Journal articles on the topic 'High on-aspirin platelet reactivity'
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1
Alemanno, Laura, Isabella Massimi, Vanessa Klaus, Maria Guarino, Teresa Maltese, Luigi Frati, Dominick Angiolillo, and Fabio Pulcinelli. "Impact of Multidrug Resistance Protein-4 Inhibitors on Modulating Platelet Function and High on-Aspirin Treatment Platelet Reactivity." Thrombosis and Haemostasis 118, no. 03 (February 15, 2018): 490–501. http://dx.doi.org/10.1055/s-0038-1629920.
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AbstractPlatelet multidrug resistance protein 4 (MRP4) plays a modulating role on platelet activation. Platelet function and thrombus formation are impaired in MRP4 knockout mice models, and, among aspirin-treated patients, high on-aspirin residual platelet reactivity (HARPR) positively correlates with MRP4 levels. To better understand the effects of MRP4 on platelet function, the aim of this investigation was to assess the impact of cilostazol-induced inhibition of MRP4-mediated transport and assess aspirin-induced antiplatelet effects and rates of HARPR in human subjects.Cilostazol-dependent inhibition of MRP4-mediated transport was assessed with the release of the fluorescent adduct bimane-glutathione and aspirin entrapment. Effect of Cilostazol on cAMP inhibition was evaluated by vasodilator-stimulated phosphoprotein (VASP). Platelet function was studied by collagen and TRAP-6-induced platelet aggregation and secretion.Cilostazol reduced the release of bimane-glutathione and enhanced aspirin entrapment demonstrating an inhibitory effect on MRP4 in platelets. VASP phosphorylation was absent until 10 seconds after addition of cilostazol, and becomes evident after 30 seconds. An inhibitory effect on platelet aggregation and secretion was found in activated platelets, with threshold concentration of agonists, 10 seconds after addition of cilostazol, supporting a role of MRP4 on platelet function that is cAMP independent. Cilostazol effects were also shown in aspirin-treated platelets. A reduction of platelet aggregation and secretion were observed in aspirin-treated patients with HARPR.This study supports the role of MRP4 on modulating platelet function which occurs through cAMP-independent mechanisms. Moreover, inhibition of MRP4 induced by cilostazol enhances aspirin-induced antiplatelet effects and reduces HARPR.
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Wang, Yilong, Yi Lin, Xia Meng, Weiqi Chen, Guohua Chen, Zhimin Wang, Jialing Wu, et al. "Effect of ticagrelor with clopidogrel on high on-treatment platelet reactivity in acute stroke or transient ischemic attack (PRINCE) trial: Rationale and design." International Journal of Stroke 12, no. 3 (February 23, 2017): 321–25. http://dx.doi.org/10.1177/1747493017694390.
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Rationale and aim Little is known about the safety and efficacy of the combination of ticagrelor and aspirin in acute ischemic stroke. This study aimed to evaluate whether the combination of ticagrelor and aspirin was superior to that of clopidogrel and aspirin in reducing the 90-day high on-treatment platelet reactivity for acute minor stroke or transient ischemic attack, especially for carriers of cytochrome P450 2C19 loss-of-function allele. Sample size and design This study was designed as a prospective, multicenter, randomized, open-label, active-controlled, and blind-endpoint, phase II b trial. The required sample size was 952 patients. It was registered with ClinicalTrials.gov (NCT02506140). Study outcomes The primary outcome was the proportion of patients with high on-treatment platelet reactivity at 90 days. High on-treatment platelet reactivity is defined as the P2Y12 reaction unit >208 measured using the VerifyNow P2Y12 assay. Conclusion The Platelet Reactivity in Acute Non-disabling Cerebrovascular Events study explored whether ticagrelor combined with aspirin could reduce further the proportion of patients with high on-treatment platelet reactivity at 90 days after acute minor stroke or transient ischemic attack compared with clopidogrel and aspirin.
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Massimi, Isabella, Lavinia Lotti, Flavia Temperilli, Massimo Mancone, Gennaro Sardella, Simone Calcagno, Ombretta Turriziani, Luigi Frati, and Fabio M. Pulcinelli. "Enhanced platelet MRP4 expression and correlation with platelet function in patients under chronic aspirin treatment." Thrombosis and Haemostasis 116, no. 12 (November 2016): 1100–1110. http://dx.doi.org/10.1160/th16-04-0316.
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SummaryPlatelet multidrug resistance protein4 (MRP4)-overexpression has a role in reducing aspirin action. Aspirin in vivo treatment enhances platelet MRP4 expression and MRP4 mediated transport inhibition reduces platelet function and delays thrombus formation. The aim of our work was to verify whether MRP4 expression is enhanced in platelets obtained from patients under chronic aspirin treatment and whether it correlates with residual platelet reactivity. We evaluated changes on mRNA and protein-MRP4 expression and platelet aggregation in four populations: healthy volunteers (HV), aspirin-free control population (CTR), patients who started the treatment less than one month ago (ASA<1 month patients) and aspirinated patients who started the treatment more than two months ago (ASA>2 months patients). In platelets obtained from ASA>2 months patients, it was found a statistically significant MRP4 enhancement of both mRNA and protein expression compared to HV, CTR and ASA<1 month patients. Platelets obtained from ASA>2 months patients that present high levels of platelet MRP4, have higher serum TxB2 levels and collagen-induced platelet aggregation compared to patient with low levels of MRP4 in platelets. In addition collagen induced platelet aggregation is higher in in vitro aspirinated platelets obtained from patients with high levels of MRP4 patients compared to those obtained from patients with low MRP4 levels. We can assert that, in patients under chronic aspirin treatment, platelets that present high MRP4 levels have an increase of residual platelet reactivity, which is due in part to incomplete COX-1 inhibition, and in part to COX-1–independent mechanism.
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Barale, Cristina, Franco Cavalot, Chiara Frascaroli, Katia Bonomo, Alessandro Morotti, Angelo Guerrasio, and Isabella Russo. "Association between High On-Aspirin Platelet Reactivity and Reduced Superoxide Dismutase Activity in Patients Affected by Type 2 Diabetes Mellitus or Primary Hypercholesterolemia." International Journal of Molecular Sciences 21, no. 14 (July 15, 2020): 4983. http://dx.doi.org/10.3390/ijms21144983.
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Platelet hyperactivation is involved in the established prothrombotic condition of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM) and familial hypercholesterolemia (HC), justifying the therapy with aspirin, a suppressor of thromboxane synthesis through the irreversible inhibition of cyclooxygenase-1 (COX-1), to prevent cardiovascular diseases. However, some patients on aspirin show a higher than expected platelet reactivity due, at least in part, to a pro-oxidant milieu. The aim of this study was to investigate platelet reactivity in T2DM (n = 103) or HC (n = 61) patients (aspirin, 100 mg/day) and its correlation with biomarkers of redox function including the superoxide anion scavenger superoxide dismutase (SOD) and the in vivo marker of oxidative stress urinary 8-iso-prostaglandin F2α. As results, in T2DM and HC subjects the prevalence of high on-aspirin platelet reactivity was comparable when both non-COX-1-dependent and COX-1-dependent assays were performed, and platelet reactivity is associated with a lower SOD activity that in a stepwise linear regression appears as the only predictor of platelet reactivity. To conclude, in T2DM and HC, similarly, the impairment of redox equilibrium associated with a decrease of SOD activity could contribute to a suboptimal response to aspirin.
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Saris, Anno, Monique van Oostrom, Jaapjan Snoep, Frits Rosendaal, Jaap Zwaginga, Jeroen Eikenboom, Pieter van der Meer, Johanna van der Bom, and Tobias Bonten. "Effect of aspirin intake at bedtime versus on awakening on circadian rhythm of platelet reactivity." Thrombosis and Haemostasis 112, no. 12 (2014): 1209–18. http://dx.doi.org/10.1160/th14-05-0453.
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SummaryThe risk of acute cardiovascular events is highest during morning hours, and platelet activity peaks during morning hours. The effect of timing of aspirin intake on circadian rhythm and morning peak of platelet reactivity is not known. It was our objective to evaluate the effect of timing of aspirin intake on circadian rhythm and morning peak of platelet reactivity. A randomised open-label cross-over trial in healthy subjects (n=14) was conducted. Participants used acetylsalicylic acid (80 mg) on awakening or at bedtime for two periods of two weeks, separated by a four-week wash-out period. At the end of both periods blood was drawn every 3 hours to measure COX-1-dependent (VerifyNow- Aspirin; Serum Thromboxane B2 [STxB2]) and COX-1-independent (flow cytometry surface CD62p expression; microaggregation) platelet activity. VerifyNow platelet reactivity over the whole day was similar with intake on awakening and at bedtime (mean difference: –9 [95 % confidence interval (CI) –21 to 4]). However, the morning increase in COX-1-dependent platelet activity was reduced by intake of aspirin at bedtime compared with on awakening (mean difference VerifyNow: –23 Aspirin Reaction Units [CI –50 to 4]; STxB2: –1.7 ng/ml [CI –2.7 to –0.8]). COX-1-independent assays were not affected by aspirin intake or its timing. Low-dose aspirin taken at bedtime compared with intake on awakening reduces COX-1-dependent platelet reactivity during morning hours in healthy subjects. Future clinical trials are required to investigate whether simply switching to aspirin intake at bedtime reduces the risk of cardiovascular events during the high risk morning hours.
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Mohring, Annemarie, Kerstin Piayda, Lisa Dannenberg, Saif Zako, Theresa Schneider, Kirsten Bartkowski, Bodo Levkau, et al. "Thromboxane Formation Assay to Identify High On-Treatment Platelet Reactivity to Aspirin." Pharmacology 100, no. 3-4 (2017): 127–30. http://dx.doi.org/10.1159/000477303.
