platelet inhibition by clopidogrel in cats with the P2RY1:A236G and the P2RY12:V34I variants. The association with the P2RY1:A236G variant and clopidogrel resistance remained significant after adjustment for multiple comparisons. This study demonstrated that a genetic polymorphism in the P2RY1 gene altered response to clopidogrel therapy and suggests that clinicians may consider alternative or additional thromboprophylactic therapy in cats with the P2RY:A236G variant.

scholarly journals A genetic polymorphism in P2RY1 impacts response to clopidogrel in cats with hypertrophic cardiomyopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu Ueda ◽  
Ronald H. L. Li ◽  
Nghi Nguyen ◽  
Eric S. Ontiveros ◽  
Samantha L. Kovacs ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Genetic Polymorphism ◽  
Hypertrophic Cardiomyopathy ◽  
Whole Blood ◽  
Blood Platelet ◽  
Platelet Inhibition ◽  
Platelet Aggregometry ◽  
Clopidogrel Therapy ◽  
Adp Receptor ◽  
The Impact

AbstractClopidogrel is converted to its active metabolite by cytochrome P450 isoenzymes and irreversibly inhibits platelet activation by antagonizing the adenosine-diphosphate (ADP) receptor. It is frequently used in cats with hypertrophic cardiomyopathy (HCM) to prevent thromboembolic complications. However, significant interpatient variability of the response to clopidogrel therapy has been suspected. In this study, we assessed the impact of single nucleotide polymorphisms (SNPs) within ADP receptor (P2RY1, P2RY12) and cytochrome P450 isoenzyme (CYP2C41) genes on platelet inhibition by clopidogrel administration in cats with HCM. Forty-nine cats completed the study, and blood samples were obtained before and after clopidogrel therapy to assess the degree of platelet inhibition based on flow cytometry and whole blood platelet aggregometry. Plasma concentrations of clopidogrel metabolites were measured after the last dose of clopidogrel. Whole blood platelet aggregometry revealed a significant reduction of platelet inhibition by clopidogrel in cats with the P2RY1:A236G and the P2RY12:V34I variants. The association with the P2RY1:A236G variant and clopidogrel resistance remained significant after adjustment for multiple comparisons. This study demonstrated that a genetic polymorphism in the P2RY1 gene altered response to clopidogrel therapy and suggests that clinicians may consider alternative or additional thromboprophylactic therapy in cats with the P2RY1:A236G variant.

Multiple electrode aggregometry: A new device to measure platelet aggregation in whole blood

2006 ◽  
Vol 96 (12) ◽  
pp. 781-788 ◽  
Author(s):  
Andreas Calatzis ◽  
Sandra Penz ◽  
Hajna Losonczy ◽  
Wolfgang Siess ◽  
Orsolya Tóth
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Blood Platelet ◽  
Platelet Inhibition ◽  
New Device ◽  
Platelet Aggregometry ◽  
Spontaneous Platelet Aggregation ◽  
Induced Aggregation ◽  
Blood Platelet Aggregation ◽  
Multiple Electrode

SummarySeveral methods are used to analyse platelet function in whole blood. A new device to measure whole blood platelet aggregation has been developed, called multiple electrode platelet aggregometry (MEA). Our aim was to evaluate MEA in comparison with the single platelet counting (SPC) method for the measurement of platelet aggregation and platelet inhibition by aspirin or apyrase in diluted whole blood. Platelet aggregation induced by different concentrations of ADP, collagen and TRAP-6 and platelet inhibition by apyrase or aspirin were determined in citrateor hirudin-anticoagulated blood by MEA and SPC. MEA indicated that spontaneous platelet aggregation was lower, and stimulated platelet aggregation was higher in hirudin- than citrate-anticoagulated blood. In hirudin-anticoagulated, but not citrate-anticoagulated blood, spontaneous platelet aggregation measured by MEA was inhibited by apyrase. For MEA compared with SPC the dose response-curves of agonist-induced platelet aggregation in citrate- and hirudin-blood showed similar EC50 values for TRAP, and higher EC50 values for ADP (non-significant) and collagen (p<0.05). MEA and the SPC method gave similar results concerning platelet-inhibition by apyrase and aspirin. MEA was more sensitive than SPC to the inhibitory effect of aspirin in collagen-induced aggregation. In conclusion, MEA is an easy, reproducible and sensitive method for measuring spontaneous and stimulated platelet aggregation, and evaluating antiplatelet drugs in diluted whole blood. The use of hirudin as an anticoagulant is preferable to the use of citrate. MEA is a promising technique for experimental and clinical applications.

scholarly journals Determination of Aspirin Responsiveness by Use of Whole Blood Platelet Aggregometry

2007 ◽  
Vol 53 (4) ◽  
pp. 614-619 ◽  
Author(s):  
Boris T Ivandic ◽  
Evangelos Giannitsis ◽  
Philipp Schlick ◽  
Peter Staritz ◽  
Hugo A Katus ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Whole Blood ◽  
Stable Coronary Artery Disease ◽  
Blood Platelet ◽  
Platelet Inhibition ◽  
Impedance Aggregometry ◽  
Platelet Aggregometry ◽  
Healthy Control ◽  
Artery Disease

