Articles de revues : « Low on-treatment platelet reactivity »

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Massimi, Isabella, Lavinia Lotti, Flavia Temperilli, Massimo Mancone, Gennaro Sardella, Simone Calcagno, Ombretta Turriziani, Luigi Frati et Fabio M. Pulcinelli. « Enhanced platelet MRP4 expression and correlation with platelet function in patients under chronic aspirin treatment ». Thrombosis and Haemostasis 116, n^o 12 (novembre 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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Cardona, Francesco, Jens Schwindt, Angelika Berger, Stefan Kuhle, Monika Homoncik, Petra Jilma-Stohlawetz, Arnold Pollak, Bernd Jilma et Nadja Haiden. « Changes in thrombopoiesis and platelet reactivity in extremely low birth weight infants undergoing erythropoietin therapy for treatment of anaemia of prematurity ». Thrombosis and Haemostasis 93, n^o 01 (2005) : 118–23. http://dx.doi.org/10.1160/th04-02-0093.

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SummaryErythropoietin (Epo) is frequently administered to premature infants to stimulate erythropoiesis. There is evidence from studies in animals and healthy adults that Epo also interacts with thrombopoiesis and platelet function.This study investigates the effect of Epo therapy on platelet reactivity, peripheral platelet counts and thiazole orange-positive (TO+) platelets in extremely low birth weight (ELBW) infants. In a randomised-controlled trial, ELBW infants with a birth weight ≤ 800g and a gestational age ≤ 32 weeks were either randomised to a group receiving Epo during the first weeks of life or to a control group. Our results show that thrombin receptor-activating peptide (TRAP-6) -induced expression of P-selectin increased significantly during the first two weeks of Epo treatment.With the exception of week five, the number of TO+ platelets was significantly higher during the first eight weeks in Epo-treated infants compared to controls. The increase of TO+ platelets was not paralleled by an increase in total platelet count.We can conclude that Epo therapy has a short-lasting effect on platelet reactivity toTRAP-6 in ELBW infants during the first two weeks of life.Furthermore, Epo therapy is associated with an increase in the number of TO+ platelets compared to controls.

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Tscharre, Maximilian, Silvia Lee, Christoph W. Kopp, Simon Panzer et Thomas Gremmel. « Mean Corpuscular Volume Predicts Adverse Outcomes Following Peripheral Angioplasty With Stenting and Is Associated With On-Treatment Platelet Reactivity ». Angiology 72, n^o 1 (24 juillet 2020) : 16–23. http://dx.doi.org/10.1177/0003319720943816.

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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.

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Pedersen, Oliver Buchhave, Leonardo Pasalic, Erik Lerkevang Grove, Steen Dalby Kristensen, Anne-Mette Hvas et Peter H. Nissen. « Advanced Flow Cytometry Using the SYTO-13 Dye for the Assessment of Platelet Reactivity and Maturity in Whole Blood ». Methods and Protocols 6, n^o 1 (13 janvier 2023) : 8. http://dx.doi.org/10.3390/mps6010008.

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Newly produced immature platelets are larger, contain higher amounts of residual RNA, and are more reactive than mature platelets. Flow cytometry using the SYTO-13 dye is a method for the subdivision of immature platelets from mature platelets based on the labelling of intracellular platelet RNA, enabling the simultaneous investigation of the reactivity of each platelet population. This method provides detailed information on several aspects of platelet physiology using a combination of platelet surface markers and agonists. Currently, no standardized protocol exists across laboratories. Here, we describe a flow cytometry protocol in detail to investigate platelet reactivity and its relation to platelet maturity. We analyzed 20 healthy individuals with the protocol and compared the platelet subpopulation with the highest SYTO-13 labelling (in the first quintile, “SYTO-high”) corresponding to the most immature platelets (highest RNA content) with the platelet subpopulation with the lowest SYTO-13 labelling (in the fifth quintile, “SYTO-low”) corresponding to the mature platelets with the lowest RNA content. SYTO-high platelets had overall significantly increased platelet reactivity compared with that of SYTO-low platelets. The presented method may be a valuable research tool for the analysis of platelet reactivity and its relation to platelet maturity.

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Berger, Martin, Alexander Dressel, Marcus E. Kleber, Winfried März, Peter Hellstern, Nikolaus Marx et Katharina Schütt. « Platelet Reactivity and Cardiovascular Mortality Risk in the LURIC Study ». Journal of Clinical Medicine 12, n^o 5 (28 février 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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Psaila, Bethan, James B. Bussel, Matthew D. Linden, Bracken Babula, Youfu Li, Marc R. Barnard, Chinara Tate, Kanika Mathur, Andrew L. Frelinger et Alan D. Michelson. « In vivo effects of eltrombopag on platelet function in immune thrombocytopenia : no evidence of platelet activation ». Blood 119, n^o 17 (26 avril 2012) : 4066–72. http://dx.doi.org/10.1182/blood-2011-11-393900.

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Abstract The effects of eltrombopag, a thrombopoietin-receptor agonist, on platelet function in immune thrombocytopenia (ITP) are not fully characterized. This study used whole blood flow cytometry to examine platelet function in 20 patients receiving eltrombopag treatment at days 0, 7, and 28. Platelet surface expression of activated GPIIb/IIIa, P-selectin, and GPIb was measured with and without low and high adenosine diphosphate (ADP) and thrombin receptor activating peptide (TRAP) concentrations. Before eltrombopag treatment with no ex vivo agonist, platelet activation was higher in ITP patients than controls. Platelet GPIb and activated GPIIb/IIIa expression without added agonist was unchanged following eltrombopag treatment, whereas a slight increase in P-selectin was observed. Expression of P-selectin and activated GPIIb/IIIa in response to high-dose ADP was lower during eltrombopag treatment than at baseline. Eltrombopag led to a slight increase in platelet reactivity to TRAP only in responders to eltrombopag but not to levels above those in controls; whole blood experiments demonstrated that this increase was probably because of higher platelet counts rather than higher platelet reactivity. In conclusion, although thrombocytopenic ITP patients have higher baseline platelet activation than controls, eltrombopag did not cause platelet activation or hyper-reactivity, irrespective of whether the platelet count increased.