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Platelet inhibition by aspirin is indispensable in the secondary prevention of cardiovascular events. Nevertheless, impaired aspirin antiplatelet effects (high on-treatment platelet reactivity [HTPR]) are frequent. This is associated with an enhanced risk of cardiovascular events. The current gold standard to evaluate platelet hyper-reactivity despite aspirin intake is the light-transmittance aggregometry (LTA). However, pharmacologically, the most specific test is the measurement of arachidonic acid (AA)-induced thromboxane (TX) B2 formation. Currently, the optimal cut-off to define HTPR to aspirin by inhibition of TX formation is not known. Therefore, in this pilot study, we aimed to calculate a TX formation cut-off value to detect HTPR defined by the current gold standard LTA. We measured platelet function in 2,507 samples. AA-induced TX formation by ELISA and AA-induced LTA were used to measure aspirin antiplatelet effects. TX formation correlated nonlinearly with the maximum of aggregation in the AA-induced LTA (Spearman's rho R = 0.7396; 95% CI 0.7208-0.7573, p < 0.0001). Receiver operating characteristic analysis and Youden's J statistics revealed 209.8 ng/mL as the optimal cut-off value to detect HTPR to aspirin with the TX ELISA (area under the curve: 0.92, p < 0.0001, sensitivity of 82.7%, specificity of 90.3%). In summary, TX formation ELISA is reliable in detecting HTPR to aspirin. The calculated cut-off level needs to be tested in trials with clinical end points.
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Armstrong, Paul C., Thomas Hoefer, Rebecca B. Knowles, Arthur T. Tucker, Melissa A. Hayman, Plinio M. Ferreira, Melissa V. Chan, and Timothy D. Warner. "Newly Formed Reticulated Platelets Undermine Pharmacokinetically Short-Lived Antiplatelet Therapies." Arteriosclerosis, Thrombosis, and Vascular Biology 37, no. 5 (May 2017): 949–56. http://dx.doi.org/10.1161/atvbaha.116.308763.
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Objective— Aspirin together with thienopyridine P2Y 12 inhibitors, commonly clopidogrel, is a cornerstone of antiplatelet therapy. However, many patients receiving this therapy display high on-treatment platelet reactivity, which is a major therapeutic hurdle to the prevention of recurrent thrombotic events. The emergence of uninhibited platelets after thrombopoiesis has been proposed as a contributing factor to high on-treatment platelet reactivity. Here, we investigate the influences of platelet turnover on platelet aggregation in the face of different dual-antiplatelet therapy strategies. Approach and Results— Traditional light transmission aggregometry, cytometry, advanced flow cytometric imaging, and confocal microscopy were used to follow the interactions of populations of platelets from healthy volunteers and patients with stable cardiovascular disease. Newly formed, reticulated platelets overproportionately contributed to, and clustered at, the core of forming aggregates. This phenomenon was particularly observed in samples from patients treated with aspirin plus a thienopyridine, but was absent in samples taken from patients treated with aspirin plus ticagrelor. Conclusions— Reticulated platelets are more reactive than older platelets and act as seeds for the formation of platelet aggregates even in the presence of antiplatelet therapy. This is coherent with the emergence of an uninhibited subpopulation of reticulated platelets during treatment with aspirin plus thienopyridine, explained by the short pharmacokinetic half-lives of these drugs. This phenomenon is absent during treatment with ticagrelor, because of its longer half-life and ability to act as a circulating inhibitor. These data highlight the important influences of pharmacokinetics on antiplatelet drug efficacies, especially in diseases associated with increased platelet turnover.
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Pettersen, A. A., H. Arnesen, and I. Seljeflot. "A brief review on high on-aspirin residual platelet reactivity." Vascular Pharmacology 67-69 (April 2015): 6–9. http://dx.doi.org/10.1016/j.vph.2015.03.018.
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Berger, Martin, Alexander Dressel, Marcus E. Kleber, Winfried März, Peter Hellstern, Nikolaus Marx, and Katharina Schütt. "Platelet Reactivity and Cardiovascular Mortality Risk in the LURIC Study." Journal of Clinical Medicine 12, no. 5 (February 28, 2023): 1913. http://dx.doi.org/10.3390/jcm12051913.
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Background: The clinical and prognostic implications of platelet reactivity (PR) testing in a P2Y12-inhibitor naïve population are poorly understood. Objectives: This explorative study aims to assess the role of PR and explore factors that may modify elevated mortality risk in patients with altered PR. Methods: Platelet ADP-induced CD62P and CD63 expression were measured by flow-cytometry in 1520 patients who were referred for coronary angiography in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC). Results: High- and Low-platelet reactivity to ADP were strong predictors of cardiovascular and all-cause mortality and risk equivalent to the presence of coronary artery disease. (High platelet reactivity 1.4 [95% CI 1.1–1.9]; Low platelet reactivity: 1.4 [95% CI 1.0–2.0]). Relative weight analysis indicated glucose control (HbA1c), renal function ([eGFR]), inflammation (high-sensitive C-reactive protein [hsCRP]) and antiplatelet therapy by Aspirin as consistent mortality risk modifiers in patients with Low- and High-platelet reactivity. Pre-specified stratification of patients by risk modifiers HbA1c (<7.0%), eGFR (>60 mL/min/1.73 m2) and CRP (<3 mg/L) was associated with a lower mortality risk, however irrespective of platelet reactivity. Aspirin treatment was associated with reduced mortality in patients with high platelet reactivity only (p for interaction: 0.02 for CV-death [<0.01 for all-cause mortality]. Conclusions: Cardiovascular mortality risk in patients with High- and Low platelet reactivity is equivalent to the presence of coronary artery disease. Targeted glucose control, improved kidney function and lower inflammation are associated with reduced mortality risk, however independent of platelet reactivity. In contrast, only in patients with High-platelet reactivity was Aspirin treatment associated with lower mortality.
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Larsen, Sanne, Erik Grove, Steen Kristensen, and Anne-Mette Hvas. "Reduced antiplatelet effect of aspirin is associated with low-grade inflammation in patients with coronary artery disease." Thrombosis and Haemostasis 109, no. 05 (2013): 920–29. http://dx.doi.org/10.1160/th12-09-0666.
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SummaryInflammation has been proposed to modify platelet function. This may lead to increased platelet reactivity and reduced antiplatelet drug efficacy in patients with coronary artery disease (CAD). However, this hypothesis has not been investigated in stable CAD patients receiving aspirin as mono antiplatelet therapy. It was the objective of this study to investigate the association between platelet reactivity, the inflammatory markers high-sensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6), and platelet activation. We performed a cross-sectional study on 524 stable high-risk CAD patients. Among these, 91% had a history of myocardial infarction, 23% had type 2 diabetes, and 13% had both. All patients received 75 mg aspirin daily as mono antiplatelet therapy. Platelet reactivity was assessed by multiple electrode aggregometry (Multiplate®, MEA) and VerifyNow®. Inflammation was evaluated by hs-CRP and IL-6. Platelet activation was assessed by soluble P-selectin (sP-selectin), and cyclooxygenase-1 inhibition was evaluated by measurement of serum thromboxane B2. Hs-CRP levels were significantly higher in upper platelet reactivity tertile patients than in lower platelet reactivity tertile patients (p≤0.02). Similar results were obtained with IL-6, though not statististically significant (p≥0.15). Platelet activation evaluated by sP-selectin was significantly higher in patients with MEA reactivity levels in the upper tertile than in the lower tertile (p=0.0001). Optimal compliance was confirmed by low serum thromboxane B2 levels in all patients. In conclusion, increased levels of hs-CRP were associated with augmented platelet reactivity in stable high-risk CAD patients receiving aspirin as mono antiplatelet therapy. These findings may suggest that chronic low-grade inflammation reduce the antiplatelet effect of aspirin.
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Mărginean, Alina, Valeriu Moldovan, and Mihai Mărginean. "High-on-Aspirin Residual Platelet Reactivity Evaluated Using the Multiplate® Point-of-Care Device." Acta Medica Marisiensis 62, no. 1 (March 1, 2016): 101–5. http://dx.doi.org/10.1515/amma-2015-0124.
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AbstractObjective: The aim of this study was to evaluate the prevalence of aspirin non-responsiveness using whole blood multiple electrode aggregometry and to investigate the role of different clinical and laboratory variables associated with the lack of response. Methods: The present study included 116 aspirin treated patients presented with acute coronary syndromes or stroke. Response to aspirin was assessed by impedance aggregometry using arachidonic acid as agonist, in a final concentration of 0.5 mM (ASPI test). Results: In our data set 81% (n=94) were responders and 19% (n=22) non-responders showing high-on-aspirin platelet reactivity. Correlation analysis showed that the ward of admittance, low-density lipoproteins (LDL), concomitant antibiotic treatment, beta-adrenergic receptor blockers, history of myocardial infarction as well as PCI performed on Cardiology patients have different degrees of association with aspirin response. Conclusion: Concomitant treatment with beta-adrenergic receptor inhibitors, history of myocardial infarction and Cardiology ward admittance significantly increased the chance of responding to aspirin treatment whereas antibiotic therapy and low-density lipoproteins cholesterol seemed to increase the risk of high-on-aspirin residual platelet reactivity.
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Schrick, Diana, Margit Tőkés-Füzesi, Barbara Réger, and Tihamér Molnár. "Plasma Fibrinogen Independently Predicts Hypofibrinolysis in Severe COVID-19." Metabolites 11, no. 12 (November 30, 2021): 826. http://dx.doi.org/10.3390/metabo11120826.
