ADP-induced Platelet Reactivity Research Articles

Platelet microRNAs as Potential Novel Biomarkers for Antiplatelet Therapy with P2Y12 Inhibitors and Their Association with Platelet Function.

Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) require dual antiplatelet therapy (DAPT). However, the response to treatment can vary considerably. Certain platelet microRNAs (miRs) are suspected to predict DAPT response and influence platelet function. This study aimed to analyze selected miRs' expressions and compare them among patients treated with different P2Y12 inhibitors while assessing their association with platelet activity and turnover parameters. We recruited 79 ACS patients post-PCI treated with clopidogrel, ticagrelor, or prasugrel, along with 18 healthy volunteers. Expression levels of miR-126-3p, miR223-3p, miR-21-5p, miR-197-3p, and miR-24-3p, as well as immature platelet fraction (IPF) and ADP-induced platelet reactivity, were measured and compared between groups. Analyses revealed significantly lower expressions of miR-126-3p, miR-223-3p, miR-21-5p, and miR-197-3p in patients treated with ticagrelor, compared to clopidogrel (fold changes from -1.43 to -1.27, p-values from 0.028 to 0.048). Positive correlations were observed between platelet function and the expressions of miR-223-3p (r = 0.400, p = 0.019) and miR-21-5p (r = 0.423, p = 0.013) in patients treated with potent drugs. Additionally, miR-24-3p (r = 0.411, p = 0.012) and miR-197-3p (r = 0.333, p = 0.044) showed correlations with IPF. The identified platelet miRs hold potential as biomarkers for antiplatelet therapy. (ClinicalTrials.gov number, NCT06177587).

Elevated serum C1q is an independent predictor of high residual platelet reactivity in CAD patients receiving clopidogrel therapy.

BackgroundInflammation increases the risk of thrombosis in coronary artery disease (CAD) patients and affects the antiplatelet efficacy of clopidogrel. C1q interacts with platelets to activate platelets and induce thrombosis by participating in and regulating the inflammatory response. Whether C1q affects adenosine diphosphate (ADP)-induced platelet reactivity during clopidogrel therapy was unclear and our study aimed to explore the issue.MethodWe enrolled 1,334 CAD patients receiving clopidogrel therapy and evaluated the association between C1q level and high residual platelet reactivity (HRPR) using logistic regression and restricted cubic spline (RCS). HRPR was defined as ADP-induced maximum amplitude (MAADP) > 47 mm plus ADP-induced platelet aggregation (ADPi) < 50%.ResultsA total of 516 patients (38.7%) performed HRPR. The frequency of HRPR increases with the increase in C1q level (26.3%, 38.4%, 43.2%, and 46.7% for the 1st to 4th quartile of C1q). The result of multivariate logistic regression demonstrated elevated C1q as an independent predictor for HRPR (2nd quartile: OR = 1.722, 95% CI 1.215–2.440; 3rd quartile: OR = 2.015, 95% CI 1.413–2.874; 4th quartile: OR = 2.362, 95% CI 1.631–3.421, compared to the 1st quartile). RCS depicted the nonlinear relationship between C1q and HRPR risk (p for non-linear < 0.05).ConclusionThe current research is the first to explore the association of C1q and ADP-induced platelet reactivity and to demonstrate elevated C1q as an independent risk factor for HRPR in CAD patients during clopidogrel therapy.

The amino acid content in the daily diet of seniors negatively correlates with the degree of platelet aggregation in a sex- and agonist-specific manner.

Aging is a significant risk factor for the development of thrombotic diseases, dependent on blood platelet reactivity. However, the risk of thrombosis also appears to be significantly modulated by dietary nutrient content.The aim of the current study was to assess the relationship between the amount of amino acids present in the daily diet (not supplemented) and the reactivity of blood platelets to arachidonate, collagen and ADP in 246 women and men aged 60–65 years.Platelet reactivity was tested using whole blood impedance aggregometry. Amino acid intake was assessed with a 24-hour Recall Questionnaire and calculated with Dieta 5.0 software.Older subjects receiving higher amounts of all essential amino acids with their daily diet exhibit significantly lower platelet responsiveness to AA-, COL- and ADP in a sex-specific manner: dietary amino acid content was more closely associated with AA- and, to some extent, ADP-induced platelet reactivity in women, and with COL-induced platelet aggregability in men. Therefore, dietary amino acid content may be a novel factor responsible for attenuating platelet reactivity in a sex- and agonist-specific manner.