Abstract Background: Insufficient platelet inhibition is associated with an increased cardiovascular risk in up to 30% of patients taking regular doses of aspirin. We describe an assay to study aspirin responsiveness. Methods: We performed impedance aggregometry on diluted whole blood with 1 mg/L collagen and 0.5 mmol/L arachidonic acid (AA). We measured thromboxane B2 (TXB2) by RIA. We examined 66 healthy control individuals, 144 aspirin users with stable coronary artery disease (CAD), and 245 CAD patients treated with aspirin and clopidogrel. Nonresponsive samples were incubated with excess dl-lysinmonoacetylsalicylic acid. Results: Assay imprecision (CV) was 9.8% and 8.2% at mean (SD) 6-min impedance of 13.7 (2.8) Ω and 13.6 (2.3) Ω for collagen and AA, respectively. Collagen induced stronger aggregation (P = 0.0199) in women [n = 28, 14.6 (2.4) Ω] than in men [n = 38, 13.1 (2.9) Ω], even after sample incubation with 0.1 mmol/L acetylsalicylic acid (ASA) or 1 μmol/L terbogrel, a combined inhibitor of thromboxane synthase and receptors. The sex association persisted in aspirin users, but not if clopidogrel was also taken. A 6-min impedance &gt;8 Ω with collagen (mean − 2 SD of the controls) was taken as evidence of nonresponsiveness, particularly if incubation with ASA did not inhibit aggregation further (&gt;2 Ω). Compared with AA, collagen identified more nonresponsive samples among aspirin users (15%) and CAD patients who also received clopidogrel (10%). Incubation with ASA improved inhibition of aggregation in 70% of samples and consistently reduced TXB2 formation during aggregation. Conclusions: Impedance aggregometry may prove useful to study aspirin responsiveness, and incubation with ASA may help to identify nonresponders and classify resistance.

Effect of Dipyridamole on Spontaneous Platelet Aggregation in Whole Blood Decreases with the Time After Venepuncture: Evidence for the Role of ADP

1987 ◽  
Vol 58 (02) ◽  
pp. 744-748 ◽  
Author(s):  
A R Saniabadi ◽  
G D O Lowe ◽  
J C Barbenel ◽  
C D Forbes
Keyword(s):  
Platelet Aggregation ◽  
Correlation Coefficient ◽  
Whole Blood ◽  
Blood Platelet ◽  
Inhibitory Effect ◽  
Time Interval ◽  
Adp Receptor ◽  
Spontaneous Platelet Aggregation

SummarySpontaneous platelet aggregation (SPA) was studied in human whole blood at 3, 5, 10, 20, 30, 40 and 60 minutes after venepuncture. Using a whole blood platelet counter, SPA was quantified by measuring the fall in single platelet count upon rollermixing aliquots of citrated blood at 37° C. The extent of SPA increased with the time after venepuncture, with a correlation coefficient of 0.819. The inhibitory effect of dipyridamole (Dipy) on SPA was studied: (a) 10 μM at each time interval; (b) 0.5-100 μM at 3 and 30 minutes and (c) 15 μM in combination with 100 μM adenosine, 8 μM 2-chloroadenosine (2ClAd, an ADP receptor blocker) and 50 μM aspirin. There was a rapid decrease in the inhibitory effect of Dipy with the time after venepuncture; the correlation coefficient was -0.533. At all the concentrations studied, Dipy was more effective at 3 minutes than at 30 minutes after venepuncture. A combination of Dipy with adenosine, 2ClAd or aspirin was a more effective inhibitor of SPA than either drug alone. However, when 15 μM Dipy and 10 μM Ad were added together, the inhibitory effect of Dipy was not increased significantly, suggesting that Dipy inhibits platelet aggregation independent of Ad. The increase in SPA with the time after venepuncture was abolished when blood was taken directly into the anticoagulant containing 5 μM 2ClAd. It is suggested that ADP released from the red blood cells is responsible for the increased platelet aggregability with the time after venepuncture and makes a serious contribution to the artifacts of in vitro platelet function studies.

Comparison of methods to evaluate clopidogrel-mediated platelet inhibition after percutaneous intervention with stent implantation

2009 ◽  
Vol 101 (02) ◽  
pp. 333-339 ◽  
Author(s):  
Sabine Steiner ◽  
Daniela Seidinger ◽  
Renate Koppensteiner ◽  
Thomas Gremmel ◽  
Simon Panzer ◽  
...  
Keyword(s):  
Stent Implantation ◽  
Light Transmission ◽  
Platelet Reactivity ◽  
Platelet Inhibition ◽  
Percutaneous Intervention ◽  
Adverse Outcomes ◽  
Gold Standard Method ◽  
Platelet Aggregometry ◽  
Increased Risk ◽  
The Impact