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High rates of thrombosis are present in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Deeper insight into the prothrombotic state is essential to provide the best thromboprophylaxis care. Here, we aimed to explore associations among platelet indices, conventional hemostasis parameters, and viscoelastometry data. This pilot study included patients with severe COVID-19 (n = 21) and age-matched controls (n = 21). Each patient received 100 mg aspirin therapy at the time of blood sampling. Total platelet count, high immature platelet fraction (H-IPF), fibrinogen, D-dimer, Activated Partial Thromboplastin Time, von Willebrand factor antigen and von Willebrand factor ristocetin cofactor activity, plasminogen, and alpha2-antiplasmin were measured. To monitor the aspirin therapy, a platelet function test from hirudin anticoagulated whole blood was performed using the ASPI test by Multiplate analyser. High on-aspirin platelet reactivity (n = 8) was defined with an AUC > 40 cut-off value by ASPI tests. In addition, in vitro viscoelastometric tests were carried out using a ClotPro analyser in COVID-associated thromboembolic events (n = 8) (p = 0.071) nor the survival rate (p = 0.854) showed associations with high on-aspirin platelet reactivity status. The platelet count (p = 0.03), all subjects. COVID-19 patients presented with higher levels of inflammatory markers, compared with the controls, along with evidence of hypercoagulability by ClotPro. H-IPF (%) was significantly higher among non-survivors (n = 18) compared to survivors (p = 0.011), and a negative correlation (p = 0.002) was found between H-IPF and plasminogen level in the total population. The platelet count was significantly higher among patients with high on-aspirin platelet reactivity (p = 0.03). Neither the ECA-A10 (p = 0.008), and ECA-MCF (p = 0.016) were significantly higher, while the tPA-CFT (p < 0.001) was significantly lower among patients with high on-aspirin platelet reactivity. However, only fibrinogen proved to be an independent predictor of hypofibrinolysis in severe COVID-19 patients. In conclusion, a faster developing, more solid clot formation was observed in aspirin ‘non-responder’ COVID-19 patients. Therefore, an individually tailored thromboprophylaxis is needed to prevent thrombotic complications, particularly in the hypofibrinolytic cluster.
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Wiśniewski, Adam, Karolina Filipska, Joanna Sikora, Robert Ślusarz, and Grzegorz Kozera. "The Prognostic Value of High Platelet Reactivity in Ischemic Stroke Depends on the Etiology: A Pilot Study." Journal of Clinical Medicine 9, no. 3 (March 20, 2020): 859. http://dx.doi.org/10.3390/jcm9030859.
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Background: Reduced aspirin response may result in a worse prognosis and a poor clinical outcome in ischemic stroke. The aim of this prospective pilot study was to assess the relationship between platelet reactivity and early and late prognosis, and the clinical and functional status in ischemic stroke, with the role of stroke etiology. Methods: The study involved 69 subjects with ischemic stroke, divided into large and small vessel etiological subgroups. Platelet function testing was performed with two aggregometric methods—impedance and optical—while the clinical condition was assessed using the National Institute of Health Stroke Scale (NIHSS) and the functional status was assessed using the modified Rankin Scale (mRS) on the first and eighth day (early prognosis) and the 90th day of stroke (late prognosis). Results: The initial platelet reactivity was found to be higher in patients with severe neurological deficits on the 90th day after stroke, than in the group with mild neurological deficits (median, respectively, 40 area under the curve (AUC) units vs. 25 AUC units, p = 0.033). In the large vessel disease group, a significant correlation between the platelet reactivity and the functional status on the first day of stroke was found (correlation coefficient (R) = 0.4526; p = 0.0451), the platelet reactivity was higher in the subgroup with a severe clinical condition compared to a mild clinical condition on the first day of stroke (p = 0.0372), and patients resistant to acetylsalicylic acid (aspirin) had a significantly greater possibility of a severe neurological deficit on the first day of stroke compared to those who were sensitive to aspirin (odds ratio (OR) = 14.00, 95% confidence interval (CI) 1.25–156.12, p = 0.0322). Conclusion: High on-treatment platelet reactivity in ischemic stroke was associated with a worse late prognosis regardless of the etiology. We demonstrated a significant relationship between high platelet reactivity and worse early prognosis and poor clinical and functional condition in the large vessel etiologic subgroup. However, due to the pilot nature of this study, its results should be interpreted with caution and further validation on a larger cohort is required.
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Broekman, MJ, AM Eiroa, and AJ Marcus. "Inhibition of human platelet reactivity by endothelium-derived relaxing factor from human umbilical vein endothelial cells in suspension: blockade of aggregation and secretion by an aspirin-insensitive mechanism." Blood 78, no. 4 (August 15, 1991): 1033–40. http://dx.doi.org/10.1182/blood.v78.4.1033.1033.
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Abstract To determine a role for endothelium-derived relaxing factor/nitric oxide (EDRF/NO) in regulation of human platelet reactivity by human endothelial cells (EC), we studied combined suspensions of human umbilical vein endothelial cells (HU-VEC, passage 2 through 3) and washed human platelets. Confluent HUVEC monolayers were treated with aspirin (1 mmol/L) to prevent prostacyclin (PGI2) formation, washed, and harvested. Aspirin-treated platelets alone (58 x 10(6)) were fully aggregated by thrombin at 0.05 U/mL or more. In the presence of 10(6) HUVEC, however, platelet serotonin release and aggregation in response to thrombin at doses as high as 0.5 U/mL were blocked. We demonstrated for the first time that inhibition of aggregation and serotonin release, due to EDRF/NO, occurred in parallel. HUVEC-dependent inhibition of platelet responsiveness was enhanced by superoxide dismutase (SOD) and reversed by hemoglobin. The inhibitory effect was also reversed by preincubation of HUVEC with NG-monomethyl-L-arginine (NMA) or NG-nitro-L-arginine (NNA) through competitive blockade of arginine metabolism. Pretreatment of platelets with methylene blue indicated that EC-dependent inhibition of platelet reactivity occurred through activation of platelet soluble guanylate cyclase. When platelets and HUVEC were separated by a permeable membrane and both cells were stimulated by thrombin, platelets remained unresponsive. This indicated that inhibition was induced by a fluid-phase mediator, independent of direct cell-cell contact. These data demonstrate that EDRF/NO formation from L-arginine by human EC plays an important role as an aspirin-insensitive fluid-phase inhibitor of human platelet reactivity.
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Broekman, MJ, AM Eiroa, and AJ Marcus. "Inhibition of human platelet reactivity by endothelium-derived relaxing factor from human umbilical vein endothelial cells in suspension: blockade of aggregation and secretion by an aspirin-insensitive mechanism." Blood 78, no. 4 (August 15, 1991): 1033–40. http://dx.doi.org/10.1182/blood.v78.4.1033.bloodjournal7841033.
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To determine a role for endothelium-derived relaxing factor/nitric oxide (EDRF/NO) in regulation of human platelet reactivity by human endothelial cells (EC), we studied combined suspensions of human umbilical vein endothelial cells (HU-VEC, passage 2 through 3) and washed human platelets. Confluent HUVEC monolayers were treated with aspirin (1 mmol/L) to prevent prostacyclin (PGI2) formation, washed, and harvested. Aspirin-treated platelets alone (58 x 10(6)) were fully aggregated by thrombin at 0.05 U/mL or more. In the presence of 10(6) HUVEC, however, platelet serotonin release and aggregation in response to thrombin at doses as high as 0.5 U/mL were blocked. We demonstrated for the first time that inhibition of aggregation and serotonin release, due to EDRF/NO, occurred in parallel. HUVEC-dependent inhibition of platelet responsiveness was enhanced by superoxide dismutase (SOD) and reversed by hemoglobin. The inhibitory effect was also reversed by preincubation of HUVEC with NG-monomethyl-L-arginine (NMA) or NG-nitro-L-arginine (NNA) through competitive blockade of arginine metabolism. Pretreatment of platelets with methylene blue indicated that EC-dependent inhibition of platelet reactivity occurred through activation of platelet soluble guanylate cyclase. When platelets and HUVEC were separated by a permeable membrane and both cells were stimulated by thrombin, platelets remained unresponsive. This indicated that inhibition was induced by a fluid-phase mediator, independent of direct cell-cell contact. These data demonstrate that EDRF/NO formation from L-arginine by human EC plays an important role as an aspirin-insensitive fluid-phase inhibitor of human platelet reactivity.
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Breet, Nicoline, Corine de Jong, Willem Jan Bos, Jochem van Werkum, Heleen Bouman, Johannes Kelder, Thomas Bergmeijer, Felix Zijlstra, Christian Hackeng, and Jurriën ten Berg. "The impact of renal function on platelet reactivity and clinical outcome in patients undergoing percutaneous coronary intervention with stenting." Thrombosis and Haemostasis 112, no. 12 (2014): 1174–81. http://dx.doi.org/10.1160/th14-04-0302.
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SummaryPatients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Previous studies have suggested that patients with CKD have less therapeutic benefit of antiplatelet therapy. However, the relation between renal function and platelet reactivity is still under debate. On-treatment platelet reactivity was determined in parallel by ADP- and AA-induced light transmittance aggregometry (LTA) and the VerifyNow® System (P2Y12 and Aspirin) in 988 patients on dual antiplatelet therapy, undergoing elective coronary stenting. Patients were divided into two groups according to the presence or absence of moderate/severe CKD (GFR<60 ml/min/1.73 m2). Furthermore, the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and stroke at one-year was evaluated. Patients with CKD (n=180) had significantly higher platelet reactivity, regardless of the platelet function test used. Patients with CKD more frequently had high on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) regardless of the platelet function test used. After adjustment for potential confounders, this was no longer significant. The event-rate was the highest in patients with both high on-treatment platelet reactivity (HPR) and CKD compared to those with neither high on-treatment platelet reactivity nor CKD. In conclusion, the magnitude of platelet reactivity as well as the incidence of HPR was higher in patients with CKD. However, since the incidence of HPR was similar after adjustment, a higher rate of co-morbidities in patients with CKD might be the major cause for this observation rather than CKD itself. CKD-patients with HCPR were at the highest risk of long-term cardiovascular events.Clinical Trial Registration: www.clinicaltrials.gov: NCT00352014.
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Malý, Martin, Ivana Hadačová, Petr Hájek, David Zemánek, and Josef Veselka. "High-residual platelet activity despite dual antiplatelet treatment associated with subacute stent thrombosis." Open Medicine 4, no. 1 (March 1, 2009): 119–24. http://dx.doi.org/10.2478/s11536-009-0007-8.