High concentration of symmetric dimethylarginine is associated with low platelet reactivity and increased bleeding risk in patients with acute coronary syndrome

BackgroundDual antiplatelet therapy (DAPT) prevents ischemic events in patients with acute coronary syndrome (ACS), but is associated with increased risk of bleeding events. Symmetric dimethylarginine (SDMA) is one of nitric oxide (NO)-related pathway metabolites and stands as a promising biomarker of early chronic kidney disease (CKD) and cardiovascular diseases (CVDs). ObjectivesOur study evaluated the role of SDMA in predicting bleeding events in patients after ACS treated with DAPT. MethodsWe compared plasma concentrations of NO-related pathway metabolites in patients with ACS (n = 291) and investigated the prognostic value of SDMA as a bleeding predictor during 1-year follow-up. We measured the metabolites concentration using ultra performance liquid chromatography. Platelet reactivity was determined using impedance aggregometry. ResultsPatients with the highest quartile (4th) of SDMA concentration had significantly lower platelet aggregation compared to those in the 1st-3rd quartiles of SDMA, based on ADP + PGE1-, AA-, and ADP-induced platelet reactivity tests (p = 0.0004, p = 0.002, p = 0.014, respectively). Patients with major or minor bleeding events had significantly higher concentrations of SDMA as compared to those without bleeding events or to those with minimal bleeding events (p = 0.019, p = 0.019, respectively). ConclusionHigher SDMA concentration is associated with lower platelet reactivity and is associated with major and minor bleeding events in patients with ACS on DAPT. Therefore, SDMA stands as a potential biomarker for individualization of duration and potency of antiplatelet therapies in the ACS population at high risk of bleeding complications.

Comparative analysis of hemostasis system state indicators in severe COVID-19

Introduction. Clinical experience in managing patients with a new coronavirus infection caused by the SARS-CoV-2 allowed to identify specific hemostasis disorders, and enables to introduce the concept of COVID-associated coagulopathy. The aim of the study was to assess the direction of coagulogram parameter changes, whole blood clotting parameters and characteristics of platelet and plasma hemostasis in patients with severe COVID-19. Materials and methods. The parameters of the hemostasis system were assessed using venous blood of 12 patients with severe COVID-19 and 16 healthy volunteers. The whole blood clotting process was investigated by low-frequency piezothromboelastography. The platelet count and indicators of spontaneous and ADP-induced platelet aggregation were estimated with the help of a laser platelet aggregation analyzer. Fibrinolytic activity of plasma, plasminogen activity, content of fibrinogen, D-dimer, PTT, APTT, PTI and INR were assessed. Results. An increased level of fibrinogen, a 6-fold increased D-dimer level, and increased PTT were found in patients with severe COVID-19. The patient platelets count was reduced by 51 % (p &lt;0.05), spontaneous platelet aggregation remained at nearly normal level. Almost complete inhibition of ADP-induced platelet reactivity and inhibition of XIIa-dependent fibrinolysis was revealed, despite an increased by 19.3 % (p &lt;0.05) plasminogen activity. Parameters of the whole blood coagulation process pointed a pronounced activation of platelet hemostasis, a significant intensification of the polymerization stage of clot formation and an increased intensity of clot lysis and retraction. Conclusion. The significant increase of D-dimer level and paradoxical inhibition of plasma fibrinolytic activity revealed by test of XIIa-dependent fibrinolysis (in contrast to the increased intensity of clot lysis when assessing the coagulation of whole blood) indicate the complex pathogenic mechanisms of coagulopathy caused by SARS-CoV-2 infection, and the involvement of blood cells and the vascular wall in the process of pathological thrombus formation.

Abstract 11338: On-Clopidogrel Platelet Reactivity in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention and Association with Patient Characteristics