SummaryA high on-treatment residual ADP-inducible platelet reactivity in light transmission aggregometry (LTA) has been associated with an increased risk of adverse outcomes after percutaneous coronary intervention (PCI). However, LTA is weakly standardized, and results obtained in one laboratory may not be comparable to those obtained in another one. We therefore sought to determine the test correlating best with LTA to estimate clopidogrel-mediated platelet inhibition in 80 patients on dual antiplatelet therapy after elective percutaneous intervention with stent implantation. We selected the VerifyNow P2Y12 assay, the vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode platelet aggregometry and the Impact-R for comparisons with LTA. Cut-off values for residual ADP-inducible platelet reactivity were defined according to quartiles of each assay. Sensitivities and specificities of the different platelet function tests were based on the results from LTA. The results from all four assays correlated significantly with those from LTA. The VerifyNow P2Y12 assay revealed the strongest correlation (r = 0.61, p < 0.001). Sensitivities and specificities ranged from 35% to 55%, and from 78.3% to 85%, respectively. In conclusion, although all assays correlated significantly with LTA, they need to be improved to become clinically used diagnostic tests. Further, it may be too early to define the gold standard method for assessing residual ADP-inducible platelet reactivity and generally acceptable cut-off values.

scholarly journals Determination of Clopidogrel Resistance by Whole Blood Platelet Aggregometry and Inhibitors of the P2Y12 Receptor

2006 ◽  
Vol 52 (3) ◽  
pp. 383-388 ◽  
Author(s):  
Boris T Ivandic ◽  
Philipp Schlick ◽  
Peter Staritz ◽  
Kerstin Kurz ◽  
Hugo A Katus ◽  
...  
Keyword(s):  
Whole Blood ◽  
Adenosine Monophosphate ◽  
Blood Platelet ◽  
P2y12 Receptor ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Clopidogrel Resistance ◽  
Impedance Aggregometry ◽  
Platelet Aggregometry ◽  
Increased Risk

Abstract Background: Inhibition of platelet aggregation by clopidogrel may be insufficient in up to 30% of users. These nonresponders carry an increased risk of cardiovascular events. We reported here a simple assay to study clopidogrel responsiveness. Methods: Electrical impedance aggregometry was performed in diluted whole blood in the presence of 5 and 20 μmol/L ADP. Some samples were incubated with 0.1 mmol/L methyl-S-adenosine monophosphate (MeSAMP), a P2Y12 receptor blocker, to maximize inhibition of aggregation before aggregometry. To validate the assay, we analyzed 6-min impedance in 21 healthy probands and 244 patients with coronary artery disease (CAD). Results: At 5 μmol/L ADP, the imprecision of the assay was 11%. Mean (SD) impedance of the healthy cohort was 12.2 (2.2) Ω. The mean − 3 SD was used to define the cutoff for clopidogrel responsiveness: responders and nonresponders exhibited a 6-min impedance ≤5 Ω and &gt;5 Ω, respectively. Samples from nonresponders were incubated with MeSAMP and analyzed again to distinguish pharmacokinetic and pharmacodynamic types of resistance. Sixteen percent of CAD patients were classified as nonresponders (38 and 2 cases of pharmacokinetic and pharmacodynamic resistance, respectively). Female sex was strongly associated with clopidogrel resistance (P = 0.0002, Fisher exact test). A higher clopidogrel loading dose (P = 0.0353, Mann–Whitney U-test) was given to responders (median, 450 mg) than nonresponders (median, 300 mg). Age and cardiovascular diagnosis showed no significant associations. Conclusions: Impedance aggregometry using 5 μmol/L ADP is a useful tool for studying clopidogrel responsiveness. MeSAMP allows characterization of responsiveness “on treatment” and may be useful for optimizing clopidogrel dosing.

scholarly journals An introduction to point-of-care testing in extracorporeal circulation and LVADs

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 516-521 ◽  
Author(s):  
Rachel Sara Bercovitz
Keyword(s):  
Whole Blood ◽  
Point Of Care ◽  
Blood Platelet ◽  
Ventricular Assist Devices ◽  
Bleeding Complications ◽  
Future Research ◽  
Ventricular Assist ◽  
Assist Devices ◽  
Platelet Aggregometry ◽  
Coagulation Tests

Abstract There is a delicate balance between bleeding and clotting in patients on circuits such as ventricular assist devices or extracorporeal membrane oxygenation. Traditional coagulation tests, prothrombin time, activated partial thromboplastin time, and anti-factor Xa levels, are used to monitor patients on these devices. However, turnaround times and inability to assess global hemostasis, including platelets and fibrinogen have contributed to a recognition that faster, accurate, and more informative coagulation tests are needed. Activated clotting time is used to monitor heparin in patients on circuits and has the advantages of being a near-patient point-of-care test. However, its utility is limited to heparin monitoring. Viscoelastic tests (thromboelastometry and thromboelastography) are global, whole-blood coagulation tests, and whole-blood platelet aggregometry evaluates platelet function. Ideally, these tests can ensure that patients are within the therapeutic range of their antithrombotic medications, identify patients at risk for hemorrhagic or thrombotic complications, and guide management of acute bleeding complications. This ideal is currently hampered by a lack of studies that delineate clear ranges that are clinically relevant. Future research is needed to better understand the optimal use of point-of-care coagulation testing in patients on extracorporeal circuits and ventricular assist devices.

Sign in / Sign up

Export Citation Format

Share Document