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AbstractHigh-residual platelet activity despite the dual antiplatelet treatment with aspirin and clopidogrel is associated with major adverse cardiac events, including stent thrombosis. Acute and subacute stent thrombosis is rare, but presents itself with serious complications including high mortality and morbidity rates. Light transmittance aggregometry with specific agonists — arachidonic acid and 5-adenosin diphosphate — is still considered a standard for the assessment of platelet reactivity, besides novel methods like vasodilator-stimulated phosphoprotein phosphorylation. In our case study, we report the coincidence of high-residual platelet activity with subacute stent thrombosis despite the recommended doses of antiplatelet agents — aspirin and clopidogrel. Stent thrombosis was treated by aspiration thrombectomy, and antiplatelet treatment was modified by increasing the dose of aspirin and substituting clopidogrel with a firstgeneration thienopyridin — ticlopidin. The effect of the treatment was documented by reaching the optimal inhibition of platelet reactivity. In the 6- and 12-month follow-up, the patient presented no ischemic events.
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Kuliczkowski, Wiktor, Marek Radomski, Mariusz Gąsior, Joanna Urbaniak, Jacek Kaczmarski, Andrzej Mysiak, Marta Negrusz-Kawecka, and Iwona Bil-Lula. "MMP-2, MMP-9, and TIMP-4 and Response to Aspirin in Diabetic and Nondiabetic Patients with Stable Coronary Artery Disease: A Pilot Study." BioMed Research International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/9352015.
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Background. High on-aspirin treatment platelets reactivity (HPR) is a significant problem in long-term secondary prevention of cardiovascular events. We hypothesize that imbalance between platelets MMPs/TIMPs results in cardiovascular disorders. We also explored whether chronically elevated blood glucose affects MMP-2/TIMP-4 release from platelets. Materials and Methods. Seventy patients with stable coronary artery disease, supplemented with aspirin, participated in this pilot study. The presence of HPR and/or diabetes mellitus was considered as the differentiating factor. Light aggregometry, impedance aggregometry, and ELISA tests for TXB2, MMP-2, MMP-9, and TIMP-4 were performed in serum, plasma, platelet-rich plasma, and platelets-poor plasma, as appropriate. Results. Aspirin-HPR did not affect plasma MMP-2, MMP-9, and TIMP-4. Arachidonic acid-induced aggregation of platelets from aspirin-HPR patients did not lead to increased release of MMP-2, MMP-9, and TIMP-4. Studying patients at the lowest TXB2 serum concentration quartile revealed that high concentration of plasma TIMP-4 and TIMP-4 negatively correlated with TXB2 and platelet aggregation. Diabetics showed an increased plasma MMP-2 as well as an increased MMP-2 in supernatants after platelet aggregation. However, diabetes mellitus did not affect MMP-9 and TIMP-4. Conclusion. Aspirin-HPR did not affect the translocation and release of MMPs and TIMP-4 from platelets. TIMP-4 may serve as a marker of TXA2-mediated platelet aggregation. Chronically elevated plasma glucose increases plasma MMP-2, and HPR potentiates this phenomenon.
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Kopjar, Tomislav, Mate Petricevic, Hrvoje Gasparovic, Lucija Svetina, Davor Milicic, and Bojan Biocina. "Postoperative Atrial Fibrillation Is Associated With High On-Aspirin Platelet Reactivity." Annals of Thoracic Surgery 100, no. 5 (November 2015): 1704–11. http://dx.doi.org/10.1016/j.athoracsur.2015.05.001.
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Lim, Woo-Hyun, In-Ho Chae, Chang-Hwan Yoon, Dong-Ju Choi, Sang Lim, Woo Park, Joon-Hyung Doh, et al. "Comparison of dual antiplatelet therapy prescribed as one-pill versus two-pill regimen." Thrombosis and Haemostasis 116, no. 07 (January 2016): 78–86. http://dx.doi.org/10.1160/th15-12-0931.
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SummaryFixed-dose combination (FDC) drugs can simplify the medication regimen and potentially improve adherence. However, evidence is lacking about the efficacy and safety of FDC drugs of clopidogrel plus aspirin. Individual data from the three independent MR-CAPCIS trials were pooled and analysed. In those trials, subjects who had been treated with either dual antiplatelet therapy (DAPT) or aspirin alone after drug-eluting stent (DES) implantation were randomly assigned to one-pill or to two-pill DAPT group. Platelet reactivity was measured with VerifyNow-P2Y12 and aspirin point-of-care assays at baseline and eight weeks after treatment. In the present study, primary efficacy endpoint was changes in platelet reactivity unit (PRU) between baseline and eight weeks. A total of 965 subjects were analysed. In prior clopidogrel and aspirin users, PRU was well maintained regardless of switching to either one-pill or two-pill DAPT (ΔPRU=0.4 vs 0.0, p=0.939). In prior aspirin users, PRU was decreased by 73.7 in one-pill DAPT and 77.5 in two-pill DAPT group, with no differences between them (p=0.499). The incidence of high on-treatment platelet reactivity at eight weeks, defined as PRU≥235 in Western people, was 34.8 % in one-pill DAPT group and 37.6 % in two-pill DAPT group (p=0.380), and that defined as PRU ≥275 in Oriental people was 17.7 vs 21.7 % (p=0.129). Independent predictors of high platelet reactivity on clopidogrel were female gender, increasing age, and diabetes. Study drugs were well tolerated. In conclusion, FDC one-pill DAPT showed similar efficacy to two-pill DAPT in terms of platelet reactivity in patients receiving DES in Korea.
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Sibbing, Dirk, Robert A. Byrne, Isabell Bernlochner, and Adnan Kastrati. "High platelet reactivity and clinical outcome – Fact and fiction." Thrombosis and Haemostasis 106, no. 08 (2011): 191–202. http://dx.doi.org/10.1160/th11-01-0040.
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SummaryIn patients suffering from acute coronary syndromes or undergoing percutaneous coronary intervention, oral antiplatelet treatment is routinely administered with the primary aim of inhibiting platelet-mediated thrombus formation and subsequent abrupt vessel occlusion. Simultaneous inhibition of blood platelet cyclooxygenase-1 by aspirin and of the P2Y12 receptor by clopidogrel or prasugrel is currently recommended in this setting. Inter-individual response variability to aspirin and especially to clopidogrel is the subject of much debate as evidence has grown over the years linking an attenuated response to treatment with the occurrence of ischaemic events. Consequently, the clinical entity of high (on-treatment) platelet reactivity (HPR) was born and subsequently characterised in numerous studies over the last decade. Until recently, alternative treatment options were limited in patients exhibiting HPR. At present the antiplatelet therapy landscape is changing with the advent of prasugrel and ticagrelor as alternative and more potent treatment options. Different tests for monitoring platelet function are available and are being increasingly employed in research projects and clinical routine. These tests may prove useful for achieving optimal platelet inhibition for the individual patient, and several centres now incorporate such testing in day-to-day practice. Widespread adoption of this practice and incorporation into clinical guidelines awaits the results of ongoing trials in which treatment is changed based on platelet function monitoring. This review aims to summarise available facts and fiction in relation to platelet function testing and reactivity with a particular focus on P2Y12 receptor inhibition in patients undergoing coronary stent placement.
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Bath, Philip M., Jane May, Katie Flaherty, Lisa J. Woodhouse, Natalia Dovlatova, Sue C. Fox, Timothy J. England, et al. "Remote Assessment of Platelet Function in Patients with Acute Stroke or Transient Ischaemic Attack." Stroke Research and Treatment 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/7365684.
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Background. The TARDIS trial assessed the safety and efficacy of intensive versus guideline antiplatelet agents given for one month in patients with acute stroke or TIA. The aim of this substudy was to assess the effect of antiplatelet agents taken at baseline on platelet function reactivity and activation.Methods. Platelet function, assessed by remotely measured surface expression of P-selectin, was assessed in patients at their time of randomisation. Data are median fluorescence values.Results. The aspirin P-selectin test demonstrated that platelet expression was lower in 494 patients taking aspirin than in 162 patients not: mean 210 (SD 188) versus 570 (435), difference 360.3 (95% CI 312.2–408.4) (2p<0.001). Aspirin did not suppress P-selectin levels below 500 units in 23 (4.7%) patients. The clopidogrel test showed that platelet reactivity was lower in 97 patients taking clopidogrel than in 585 patients not: 655 (296) versus 969 (315), difference 314.5 (95% CI 247.3–381.7) (2p<0.001). Clopidogrel did not suppress P-selectin level below 860 units in 24 (24.7%) patients.Conclusions. Aspirin and clopidogrel suppress stimulated platelet P-selectin, although one-quarter of patients on clopidogrel have high on-treatment platelet reactivity. Platelet function testing may be performed remotely in the context of a large multicentre trial. Trial registrationISRCTN47823388.
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Kessler, Thorsten, Bernhard Wolf, Niclas Eriksson, Daniel Kofink, Bakhtawar K. Mahmoodi, Himanshu Rai, Vinicius Tragante, et al. "Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention." Cardiovascular Research 115, no. 10 (February 14, 2019): 1512–18. http://dx.doi.org/10.1093/cvr/cvz015.
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AbstractAimA common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention.Methods and resultsThe association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n = 1678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30 days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n = 3236), and the Utrecht Coronary Biobank (n = 1003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91–209) vs. 134 (85–194) AU⋅min, P < 0.01]. More homozygous risk allele carriers, compared with non-risk allele carriers, were assigned to the high-risk group for ischaemic events (>203 AU⋅min; 29.5 vs. 24.2%, P = 0.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08–2.68; P = 0.02). Bleeding risk was not altered.ConclusionWe conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated.