Introduction: On-clopidogrel platelet reactivity (PR) is associated with thrombotic and bleeding risk in patients undergoing percutaneous coronary intervention (PCI). Patient-related factors affect the level of PR. Patients with atrial fibrillation (AF) undergoing PCI are treated concomitantly with oral anticoagulants (OAC) potentially interacting with platelet function. This study aimed to investigate the association of PR with demographic and clinical characteristics in these patients. Methods: In this single-centre prospective observational cohort study, patients with AF with an indication for OAC were enrolled during hospitalization after PCI with clopidogrel. TRAP- and ADP- induced PR (TRAP 32 μM, ADP 6.4 μM) were assessed by multiple electrode aggregometry. ADP-induced PR was normalized to TRAP-induced PR (r-ADP-agg). Results: 159 patients were enrolled between May 2020 and May 2021. The median age was 78 years (interquartile range, IQR 72-82), 112 (70%) were male and 39 (25%) presented with ACS. 68 (43%) presented with chronic kidney disease (CKD), defined as GFR&lt;60. 54 (34%) patients received apixaban, 6 (4%) dabigatran, 18 (11%) edoxaban, 74 (47%) rivaroxaban and 4 (3%) marcumar. 128 (81%) patients received clopidogrel loading. Median ADP-induced PR was 12 U (IQR 6-17); median r-ADP-agg was 24% (IQR 14-39). ADP-induced PA is significantly correlated with age (r=-0.22; p=0.035) and platelet count (r=0.22; p=0.006). Compared to the patients without CKD,patients with CKD had a significantly lower ADP-induced PA (median 8 [IQR 10] vs. median 13 [IQR 10]; p&lt;0.001) and r-ADP-agg. (median 20 [IQR 25] vs median 28 [IQR 24]; p=0.003).In a multivariable linear regression, ADP-induced PR was significantly associated with age (r=-0.177, CI:-0.481 to -0.018, p=0.035), immature platelet count (r=0.178, CI: 0.003 to 0.729, p=0.048), and diabetes mellitus (r=0.21, CI: 1.192 to 9.087, p=0.011). CKD was associated with both: lower ADP-PR (r=-0.262, CI:-9.962 to -2.396, p=-0.002) and lower r-ADP-agg (r=-0.253, CI:-9.962 to -2.396, p=0.003). Conclusions: In this patient cohort the association of on-clopidogrel PR as assessed by multiple electrode aggregometry with patient related factors was weak and most pronounced for chronic kidney disease.

ADP-induced platelet reactivity and bleeding events in patients with acute myocardial infarction complicated by cardiogenic shock

While previous reports showed ADP-induced platelet reactivity to be an independent predictor of bleeding after PCI in stable patients, this has never been investigated in patients with cardiogenic shock. The association of bleeding events with respect to ADP-induced platelet aggregation was investigated in patients undergoing primary PCI for acute myocardial infarction complicated by cardiogenic shock and with available on-treatment ADP-induced platelet aggregation measurements. Out of 233 patients, 74 suffered from a severe BARC3 or higher bleed. ADP-induced platelet aggregation was significantly lower in patients with BARC≥3 bleedings (p < .001). Multivariate analysis identified on-treatment ADP-induced platelet aggregation as an independent risk factor for bleeding (HR = 0.968 per AU). An optimal cutoff value of <12 AU for ADP-induced platelet aggregation to predict BARC≥3 bleedings was identified via ROC analysis. Moreover, the use of VA-ECMO (HR 1.972) or coaxial left ventricular pump (HR 2.593), first lactate (HR 1.093 per mmol/l) and thrombocyte count (HR 0.994 per G/l) were independent predictors of BARC≥3 bleedings. In conclusion, lower on-treatment ADP-induced platelet aggregation was independently associated with severe bleeding events in patients with AMI-CS. The value of platelet function testing for bleeding risk prediction and guidance of anti-thrombotic treatment in cardiogenic shock warrants further investigation.

ADP-induced platelet reactivity and bleeding events in patients with acute myocardial infarction complicated by cardiogenic shock

Abstract Funding Acknowledgements Type of funding sources: None. Background While previous reports showed ADP-induced platelet reactivity to be an independent predictor of bleeding after PCI in stable patients, this has never been investigated in patients with cardiogenic shock (CS). Methods The association of bleeding events with respect to ADP-induced platelet aggregation was investigated in patients undergoing primary PCI for acute myocardial infarction complicated by cardiogenic shock (AMI-CS) and with available on-treatment ADP-induced platelet aggregation measurements. Results Out of 233 patients, 74 suffered from a severe BARC 3 or higher bleed. ADP-induced platelet aggregation was significantly lower in patients with BARC≥3 bleedings (10 AU [IQR 3 - 13] vs. 15 AU [IQR 9 - 25], p &amp;lt; 0.001). Multivariate analysis identified on-treatment ADP-induced platelet aggregation as an independent risk factor for bleeding (HR = 0.968 per AU, 95% confidence interval (CI) 0.942-0.994). An optimal cut-off value of &amp;lt;12 AU for ADP-induced platelet aggregation to predict BARC≥3 bleedings was identified via ROC analysis. Moreover, use of VA-ECMO (HR 1.972, 95% CI 1.003-3.879) or coaxial left ventricular pump (HR 2.593, 95% CI 1.509-4.455), first lactate (HR 1.093 per mmol/l, 95% CI 1.037-1.152) and thrombocyte count (HR 0.994 per G/l, 95% CI 0.990-0.998) were independent predictors of BARC≥3 bleedings. There was no significant difference in survival nor ischemic events between patients with low and high on-treatment platelet reactivity. Conclusion: Lower on-treatment ADP-induced platelet aggregation was independently associated with severe bleeding events in patients with AMI-CS. The value of platelet function testing for bleeding risk prediction and guidance of anti-thrombotic treatment in CS warrants further investigation.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Acute Coronary Syndrome: Implications for Platelet Reactivity?

BackgroundIn patients with acute coronary syndrome (ACS), angiotensin-converting enzyme (ACE) inhibitors are preferred over angiotensin receptor blockers (ARBs). However, in a recent pilot study, treatment with ACE inhibitors was associated with increased platelet reactivity compared to ARBs. Therefore, we sought to investigate the impact of renin-angiotensin-aldosterone system (RAAS) blockade with ACE inhibitors and ARBs on platelet aggregation in patients with ACS undergoing percutaneous coronary intervention.MethodsOn-treatment residual platelet reactivity in response to arachidonic acid (AA), adenosine diphosphate (ADP), SFLLRN, AYPGKF, and collagen was assessed by multiple electrode aggregometry (MEA) in 197 ACS patients on dual antiplatelet therapy (DAPT) with aspirin and either prasugrel or ticagrelor.ResultsOne hundred sixty-five (83.7%) patients were treated with ACE inhibitors, 32 (16.3%) with ARBs. On-treatment residual AA- and ADP-inducible platelet reactivity was significantly higher in patients with ACE inhibitors (both p < 0.05). Likewise, SFLLRN was significantly higher in patients with ACE inhibitors (p = 0.036) and there was a trend for higher AYPGKF- and collagen-inducible platelet reactivity (p = 0.053 and p = 0.082). The incidence of high on-treatment residual platelet reactivity AA was significantly higher in patients with ACE inhibitors (52 [31.5%] vs. 3 [9.4%] patients; p = 0.019).ConclusionACE inhibitors are associated with increased on-treatment residual platelet reactivity in ACS patients with potent DAPT. Further clinical trials are needed to elucidate the role of RAAS blockade with ACE inhibitors and ARBs in ACS patients treated according to current standards.

Comparison of Light Transmission Aggregometry With Impedance Aggregometry in Patients on Potent P2Y12 Inhibitors.

Since data on the agreement between light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) in patients on the more potent P2Y12 inhibitors are missing so far, we investigated if the evaluation of the responsiveness to therapy by LTA can be replaced by MEA in 160 acute coronary syndrome (ACS) patients on dual antiplatelet therapy with aspirin and prasugrel or ticagrelor (n = 80 each). Cut-off values for high on-treatment residual platelet reactivity (HRPR) in response to adenosine diphosphate (ADP) or arachidonic acid (AA) were defined according to previous studies showing an association of HRPR with the occurrence of adverse ischemic outcomes. ADP- inducible platelet aggregation was 33% and 37% (P = 0.07) by LTA and 19 AU and 20 AU (P = 0.38) by MEA in prasugrel- and ticagrelor-treated patients, respectively. AA- inducible platelet aggregation was 2% and 3% by LTA and 15 AU and 16 AU by MEA, (all P ≥ 0.3) in patients on prasugrel and ticagrelor, respectively. By LTA, HRPR ADP and HRPR AA were seen in 5%/5% and in 4%/ 13% of patients receiving prasugrel- and ticagrelor, respectively. By MEA, HRPR ADP and HRPR AA were seen in 3%/ 25% and 0%/24% of prasugrel- and ticagrelor-treated patients, respectively. ADP-inducible platelet reactivity by MEA correlated significantly with LTA ADP in prasugrel-treated patients (r = 0.4, P < 0.001), but not in those receiving ticagrelor (r = 0.09, P = 0.45). AA-inducible platelet aggregation by LTA and MEA did not correlate in prasugrel- and ticagrelor-treated patients. Sensitivity/specificity of HRPR by MEA to detect HRPR by LTA were 25%/99% for MEA ADP and 100%/79% for MEA AA in prasugrel-treated patients, and 0%/100% for MEA ADP and 70%/83% for MEA AA in ticagrelor-treated patients. In conclusion, on-treatment residual ADP-inducible platelet reactivity by LTA and MEA shows a significant correlation in prasugrel- but not ticagrelor-treated patients. However, in both groups LTA and MEA revealed heterogeneous results regarding the classification of patients as responders or non-responders to P2Y12 inhibition.