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Stratz, Christian, Stefan Leggewie, Willibald Hochholzer, Christian M. Valina, Michael Gick, Ajay J. Kirtane, Gregg W. Stone, Franz-Josef Neumann, Dietmar Trenk, and Thomas G. Nührenberg. "Temporal variability in the antiplatelet effects of clopidogrel and aspirin after elective drug-eluting stent implantation." Thrombosis and Haemostasis 114, no. 11 (2015): 1020–27. http://dx.doi.org/10.1160/th15-03-0257.
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SummaryGiven conflicting data on temporal variability in pharmacodynamic platelet responses to clopidogrel, we investigated platelet reactivity on clopidogrel and aspirin for up to six months after elective percutaneous coronary intervention (PCI) with drug-eluting stents. Platelet reactivity was determined in 102 patients before loading with clopidogrel and aspirin, and on maintenance therapy after PCI on day 1, at one month and six months by VerifyNow™ P2Y12 and Aspirin assays and by residual platelet aggregation (RPA) on light transmission aggregometry using adenosine diphosphate and arachidonic acid. By VerifyNow testing, median (interquartile range) P2Y12 reaction units (PRU) on clopidogrel were 166 (90–234), 195 (124–257), and 198 (141–252) on day 1, one month and six months after PCI, respectively (p=0.005 day 1 to 1 month, and p=0.86 1 month to 6 months). Using a cut-off of > 208 PRU, 35% of patients had high platelet reactivity (HPR) to clopidogrel on day 1, 43% at one month, and 46% at six months after PCI. Between day 1 and six months after PCI, 38.2% of patients changed clopidogrel responder status at least once. Other cut-offs and RPA yielded similar results. Platelet inhibition by aspirin was consistent over time with only five patients being characterised as having HPR. Considerable variation in individual on-clopidogrel platelet reactivity was present during both the subacute and the late phases of maintenance therapy after elective PCI. Hence, the utility of contemporary platelet function testing to guide antiplatelet therapy may be limited.
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Wiśniewski, Adam, Joanna Sikora, Agata Sławińska, Karolina Filipska, Aleksandra Karczmarska-Wódzka, Zbigniew Serafin, and Grzegorz Kozera. "High On-Treatment Platelet Reactivity Affects the Extent of Ischemic Lesions in Stroke Patients Due to Large-Vessel Disease." Journal of Clinical Medicine 9, no. 1 (January 17, 2020): 251. http://dx.doi.org/10.3390/jcm9010251.
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Background: Excessive platelet activation and aggregation plays an important role in the pathogenesis of ischemic stroke. Correlation between platelet reactivity and ischemic lesions in the brain shows contradictory results and there are not enough data about the potential role of stroke etiology and its relationships with chronic lesions. The aim of this study is to assess the relationship between platelet reactivity and the extent of ischemic lesions with the particular role of etiopathogenesis. Methods: The study involved 69 patients with ischemic stroke, including 20 patients with large-vessel disease and 49 patients with small-vessel disease. Evaluation of platelet reactivity was performed within 24 h after the onset of stroke using two aggregometric methods (impedance and optical), while ischemic volume measurement in the brain was performed using magnetic resonance imaging (in diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences) at day 2–5 after the onset of stroke. Results: In the large-vessel disease subgroup, a correlation was found between platelet reactivity and acute ischemic focus volume (correlation coefficient (R) = 0.6858 and p = 0.0068 for DWI; R = 0.6064 and p = 0.0215 for FLAIR). Aspirin-resistant subjects were significantly more likely to have a large ischemic focus (Odds Ratio (OR) = 45.00, 95% Confidence Interval (CI) = 1.49–135.36, p = 0.0285 for DWI; OR = 28.00, 95% CI = 1.35–58.59, p = 0.0312 for FLAIR) than aspirin-sensitive subjects with large-vessel disease. Conclusion: In patients with ischemic stroke due to large-vessel disease, high on-treatment platelet reactivity affects the extent of acute and chronic ischemic lesions.
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Tsujimoto, Masanori, Yukiko Enomoto, Jouji Kokuzawa, and Toru Iwama. "Diabetes mellitus and carotid artery plaques exhibiting high-intensity signals on MR angiography are related to increased platelet reactivity after carotid artery stenting." Journal of NeuroInterventional Surgery 9, no. 1 (July 1, 2016): 106–10. http://dx.doi.org/10.1136/neurintsurg-2016-012419.
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BackgroundIncreased platelet reactivity after carotid artery stenting (CAS) may cause thromboembolic complications.ObjectiveThis study aimed to investigate the incidence of increased platelet reactivity after CAS and to determine the factors related to it.MethodsPatients who underwent CAS were recruited prospectively. They received pre-procedural antiplatelet therapy comprising some combination of aspirin (100 mg/day), clopidogrel (75 mg/day), and/or cilostazol (200 mg/day) for a minimum of 7 days. ADP- and collagen-induced platelet aggregation were measured before and 4 days after CAS. Changes in platelet reactivity were reported as changes in the categorized platelet reactivity grade based on the effective dose 50%. Clinical characteristics of patients with and without increased platelet reactivity were compared.ResultsAmong 38 consecutive patients who underwent CAS, 18 (47%) exhibited increased platelet reactivity. Diabetes mellitus (OR 15.0; 95% CI 2.1 to 106.5; p=0.007) and carotid artery plaques exhibiting high-intensity signals (HIS) on time-of-flight MR angiography (TOF-MRA) (OR 25.2; 95% CI 2.0 to 316.2; p=0.013) were independently associated with increased platelet reactivity in a multivariate analysis.ConclusionsIncreased platelet reactivity occurred in nearly half of the studied patients subjected to CAS and was independently associated with diabetes mellitus and carotid artery plaques exhibiting HIS on TOF-MRA.
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Wiśniewski, Adam, Joanna Sikora, Aleksandra Karczmarska-Wódzka, and Przemysław Sobczak. "A Combination of Aspirin and Clopidogrel Predict More Favorable Dynamics of Platelet Reactivity versus Clopidogrel Alone in the Acute Phase of Minor Stroke." Healthcare 9, no. 6 (May 25, 2021): 628. http://dx.doi.org/10.3390/healthcare9060628.
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Background: The combined use of clopidogrel and aspirin is recommended for the short-term (21 days) therapy of minor stroke or transient ischemic attack. Previous studies have demonstrated its efficacy and superiority over treatment with a single antiplatelet agent. However, there is insufficient support for the advantages of such therapy based on platelet function testing. We aimed to compare the effect of the concomitant use of clopidogrel and aspirin versus clopidogrel alone on the dynamics of platelet reactivity over time to determine the appropriate antiplatelet treatment strategy for minor strokes. Methods: We enrolled 74 ischemic stroke subjects, including 38 minor strokes. Platelet reactivity was assessed by impedance aggregometry (Multiplate Analyzer) 48 and 96 h after a first 75 mg dose of clopidogrel, using the acetylsalicylic acid platelet inhibition (ASPI) test and the adenosine diphosphate (ADP) test. Dual antiplatelet therapy was strictly reserved only to minor strokes, as the other strokes received clopidogrel alone in the secondary prevention. The dynamics of platelet reactivity refer to the difference between two assessments, and a decrease in values over time was considered favorable. Results: The incidence of clopidogrel non-responsiveness was 64.8%, and this was similar in the group of minor strokes and the group of more disabling strokes. We indicated diabetes mellitus as an independent predictor of high on-clopidogrel platelet reactivity (Odds ratio OR 5.69 95% Confidence Interval CI 1.13–41.26, p = 0.0386). Among minor strokes treated with dual antiplatelet therapy, in relation to clopidogrel, we reported a trend toward more favorable dynamics of platelet reactivity over time compared to the group using clopidogrel alone (p = 0.0652 vs. p = 0.3384, respectively). We identified five predictors (sex, female; small-vessel disease; no diabetes; no hyperlipidemia; and no alcohol abuse) related to a significant decrease in platelet reactivity over time with respect to clopidogrel. No significant dynamics of platelet reactivity when using aspirin were found. Conclusions: Our findings, based on the favorable dynamics of platelet reactivity over time in relation to clopidogrel, confirm the usefulness of dual antiplatelet therapy in minor strokes and support the continuation of the secondary prevention with clopidogrel alone rather than aspirin, particularly among identified beneficiaries of such a strategy.
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Saxena, Aaruni, Karsten Schrör, and Thomas Hohlfeld. "High on treatment platelet reactivity against aspirin by non-steroidal anti-inflammatory drugs – pharmacological mechanisms and clinical relevance." Thrombosis and Haemostasis 109, no. 05 (2013): 825–33. http://dx.doi.org/10.1160/th12-07-0532.
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SummaryInhibition of platelet function by aspirin results from irreversible inhibition of platelet cyclooxygenase (COX)-1. While sufficient inhibition is obtained at antiplatelet doses (75–325 mg/day) in most (≥95%) treated patients, the antiplatelet effect of aspirin and subsequent cardiovascular risk reduction is much less in clinical settings and disease-dependent. Several reasons for this “high on treatment platelet reactivity” are known. This paper reviews the evidence for an interaction between aspirin and other COX inhibitors, namely non-steroidal antiinflammatory drugs (NSAIDs). Numerous experimental studies demonstrated a pharmacodynamic interaction between aspirin and NSAIDs. This likely occurs within the hydrophobic substrate channel of platelet COX-1 and might be explained by molecular competition between inhibitor drugs and substrate (arachidonic acid) at overlapping binding sites. This interaction is found with some compounds, notably ibuprofen and dipyrone (metamizole), but not with others, such as diclofenac and acetaminophen (paracetamol). Hence, this interaction is not a class effect of NSAIDs and/or non-steroidal analgesics but rather due to specific structural requirements which still remain to be defined. In vivo studies on healthy subjects and patients tend to confirm this type of interaction as well as large differences between NSAIDs and non-steroidal analgesics, respectively. These interactions may be clinically relevant and may increase the cardiovascular risk in long-term treatment for primary and secondary cardiovascular prevention in patients with chronic inflammation, such as rheumatoid arthritis. These patients have an elevated risk for myocardial infarctions and may require chronic antiplatelet treatment by aspirin in addition to treatment of inflammatory pain.