Relation of High Lipoprotein(a) Concentrations to Platelet Reactivity in Individuals with and Without Coronary Artery Disease.

IntroductionLipoprotein (a) [Lp(a)] is a risk factor for coronary artery disease (CAD). To the best of our knowledge, this is the first study addressing the relationship between Lp(a) and platelet reactivity in primary and secondary prevention.MethodsLp(a) was evaluated in 396 individuals with (82.3%) and without (17.7%) obstructive CAD. The population was divided into two groups according to Lp(a) concentrations with a cutoff value of 50 mg/dL. The primary objective was to evaluate the association between Lp(a) and adenosine diphosphate (ADP)-induced platelet reactivity using the VerifyNow™ P2Y12 assay. Platelet reactivity was also induced by arachidonic acid and collagen–epinephrine (C-EPI) and assessed by Multiplate™, platelet function analyzer™ 100 (PFA-100), and light transmission aggregometry (LTA) assays. Secondary objectives included the assessment of the primary endpoint in individuals with or without CAD.ResultsOverall, 294 (74.2%) individuals had Lp(a) < 50 mg/dL [median (IQR) 13.2 (5.8–27.9) mg/dL] and 102 (25.8%) had Lp(a) ≥ 50 mg/dL [82.5 (67.6–114.5) mg/dL], P < 0.001. Univariate analysis in the entire population revealed no differences in ADP-induced platelet reactivity between individuals with Lp(a) ≥ 50 mg/dL (249.4 ± 43.8 PRU) versus Lp(a) < 50 mg/dL (243.1 ± 52.2 PRU), P = 0.277. Similar findings were present in individuals with (P = 0.228) and without (P = 0.669) CAD, and regardless of the agonist used or method of analysis (all P > 0.05). Finally, multivariable analysis did not show a significant association between ADP-induced platelet reactivity and Lp(a) ≥ 50 mg/dL [adjusted OR = 1.00 [(95% CI 0.99–1.01), P = 0.590].ConclusionIn individuals with or without CAD, Lp(a) ≥ 50 mg/dL was not associated with higher platelet reactivity.Electronic supplementary materialThe online version of this article (10.1007/s12325-020-01483-y) contains supplementary material, which is available to authorized users.

Decreased Platelet Inhibition by Thienopyridines in Hyperuricemia

PurposeHyperuricemia carries an increased risk of atherothrombotic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). This may at least in part be due to inadequate P2Y12 inhibition. The aim of this study was to prospectively investigate the potential association between hyperuricemia and decreased platelet inhibition by P2Y12 antagonists.MethodsLevels of uric acid as well as on-treatment residual platelet reactivity in response to adenosine diphosphate (ADP) were assessed in 301 clopidogrel-treated patients undergoing elective angioplasty and stenting, and in 206 prasugrel- (n = 118) or ticagrelor-treated (n = 88) ACS patients following acute PCI. Cut-off values for high on-treatment residual ADP-inducible platelet reactivity (HRPR) were based on previous studies showing an association of test results with clinical outcomes.ResultsHyperuricemia was significantly associated with increased on-treatment residual ADP-inducible platelet reactivity in clopidogrel- and prasugrel-treated patients in univariate analyses and after adjustment for differences in patient characteristics by multivariate regression analyses. In contrast, ticagrelor-treated patients without and with hyperuricemia showed similar levels of on-treatment residual platelet reactivity to ADP. HRPR occurred more frequently in clopidogrel- and prasugrel-treated patients with hyperuricemia than in those with normal uric acid levels. In contrast, hyperuricemic patients receiving ticagrelor did not have a higher risk of HRPR compared with those with normal uric acid levels.ConclusionHyperuricemia is associated with decreased platelet inhibition by thienopyridines but a normal response to ticagrelor. It remains to be established if lowering uric acid increases the antiplatelet effects of clopidogrel and prasugrel in hyperuricemic patients with HRPR.

MRP4 over-expression has a role on both reducing nitric oxide-dependent antiplatelet effect and enhancing ADP induced platelet activation

The impact of inhibition of multidrug resistance protein 4 (MRP4) on nitric oxide (NO) resistance and on ADP-induced platelet aggregation is unknown. The aim of this investigation was to verify whether platelet NO resistance correlates with MRP4 expression and evaluate whether this can be reduced by in vitro MRP4 inhibition mediated by cilostazol. Moreover, we assessed if inhibition of MRP4-mediated transport reduces ADP-induced platelet reactivity. The inhibitory effect of sodium nitroprusside (SNP), a NO-donor that enhances cyclic guanosine monophosphate (cGMP) cytosolic concentration, was assessed in platelets obtained from aspirin treated patients and in a control population. The inhibitory effect of SNP was evaluated by ADP-induced aggregation in SNP-treated platelets. The impact of MRP4 on ADP-induced platelet aggregation was performed in high on aspirin residual platelet reactivity (HARPR) patients and compared to healthy volunteers (HV), and a control cohort (CTR). In aspirin-treated patients with high levels of MRP4, reduced SNP inhibition was found compared to those with low levels of MRP4. MRP4 inhibition by cilostazol significantly reduced ADP-induced platelet aggregation in HARPR population, and to a lesser extent in HV and CTR populations. In conclusion, cilostazol can mitigate the hyper-reactive platelet phenotype of HARPR patients by reducing residual ADP-induced platelet aggregation and increasing NO-dependent endothelial antiplatelet effects.

Mean Corpuscular Volume Predicts Adverse Outcomes Following Peripheral Angioplasty With Stenting and Is Associated With On-Treatment Platelet Reactivity.

Structural aspects of red blood cells have been associated with cardiovascular disease. No data linking mean corpuscular volume (MCV) to clinical outcomes and on-treatment platelet reactivity in patients with peripheral artery disease (PAD) are available. We investigated a composite of atherothrombotic events and target vessel restenosis or reocclusion following infrainguinal stenting for stable PAD. Residual platelet reactivity was measured by light transmission aggregometry (LTA) and the VerifyNow assays. We included 104 patients receiving dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. In receiver-operating characteristic analysis, MCV effectively discriminated between patients with and without adverse outcomes and identified a MCV ≤90.8 fL as optimal cutoff. Adverse outcomes occurred significantly more often in patients with low MCV (log-rank P = .002). In univariable Cox regression analysis, low MCV was associated with an increased risk of future adverse outcomes (hazard ratio [HR]: 2.662 [95%CI: 1.304-5.434]; P = .007) and remained significantly associated after adjustment (HR: 2.591 [95%CI: 1.242-5.403]; P = .011). Mean corpuscular volume was inversely correlated with arachidonic acid (AA)- and adenosine diphosphate (ADP)-inducible platelet reactivity by LTA and with the VerifyNow aspirin assay. Low MCV is associated with adverse outcomes over 2 years following infrainguinal stenting. Mean corpuscular volume correlates inversely with AA- and ADP-inducible platelet reactivity during DAPT.

CYP2C19 and CYP3A4 activity and ADP-induced platelet reactivity in prasugrel- or ticagrelor-treated STEMI patients: monocentric study in PRAGUE-18 trial participants

We assessed the contribution of CYP2C19 and CYP3A4 metabolic activity to the ADP-induced platelet aggregation 1h and 24h after a loading dose of 60 mg prasugrel or 180 mg ticagrelor in patients with ST-elevation myocardial infarction (STEMI). Further, we assessed the contribution of CYP2C19 polymorphisms and medication to the CYP enzymatic activity.Patients with STEMI were randomly assigned to the treatment with prasugrel (n = 51) or ticagrelor (n = 46). Metabolic activity of CYP2C19 and CYP3A4 was assessed by the rate of 5-hydroxylation and sulfoxidation of lansoprazole. Further, patients were genotyped for CYP2C19 *2 and *17 alleles.In prasugrel-treated patients, high ADP-induced platelet reactivity 1h after the loading dose positively correlated with 5OH-lansoprazole/lansoprazole ratio (r = 0.44, p = 0.002), a marker of CYP2C19 metabolic activity, and negatively with lansoprazole-sulfone/lansoprazole ratio, which reflects CYP3A4 metabolic activity (r = −0.35, p = 0.018).CYP2C19 poor metabolizers had lower 5OH-lansoprazole/lansoprazole ratio and higher lansoprazole-sulfone/lansoprazole ratio, but without any effect on the ADP-induced platelet reactivity. The treatment with amiodarone, a CYP3A4 inhibitor, influenced neither the metabolic ratios nor the ADP-induced platelet reactivity.The CYP3A4 and CYP2C19 metabolic activity is associated with ADP-induced platelet reactivity in prasugrel-treated, but not ticagrelor-treated patients with STEMI.