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Kuliczkowski, Wiktor, Ewa Żurawska-Płaksej, Maria Podolak-Dawidziak, Magdalena Cielecka-Prynda, Bożena Karolko, Jakub Dębski, Konrad Kaaz, et al. "Platelet Reactivity and Response to Aspirin and Clopidogrel in Patients with Platelet Count Disorders." Cardiology Research and Practice 2021 (April 17, 2021): 1–7. http://dx.doi.org/10.1155/2021/6637799.
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Background. Platelet reactivity and response to antiplatelet drugs, acetylsalicylic acid (ASA) and clopidogrel, in patients with thrombocytopenia and thrombocythemia can have a potentially important effect on the outcome. The effectiveness and safety of antiplatelet drugs in such patients has not been well examined. Measuring the effect of ASA and clopidogrel on platelets could help guide the therapy. Nevertheless, platelet response to antiplatelet drugs is not routinely measured in platelet count disorders and relevant evidence is scarce. Aims. The study aimed to measure platelet reactivity and response to ASA and clopidogrel in patients with platelet count disorders. Materials and Methods. This was a cross-sectional study of consecutive patients hospitalized in cardiology and hematology departments in the years 2018–2019. The study included patients with thrombocytopenia (PLT < 150 G/L) and thrombocythemia (PLT > 450 G/L) on ASA or dual antiplatelet therapy (DAPT; ASA plus clopidogrel). Controls included patients on antiplatelet drugs with normal platelet count. Platelet reactivity was measured in whole blood (Multiplate aggregometer, Roche, Switzerland) using arachidonic acid (AA), adenosine-5′-diphosphate (ADP), and thrombin receptor agonist peptide-6 (TRAP) as agonists. Platelet aggregation was expressed in arbitrary units (AU). AA-induced aggregation was used as a measure of response to ASA with a cut-off above 30 AU showing high on-treatment platelet reactivity to ASA (HTPR-A). ADP-induced aggregation measured response to clopidogrel with a cut-off above 48 AU for high on-treatment platelet reactivity to clopidogrel (HTPR-C). TRAP-induced aggregation measured baseline platelet reactivity not affected by oral antiplatelet drugs. Results. The study included 174 patients. There were 64 patients with thrombocytopenia, 30 patients with chronic thrombocythemia, and 80 controls. All patients were on 75 mg of ASA and 32% of them additionally on 75 mg of clopidogrel due to a history of recent coronary artery angioplasty. AA- and ADP-induced aggregation was comparable between thrombocytopenic patients and controls (median (IQR) 19 (7–28) vs. 23 (15–38) for AA AU and 32 (16–44) vs. 50 (32–71) for ADP AU, respectively), while it was significantly higher in thrombocythemic patients (median (IQR) 80 (79–118) for AA AU and 124 (89–139) for ADP AU). TRAP-induced aggregation showed significantly lowest aggregation in thrombocytopenic (median (IQR) 41 (34–60) for TRAP AU) and highest in thrombocythemic patients (median (IQR) 137 (120–180) for TRAP AU). HTPR-A was frequent in thrombocythemic patients in comparison with thrombocytopenic patients and controls (60% vs. 4% vs. 15%, respectively; p < 0.0002 ). HTPR-C was highly common in thrombocythemic patients and least common in thrombocytopenic ones in comparison with controls (80% vs. 8% vs. 40%, respectively; p < 0.001 ). Conclusion. Chronic thrombocytopenia does not significantly affect platelet reactivity and response to ASA and clopidogrel in comparison with controls. Thrombocytosis significantly increases platelet reactivity and attenuates response to both ASA and clopidogrel.
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Stolarek, Wioleta, Michał Kasprzak, Joanna Sikora, Emilia Siemińska, and Grzegorz Grześk. "High on-treatment platelet reactivity to aspirin in patients after myocardial infarction." Biomedicine & Pharmacotherapy 147 (March 2022): 112618. http://dx.doi.org/10.1016/j.biopha.2022.112618.
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Patregnani, Jason, Darren Klugman, David Zurakowski, Pranava Sinha, Robert Freishtat, John Berger, and Yaser Diab. "High on Aspirin Platelet Reactivity in Pediatric Patients Undergoing the Fontan Procedure." Circulation 134, no. 17 (October 25, 2016): 1303–5. http://dx.doi.org/10.1161/circulationaha.116.023457.
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Johnston, L. R., A. S. Holley, M. Chen-Xu, A. C. La Flamme, D. Larsen, and S. A. Harding. "High Residual Platelet Reactivity on Aspirin in a New Zealand ACS Population." Heart, Lung and Circulation 21, no. 8 (August 2012): 491–92. http://dx.doi.org/10.1016/j.hlc.2012.03.043.
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Wiśniewski, Adam, Karolina Filipska, Joanna Sikora, and Grzegorz Kozera. "Aspirin Resistance Affects Medium-Term Recurrent Vascular Events after Cerebrovascular Incidents: A Three-Year Follow-up Study." Brain Sciences 10, no. 3 (March 19, 2020): 179. http://dx.doi.org/10.3390/brainsci10030179.
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Background: The aim of this prospective, a three-year follow-up study, was to establish the role of high on-treatment platelet reactivity (HTPR) in predicting the recurrence of vascular events in patients after cerebrovascular incidents, particularly in the aspect of stroke etiology. Methods: The study included 101 subjects with non-embolic cerebral ischemia (69 patients with ischemic stroke and 32 patients with transient ischemic attack) treated with 150 mg of acetylsalicylic acid (aspirin) a day. The platelet reactivity was tested in the first 24 h after the onset of cerebral ischemia by impedance aggregometry. Recurrent vascular events, including recurrent ischemic stroke, transient ischemic attack, myocardial infarction, systemic embolism, or sudden death of vascular reason, were assessed 36 months after the onset of cerebral ischemia. Results: Recurrent vascular events occurred between 3 and 9 months after onset in 8.5% of all subjects; in the HTPR subgroup, recurrent vascular events occurred in 17.9%; in the normal on-treatment platelet reactivity (NTPR) subgroup, they occurred in 4.6%. We did not notice early or long-term recurrent events. Aspirin resistant subjects had a significantly higher risk of recurrent vascular events than did aspirin sensitive subjects (Odds ratio (OR) = 4.57, 95% Confidence interval (CI) 1.00–20.64; p = 0.0486). Cox proportional hazard models showed that large-vessel disease (Hazard ratio (HR) 12.04, 95% CI 2.43–59.72; p = 0.0023) and high on-treatment platelet reactivity (HR 4.28, 95% CI 1.02–17.93; p = 0.0465) were independent predictors of recurrent vascular events. Conclusion: Aspirin resistance in the acute phase of cerebral ischemia was associated with a higher risk of recurrent medium-term vascular events, coexisting with large-vessel etiology of stroke. Platelet function-guided personalized antiplatelet treatment should be considered for patients with recurrent strokes, especially when due to large-vessel disease.
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Gruber, Susanne, Erik Grove, Thomas Weiss, Johann Wojta, Kurt Huber, and Matthias Freynhofer. "Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing." Thrombosis and Haemostasis 114, no. 09 (2015): 459–68. http://dx.doi.org/10.1160/th15-02-0179.
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SummaryPlatelets are key players in atherothrombosis. Antiplatelet therapy comprising aspirin alone or with P2Y12-inhibitors are effective for prevention of atherothrombotic complications. However, there is interindividual variability in the response to antiplatelet drugs, leaving some patients at increased risk of recurrent atherothrombotic events. Several risk factors associated with high on-treatment platelet reactivity (HTPR), including elevated platelet turnover, have been identified. Platelet turnover is adequately estimated from the fraction of reticulated platelets. Reticulated platelets are young platelets, characterised by residual messenger RNA. They are larger, haemostatically more active and there is evidence that platelet turnover is a causal and prognostic factor in atherothrombotic disease. Whether platelet turnover per se represents a key factor in pathogenesis, progression and prognosis of atherothrombotic diseases (with focus on acute coronary syndromes) or whether it merely facilitates insufficient platelet inhibition will be discussed in this state-of-the art review.
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Kristensen, Steen, Willibald Hochholzer, Franz-Josef Neumann, and Dietmar Trenk. "High on-treatment platelet reactivity and P2Y12 antagonists in clinical trials." Thrombosis and Haemostasis 109, no. 05 (2013): 834–45. http://dx.doi.org/10.1160/th12-08-0588.
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SummaryDual antiplatelet therapy with aspirin and clopidogrel in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes (ACS) has substantially decreased the rate of cardiovascular events. Within the past decade, the variability in pharmacodynamic response as well as the moderate antiplatelet efficacy of clopidogrel has raised major concerns, since high on-clopidogrel platelet reactivity has consistently been associated with increased risk for ischaemic events in PCI patients. The variability in response could be linked to genetic polymorphisms impacting on activity of cytochrome P450 enzymes as well as clinical and demographic variables, but, taken together, factors identified so far can explain only up to approximately 12% of this variability in adenosine diphosphate-induced platelet aggregation on clopidogrel. Regulatory agencies as well as major cardiac societies suggest the use of other anti-platelet medications or alternative dosing strategies for clopidogrel in patients with reduced effectiveness of clopidogrel. This review will focus on the current status of alternate strategies for more sufficient suppression of high platelet reactivity.
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Dillinger, Jean-Guillaume, Alaa Saeed, Vincent Spagnoli, Claire Bal dit Sollier, Georgios Sideris, Stephane Manzo Silberman, Sebastian Voicu, Ludovic Drouet, and Patrick Henry. "High platelet reactivity on aspirin in patients with acute ST elevation myocardial infarction." Thrombosis Research 144 (August 2016): 56–61. http://dx.doi.org/10.1016/j.thromres.2016.05.002.
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Simpson, Scot H., Ahmed S. Abdelmoneim, Dima Omran, and Travis R. Featherstone. "Prevalence of High On-treatment Platelet Reactivity in Diabetic Patients Treated with Aspirin." American Journal of Medicine 127, no. 1 (January 2014): 95.e1–95.e9. http://dx.doi.org/10.1016/j.amjmed.2013.09.019.
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Horn, E. H., E. Hardy, J. Cooper, S. Heptinstall, and P. C. Rubin. "Platelet Reactivity In Vitro in Relation to Thromboxane in Healthy Pregnancy." Thrombosis and Haemostasis 75, no. 02 (1996): 346–51. http://dx.doi.org/10.1055/s-0038-1650272.
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SummaryThere is substantial evidence of increased platelet reactivity in vivo and in vitro during pregnancy. Previous in vitro studies suggest that platelets from pregnant women show increased sensitivity to agonists, the response to which has a thromboxane dependent component. The aim of this study was to determine whether this is due to increased activity of the thromboxane biosynthetic pathway or to increased platelet sensitivity to the effects of thromboxane. During pregnancy, platelets were more sensitive to the pro-aggregatory effects in vitro of the thromboxane mimetic U46619, in whole blood and in platelet rich plasma, compared to those from non-pregnant controls. The difference in extent of U46619-induced platelet aggregation between groups was abolished in the presence of a high concentration of the specific thromboxane antagonist ICI 192605, but not by prior incubation of blood with aspirin. Platelets from pregnant women were significantly less sensitive to inhibition of arachidonic acid induced activation by the thromboxane synthetase inhibitor dazmegrel, but there was no change in platelet cyclic AMP accumulation under these conditions. Arachidonic acid induced platelet thromboxane B2 production was similar in pregnant and non-pregnant subjects. In conclusion, platelets are more sensitive to the activating effects of thromboxane during pregnancy, but there is no change in the intrinsic reactivity of the thromboxane biosynthetic pathway.
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Elsenberg, Ellen H. A. M., Ruud M. A. van de Wal, Carla A. Zomer, Heleen J. Bouman, Freek W. A. Verheugt, Jurriën M. ten Berg, Christian M. Hackeng, and Jochem W. van Werkum. "The influence of clinical characteristics, laboratory and inflammatory markers on ‘high on-treatment platelet reactivity’ as measured with different platelet function tests." Thrombosis and Haemostasis 102, no. 10 (2009): 719–27. http://dx.doi.org/10.1160/th09-05-0285.
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SummaryHigh on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are independently associated with an increased risk of atherothrombotic events. However, despite this positive correlation, the definitions of both HCPR and HAPR vary largely throughout studies and between different platelet function assays.The aim of the present study was to explore clinical and laboratory parameters that are associated with HCPR and HAPR as measured with different platelet function tests. 530 clopidogrel and aspirin pre-treated patients undergoing elective PCI (percutaneous coronary intervention) were enrolled. Platelet function measurements were performed with: optical aggregometry, the VerifyNow device and PFA-100 cartridges (including the novel INNOVANCE® P2Y assay). HCPR as measured with Adenosin-Di-Phospate-induced (ADP) aggregation based tests was associated with clinical factors such as older age, female gender and Diabetes mellitus (DM).TheVerifyNow P2Y12 assay was significantly influenced by haemoglobin and haematocrit levels. HAPR as measured with aggregation based tests was significantly influenced by the presence of malignancy, BMI (Body-Mass Index), older age and increased levels of hsCRP (high sensitivity c-reactive proteine).The PFA-100 COL/ EPI (collagen-epinephrine) and COL/ADP (collagen-ADP) cartridges were significantly influenced by monocyte count,hs-CRP, MPV (mean platelet volume), vWF-antigen (von Willebrand factor) and vWF-activity. HCPR as measured with the novel INNOVANCE® P2Y cartridge was associated with clinical determinants such as BMI,female gender,impaired LVEF (left ventricular ejection fraction), renal failure and dosing of clopidogrel. Laboratory markers that were associated with HCPR as measured with INNOVANCE® P2Y were platelet count, white blood cells (WBC), hsCRP and fibrinogen.Both HCPR and HAPR are highly dependent on the type of platelet function assay. Each platelet function assay, in turn, is significantly influenced by distinct clinical and laboratory variables.
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Mark, Gwenda, and T. A. B. Sanders. "The influence of different amounts ofn-3 polyunsaturated fatty acids on bleeding time and invivovascular reactivity." British Journal of Nutrition 71, no. 1 (January 1994): 43–52. http://dx.doi.org/10.1079/bjn19940109.
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Mesenteric bleeding time, mesenteric vascular reactivity, platelet and erythrocyte lipid fatty acid composition were measured at 2–3 weeks, 5–6 weeks and 11–22 weeks in normotensive Wistar rats, fed on high (6·5% energy) or moderate (1·6% energy) intakes of eicosapentaenoic acid (20: 5n−3; EPA) as fish oil, compared with controls fed on a diet devoid of EPA. All diets contained the same level of linoleic acid (4% energy): the moderate- and high-EPA diets also contained 1·1 and 4·4% of the energy as docosahexaenoic acid (22:6n−3) respectively. Moderate, but not high, intakes of EPA increased mesenteric bleeding time. Similar reductions in erythrocyte and platelet arachidonic acid (20: 4n−6) occurred in animals fed on either high or low amounts of EPA, but the proportion of EPA increased dose-dependently. At high intakes of EPA the proportion of oleic acid in platelets and erythrocytes was decreased. Blood pressure platelet counts, mesenteric vessel diameter and mesenteric vascular reactivity to vasopressin were unaffected by treatment. High intakes of fish oil led to a slight fall in packed cell volume. In a second experiment bleeding time and mesenteric vascular reactivity to noradrenaline were increased 2–4 weeks after receiving a moderate intake of EPA and these effects persisted 5–21 d after switching to a control diet. A similar increase in vascular reactivity to noradrenaline was observed in animals given indomethacin (6 mg/kg) but not in those given aspirin (20 mg/kg).
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Alexopoulos, Dimitrios, Iosif Xenogiannis, Panagiotis Vlachakis, Udaya Tantry, and Paul Gurbel. "Peri-Procedural Platelet Reactivity in Percutaneous Coronary Intervention." Thrombosis and Haemostasis 118, no. 07 (June 4, 2018): 1131–40. http://dx.doi.org/10.1055/s-0038-1649484.
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AbstractPlatelet activation and aggregation play a pivotal role in thrombotic complications occurring during percutaneous coronary intervention (PCI), and peri-PCI anti-platelet therapy represents a standard of care. High platelet reactivity prior to PCI has been correlated with an increased incidence of peri-procedural myonecrosis. Pre-PCI platelet reactivity predicts post-PCI platelet reactivity and has a prognostic impact on subsequent ischaemic and bleeding events, so as the platelet inhibition measured post-PCI. Many anti-platelet treatment strategies, including aspirin, glycoprotein IIb/IIIa inhibitors, P2Y12 receptor blockers and vorapaxar, are being used in the routine clinical practice to modify platelet reactivity at each stage, e.g. pre-, during and post-PCI. Anti-platelet strategies with a ‘stronger and faster’ pharmacodynamic effect than clopidogrel have been mostly adopted in patients with acute coronary syndromes. However, several issues regarding the anti-platelet treatment such as benefits/risks of anti-platelet therapy pre-treatment and duration, and definite association between speed and potency of various anti-platelet agents and clinical outcomes remain controversial. We believe that a better understanding of peri-PCI platelet reactivity and its relations to outcomes may lead to the development of more effective and safe treatment strategies.
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Ait-Mokhtar, Omar, Laurent Bonello, Saida Benamara, and Franck Paganelli. "High on Treatment Platelet Reactivity." Heart, Lung and Circulation 21, no. 1 (January 2012): 12–21. http://dx.doi.org/10.1016/j.hlc.2011.08.069.
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Wang, Zanxin, Fei Gao, Jianlong Men, Jie Yang, Paul Modi, and Minxin Wei. "Polymorphisms and high on-aspirin platelet reactivity after off-pump coronary artery bypass grafting." Scandinavian Cardiovascular Journal 47, no. 4 (May 31, 2013): 194–99. http://dx.doi.org/10.3109/14017431.2013.800640.
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Zhang, Jingwei, Wenwen Liu, Timothy McCaffrey, Xiaoquan He, Wenyi Liang, Xiahuan Chen, Xueru Feng, Sidney Fu, and Meilin Liu. "Predictors of high on-aspirin platelet reactivity in elderly patients with coronary artery disease." Clinical Interventions in Aging Volume 12 (August 2017): 1271–79. http://dx.doi.org/10.2147/cia.s138592.
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Bernlochner, Isabell, Steven Steinhubl, Siegmund Braun, Tanja Morath, Juliane Jaitner, Julia Stegherr, Julinda Mehilli, et al. "Association between inflammatory biomarkers and platelet aggregation in patients under chronic clopidogrel treatment." Thrombosis and Haemostasis 104, no. 12 (2010): 1193–200. http://dx.doi.org/10.1160/th10-05-0266.