Pretreatment with ticagrelor may offset additional inhibition of platelet and coagulation activation with bivalirudin compared to heparin during primary percutaneous coronary intervention

BackgroundIt remains unknown if bivalirudin compared to heparin confers any additional inhibition of platelet and coagulation activation during primary percutaneous coronary intervention (PPCI) after pretreatment with ticagrelor. MethodsIn this substudy of VALIDATE-SWEDEHEART trial, 103 patients pretreated with ticagrelor were randomized before PPCI to heparin or bivalirudin. Blood samples were collected before and 1 and 12 h after PPCI. We measured platelet reactivity (PR) using Multiplate, soluble P-selectin, thrombin-antithrombin complexes (TAT) and prothrombin fragments 1 + 2 (F1 + 2) as markers of platelet and coagulation activation. ResultsThe median (IQR) time from ticagrelor administration to randomization was 63 (29) vs 60 (24) minutes, p = 0.28. ADP-induced PR did not significantly differ between groups over time (heparin vs bivalirudin, AUC 73 (62) vs 74 (68), p = 0.74, 32 (42) vs 43 (51), p = 0.38, 15 (15) vs 19 (15), p = 0.29, before, 1 and 12 h after PPCI). Soluble P-selectin did not significantly differ between groups. At 1 h TAT significantly increased with bivalirudin (3.0 (1.3) to 4.3 (4.2) ug/L; p < 0.01), but not with UFH (3.1 (2.1) to 3.5 (1.6) ug/L, p = 0.24). F1 + 2 increased in both groups but the rise was numerically higher with bivalirudin (170 (85) to 213 (126) pmol/L vs 168 (118) to 191 (103) pmol/L). At 12 h, a comparable significant increase in thrombin generation was observed in both groups. ConclusionIn patients treated with ticagrelor, we found no major differences between bivalirudin and heparin in platelet aggregation or coagulation markers, which is in agreement with the neutral clinical results of the VALIDATE-SWEDEHEART study.

Impact of On-Clopidogrel Platelet Reactivity on Incidence of Hypoattenuated Leaflet Thickening After Transcatheter Aortic Valve Replacement

ObjectivesTo assess the impact of on-clopidogrel platelet reactivity (PR) on HALT, the authors prospectively tested whether patients with below-median on-clopidogrel PR have a lower incidence of HALT compared with those with above-median on-clopidogrel PR. BackgroundIt is unclear whether the apparent ineffectiveness of clopidogrel in preventing hypoattenuated leaflet thickening (HALT) after transcatheter aortic valve replacement (TAVR) questions the concept of P2Y12 inhibition after TAVR or is a consequence of an inadequate response to clopidogrel in elderly patients with severe aortic stenosis. MethodsPatients were either on long-term dual antiplatelet therapy with clopidogrel and acetylsalicylic acid or were given bolus doses of both drugs the day before TAVR. Adenosine diphosphate (ADP)–induced multielectrode impedance aggregometry was performed before TAVR. After TAVR, clopidogrel was continued in all patients. Computed tomographic angiography was performed to detect HALT. ResultsOf 331 patients enrolled, computed tomographic angiography was performed in 200 at 5 days (interquartile range: 4 to 6 days). Among patients with below-median ADP-induced PR (<180 AU · min), 16 were diagnosed with HALT, whereas 20 patients with above-median PR were diagnosed with HALT (p = 0.58). Among patients with high on-clopidogrel PR (>468 AU · min; n = 29), 7 (24%) displayed HALT, compared with 19 (17%) with ADP-induced PR ≤468 AU · min (p = 0.43). Consistently, ADP-induced PR as a continuous variable was not significantly associated with HALT (p = 0.75). Oral anticoagulation was associated with reduced rates of HALT (odds ratio: 0.41; 95% CI: 0.18 to 0.96; p = 0.04). ConclusionsOn-clopidogrel ADP-induced PR was not significantly associated with the occurrence of HALT. In contrast, oral anticoagulation was associated with reduced rates of HALT.

CYP2C19 and CYP3A4 activity and ADP-induced platelet reactivity in patients with stemi treated by prasugrel or ticagrelor

Aim: We assessed the contribution of CYP2C19 and CYP3A4 metabolic activity to the ADP-induced platelet aggregation 1h and 24h after the loading dose of 60 mg prasugrel or 180 mg ticagrelor in the patients with ST-elevations myocardial infarction (STEMI) treated by percutaneous coronary intervention. Further, we assessed the contribution of CYP2C19 polymorphisms and amiodarone treatment to the CYP 450 enzymatic activity. Methods: Total number of 89 patients with STEMI were randomly assigned to the treatment with prasugrel (n = 46) or ticagrelor (n = 43). Metabolic activity of CYP2C19 and CYP3A4 was assessed by the rate of 5-hydroxylation and sulfoxidation of lansoprazole. Further, patients were genotypized for CYP2C19 *2 and *17 alleles and the data about concomitant treatment were collected, where amiodarone was considered as CYP3A4 inhibitor. Results: In prasugrel-treated patients, high ADP-induced platelet reactivity 1h after the loading dose negatively correlated with lansoprazole-sulfone/lansoprazole ratio, which reflects CYP3A4 metabolic activity (r = -0.35, p = 0.018) and positively with 5OH-lansoprazole/lansoprazole ratio (r = 0.44, p = 0.002). There was no significant effect with respect to CYP2C19 or CYP3A4 metabolic activity after 24h or in the ticagrelor group. CYP2C19 poor metabolizers had lower 5OH-lansoprazole/lansoprazole ratio and higher lansoprazole-sulfone/lansoprazole ratio compared to the intermediate and extensive metabolizers, but this was not reflected in the ADP-induced platelet reactivity. The treatment with amiodarone did not influence neither the metabolic ratios nor the ADP-induced platelet reactivity. Conclusions: The CYP3A4 and CYP2C19 metabolic activity is associated with ADP-induced platelet reactivity in prasugrel-treated, but not ticagrelor-treated patients with STEMI.

3354Association of plasma concentration of trimethylamine N-oxide and ADP-induced platelet reactivity after a loading dose of clopidogrel 600 mg in patients undergoing elective PCI

3354Association of plasma concentration of trimethylamine N-oxide and ADP-induced platelet reactivity after a loading dose of clopidogrel 600 mg in patients undergoing elective PCI

Comparison of factors affecting platelet reactivity in various platelet function tests.

Previous studies have reported that various factors affect ADP-induced platelet reactivity during clopidogrel therapy. The aim of this study was to determine whether clinical and laboratory variables for platelet reactivity during dual antiplatelet therapy (DAPT) are dependent on the assay used. We enrolled 904 patients receiving DAPT following coronary intervention. Platelet reactivity was measured using three methods: the VerifyNow P2Y12 assay, multiple electrode aggregometry (MEA) ADP assay, and the light transmittance aggregometry (LTA) ADP assay at 24-48h following coronary intervention. The VerifyNow results demonstrated a significant inverse correlation with hematocrit value (r=-0.268, p<0.0001); however, MEA results had no such correlation with hematocrit (r=0.044, p=0.188). There was a positive correlation between the MEA results and platelet count (r=0.255, p<0.0001). LTA was weakly influenced by hematocrit (r=-0.064, p=0.057) and platelet count (r=0.069, p=0.040). Gender (odds ratio 1.53, 95% CI 1.10-2.14, p=0.013) and hematocrit (odds ratio 0.91,95% CI 0.88-0.94, p<0.0001) were the independent variables for HPR by VerifyNow. Smoking (odds ratio 0.38, 95% CI 0.16-0.94, p=0.036) and platelet count (odds ratio 1.01, 95% CI 1.00-1.01, p<0.0001) were independent factors for HPR when using the MEA assay, whereas platelet count (odds ratio 1.00, 95% CI 1.00-1.01, p=0.006) was identified as the only independent variable for HPR when using LTA. The incidence of HPR and the influencing variables involved are dependent on the platelet function test used.