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SummaryInflammatory processes in the vessel wall are associated with progression of atherosclerosis and myocardial infarction. Both high levels of C-reactive protein (CRP) and high on-clopidogrel treatment platelet reactivity (HPR) have been linked to an increased risk of ischaemic events after percutaneous coronary intervention (PCI). The aim of this study was to explore the association between biomarker levels of inflammation and platelet reactivity. Stable patients (n=1,223) eligible for this study were under chronic antiplatelet treatment with aspirin and clopidogrel due to prior coronary stent placement. ADP-induced platelet aggregation (in AU*min) was measured on a Multiplate analyser. The primary outcome measure of this retrospective study was the ADP-induced platelet aggregation in patients with versus those without elevated CRP levels. Of the patients 15.5% (n=189) showed elevated CRP levels (≥5 mg/l). Platelet aggregation (median [interquartile range]) was significantly higher in patients with elevated CRP levels compared to patients with normal (<5 mg/l) CRP levels (305 [202–504] AU*min vs. 218 [144–384] AU*min; p<0.001). A multivariable linear regression model that adjusted for known predictors of HPR confirmed a significant independent association between elevated CRP levels and high ADP-induced platelet aggregation values (p=0.0002). Elevated WBC count and fibrinogen levels were also associated with higher platelet aggregation values (p<0.001 for both). In conclusion, elevated levels of CRP, WBC count and fibrinogen were significantly associated with high platelet reactivity in patients under chronic clopidogrel treatment. Whether a direct relation between platelets and inflammation exists, as well as the clinical impact of our results, warrants further investigations.
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Franchi, Francesco, Fabiana Rollini, Emilio Garcia, Jose Rivas Rios, Andrea Rivas, Malhar Agarwal, Megha Kureti, et al. "Effects of Edoxaban on the Cellular and Protein Phase of Coagulation in Patients with Coronary Artery Disease on Dual Antiplatelet Therapy with Aspirin and Clopidogrel: Results of the EDOX-APT Study." Thrombosis and Haemostasis 120, no. 01 (August 30, 2019): 083–93. http://dx.doi.org/10.1055/s-0039-1695772.
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AbstractIn patients requiring dual antiplatelet therapy (DAPT) who also have an indication to be treated with oral anticoagulant (OAC) drugs, aspirin withdrawal reduces the risk of bleeding. There is limited data on the pharmacodynamic effects associated with adding a nonvitamin K antagonist OAC on a background of aspirin and a P2Y12 inhibitor as well as dropping aspirin. Seventy-five patients on DAPT (aspirin plus clopidogrel) were randomized to DAPT plus high-dose edoxaban (60 mg once daily, Group A), DAPT plus low-dose edoxaban (30 mg once daily, Group B), or DAPT only (Group C) for 10 ± 2 days (Phase I). Afterwards, Groups A and B interrupted aspirin and maintained clopidogrel plus edoxaban for 10 ± 2 days, while patients in Group C maintained DAPT (Phase II). Platelet aggregation and clot kinetics were assessed at baseline, end of Phase I, and end of Phase II using thrombelastography (TEG), light transmittance aggregometry (LTA), VerifyNow P2Y12, and serum thromboxane-B2. The primary endpoint was the comparison of maximum amplitude (MA) measured by TEG, a measure of clot strength, between patients on DAPT plus high-dose edoxaban and patients on DAPT only. Edoxaban prolonged in a dose-dependent manner speed of thrombin generation (TEG R; Group A: 7.7 [6.8–8.7] vs. Group B: 7.4 [6.4–8.5] vs. Group C: 6.3 [5.7–7.0]; p = 0.05) but did not affect other markers of clot kinetics, including TEG MA (Group A: 63 [61–64] vs. Group B: 65 [63–67] vs. Group C: 64 [63–65]; p = 0.10). After aspirin discontinuation, platelet reactivity assessed by LTA using thrombin receptor activating peptide as agonist increased to a greater extent with low-dose edoxaban. Stopping aspirin did not affect markers of P2Y12 reactivity and had no or marginal effects on clot kinetics, but increased markers sensitive to cyclooxygenase-1 blockade.
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Dichiara, Joseph, Kevin P. Bliden, Udaya S. Tantry, Srivasavi K. Chaganti, Rolf P. Kreutz, Tania B. Gesheff, Tania A. Geshefe, Yvonne Kreutz, and Paul A. Gurbel. "Platelet function measured by VerifyNow™ identifies generalized high platelet reactivity in aspirin treated patients." Platelets 18, no. 6 (January 2007): 414–23. http://dx.doi.org/10.1080/09537100701206824.
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Park, Yongwhi, Udaya Tantry, Jong-Hwa Ahn, Kye Hwan Kim, Jin-Sin Koh, Jeong-Rang Park, Seok-Jae Hwang, et al. "Effect of adjunctive dipyridamole to DAPT on platelet function profiles in stented patients with high platelet reactivity." Thrombosis and Haemostasis 112, no. 12 (2014): 1198–208. http://dx.doi.org/10.1160/th14-01-0040.
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SummaryAdjunctive use of phosphodiesterase (PDE) inhibitor can enhance antiplatelet and vasoprotective properties in patients with cardiovascular disease. The aim of this study was to evaluate the impact of PDE5 inhibitor dipyridamole on platelet function in stented patients with high platelet reactivity (HPR) during dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. Patients with HPR after 600-mg clopidogrel loading were randomly assigned to adjunctive dipyridamole 75 mg twice daily to standard DAPT (DIP group; n = 45) or double-dose clopidogrel of 150 mg daily (DOUBLE group; n = 46) for 30 days. Platelet function was assessed at baseline and 30-day follow-up with platelet reactivity index (PRI) by vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) assay and platelet aggregation (PA) by light transmittance aggregometry (LTA). Primary endpoint was PRI at 30-day follow-up. HPR was defined as PRI > 50%. Baseline platelet function did not differ between the groups. Following 30-day therapy, platelet function was significantly reduced in the DIP and DOUBLE groups (all p-values ≤ 0.004 and ≤ 0.068, respectively). PRI values were not significantly different between the two groups (mean difference: 3.1%; 95% confidence interval: –2.8% to 9.0%: p = 0.295). PA values and prevalence of HPR were similar between the groups. However, a significant number of patients still exhibited HPR in the DIP (75.6%) and DOUBLE (67.4%) groups. In conclusion, among stented HPR patients, adding dipyridamole to DAPT does not reduce platelet reactivity and prevalence of HPR compared with double-dose clopidogrel therapy, and therefore both strategies are inadequate to overcome HPR.
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Kuliczkowski, Wiktor, Mariusz Gasior, Damian Pres, Jacek Kaczmarski, Anna Laszowska, Marta Szewczyk, Michal Hawranek, et al. "Aspirin ‘Resistance': Impact on No-Reflow, Platelet and Inflammatory Biomarkers in Diabetics after ST-Segment Elevation Myocardial Infarction." Cardiology 131, no. 1 (2015): 41–50. http://dx.doi.org/10.1159/000371793.
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Background: The no-reflow (NR) phenomenon exists despite percutaneous coronary intervention (PCI), and is especially prevalent in diabetics. The causes(s) of NR are not fully elucidated, but may be associated with impaired residual platelet and inflammatory reactivity during dual-antiplatelet therapy. Objective: To assess the relationship between dual-antiplatelet therapy, NR and conventional biomarkers suggestive of platelet and inflammatory response in diabetics following ST-segment elevation myocardial infarction (STEMI) treated with PCI. Methods: Sixty diabetics with (n = 27) and without NR (n = 33) were prospectively enrolled. All patients were treated with clopidogrel and aspirin. Platelet and inflammatory biomarkers were assessed serially in the peripheral blood and right atrium before and after PCI and then at 24 h, 7 days and 30 days. Results: Arachidonic acid (AA)-induced platelet aggregation and the serum thromboxane B2 level before and after PCI (in the peripheral and right atrium blood) were significantly higher in the NR patients than in those with no NR. AA-induced aggregation >100 (AUC*min) before PCI predicted NR in diabetic patients with 96.2% sensitivity and 38.5% specificity (AUC 0.66; 95% CI 0.52-0.71; p = 0.029). There were no other correlations between NR and platelet reactivity (collagen, adenosine diphosphate, thrombin receptor agonist peptide-induced aggregation, vasodilator-stimulated phosphoprotein platelet reactivity index, soluble P-selectin, soluble CD40 ligand, platelet-derived growth factor AB and the level of platelet-monocyte aggregates) or between NR and inflammatory indices (i.e. high-sensitivity C-reactive protein, interleukin 6 and interleukin 10). Conclusion: An inadequate response to aspirin, but not to clopidogrel, may be associated with the occurrence of the NR phenomenon in diabetics with STEMI who have been treated with primary PCI.
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Tantry, U. S., and P. A. Gurbel. "Platelet monitoring for PCI." Hämostaseologie 29, no. 04 (2009): 368–75. http://dx.doi.org/10.1055/s-0037-1617138.
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SummaryPercutaneous coronary intervention (PCI) has significantly improved clinical outcomes in coronary artery disease patients. Since PCI is associated with platelet activation, antiplatelet therapy with aspirin, clopidogrel and GPIIb/IIIa inhibitors comprise the cornerstone strategy during and following PCI. The latter agents are arguably the most important drugs we administer to the patient with established coronary artery disease since they are specifically given to prevent the most catastrophic event, the formation of an occlusive arterial thrombus. Numerous clinical trials have confirmed the efficacy of antiplatelet therapy in attenuating recurrent ischaemic event occur-rence.Despite the extensive use of antiplatelet therapies, ischaemic event occurrence such as post-procedural myocardial infarction and stent thrombosis still remains an important concern and highlights the need for improved treatment strategies. A major limitation of current treatment is the application of a “one size fits all” strategy advocated by the guidelines that completely ignores the evaluation of the individual antiplatelet response. Pharmacodynamic studies have revealed the limitations of aspirin and clopidogrel treatment that include response variability, and a high prevalence of antiplatelet non-responsiveness associated with significant risk for recurrent ischemic event occurrence. Thus, two major paradoxes in cardiovascular medicine today are: 1) despite the overwhelming evidence that platelet reactivity strongly influences the development of potentially catastrophic events including myocardial infarction and stent thrombosis in the PCI patient, no measurement is made in clinical practice to assess the presence of blood vulnerability (platelet reactivity) and 2) despite the overwhelming evidence that the effect of dual antiplatelet therapy with aspirin and P2Y12 receptor blockers is variable, the guidelines largely recommend a uniform, “one size fits all” dosing of these agents in the PCI patient without any confirmation of an adequate antiplatelet effect.