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JEONG, Y. H., K. P. BLIDEN, U. S. TANTRY et P. A. GURBEL. « High on-treatment platelet reactivity assessed by various platelet function tests : is the consensus-defined cut-off of VASP-P platelet reactivity index too low ? » Journal of Thrombosis and Haemostasis 10, n^o 3 (29 février 2012) : 487–89. http://dx.doi.org/10.1111/j.1538-7836.2011.04604.x.

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Dhillon, Ashwat S., Jorge Caro, Han Tun, David G. Armstrong, Vincent Rowe, David M. Shavelle et Leonardo C. Clavijo. « Therapeutic Window of Clopidogrel and Ticagrelor in Patients With Critical Limb-Threatening Ischemia ». Journal of Cardiovascular Pharmacology and Therapeutics 25, n^o 2 (24 septembre 2019) : 158–63. http://dx.doi.org/10.1177/1074248419877411.

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Background: Critical limb-threatening ischemia (CLTI) is associated with an increased risk of major adverse limb events and mortality. High on-treatment platelet reactivity (HPR) is associated with an increased risk of ischemic events, while low on-treatment platelet reactivity (LPR) is associated with an increased risk of bleeding. This study investigates the frequency with which patients with CLTI on clopidogrel or ticagrelor achieve a “therapeutic window” (TW) of platelet inhibition. Methods: Data from the “Switch To Ticagrelor in Critical Limb Ischemia Anti-Platelet Study” were assessed retrospectively to determine the incidence of TW of on-treatment platelet reactivity in 50 consecutive patients with CLTI (mean age: 65.2 ± 10.5 years, 54% male). The data included 4 measurements of patients’ platelet reactivity using the VerifyNow P2Y12 Assay: baseline and steady state platelet reactivity on clopidogrel 75 mg daily and on ticagrelor 90 mg twice daily. Results: At baseline, 46% of patients on clopidogrel were within TW of on-treatment platelet reactivity compared to 10% of patients on ticagrelor ( P < .0001). At steady state, 42% of patients on clopidogrel were within the TW compared to 10% of patients on ticagrelor ( P < .0001). Patients on ticagrelor exhibited higher rates of LPR compared to those on clopidogrel at baseline as well as at steady state (baseline 88% vs 18%, steady state 88% vs 28%; P < .0001). Conclusion: Although ticagrelor has been proposed as an alternative for patients with HPR on clopidogrel, the current study observes an excess of platelet inhibition with ticagrelor in most patients with CLTI at a dose of 90 mg twice daily.

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Liu, Ru, Tianyu Li, Deshan Yuan, Yan Chen, Xiaofang Tang, Lijian Gao, Ce Zhang et al. « Long-term effects of baseline on-treatment platelet reactivity in patients with acute coronary syndrome and thrombocytopenia undergoing percutaneous coronary intervention ». Journal of International Medical Research 50, n^o 4 (avril 2022) : 030006052210817. http://dx.doi.org/10.1177/03000605221081725.

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Objective To analyse the association between on-treatment platelet reactivity (TPR) and long-term outcomes of patients with acute coronary syndrome (ACS) and thrombocytopenia (TP) in the real world. Methods This prospective observational study enrolled patients with coronary artery disease (CAD) that underwent percutaneous coronary intervention (PCI). Patients with ACS and TP under dual antiplatelet therapy were selected for analysis. The 2- and 5-year clinical outcomes were evaluated among patients with high on-treatment platelet reactivity (HTPR), low on-treatment platelet reactivity (LTPR) and normal on-treatment platelet reactivity (NTPR), as tested by thromboelastogram at baseline. Results A total of 10 724 patients with CAD that underwent PCI were identified. Of these, 474 patients with ACS and TP met the inclusion criteria: 124 (26.2%) with HTPR, 163 (34.4%) with LTPR and 187 (39.5%) with NTPR. The 5-year rates of all-cause death, major adverse cardiovascular and cerebrovascular events, cardiac death, myocardial infarction, revascularization, stroke and bleeding were not significantly different among the three groups. Multivariate Cox regression analysis demonstrated that patients with HTPR were not independently associated with any of the 5-year endpoints compared with patients with NTPR. Conclusions TPR at baseline was not independently associated with long-term outcomes in patients with ACS and TP that underwent PCI.

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Settergren, Magnus, Felix Böhm, John Pernow, Paul Hjemdahl et Rickard Malmström. « No effect of lipid lowering on platelet activity in patients with coronary artery disease and type 2 diabetes or impaired glucose tolerance ». Thrombosis and Haemostasis 101, n^o 01 (2009) : 157–64. http://dx.doi.org/10.1160/th08-06-0385.

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SummaryIn addition to lowering cholesterol, statins may reduce platelet activity and exert beneficial non-lipid (pleiotropic) effects. We evaluated the effects of two different simvastatin based treatment regimens on platelet reactivity in patients with dysglycemia and coronary artery disease (CAD). Thirty-two patients with type 2 diabetes or impaired glucose tolerance and stable CAD received six weeks of double-blind treatment with simvastatin 80 mg daily (S80; n=16) or ezetimibe 10 mg and simvastatin 10 mg daily (E10/S10; n=16). Total and low-density lipoprotein (LDL) cholesterol, and high sensitivity C-reactive protein (CRP) decreased similarly in the two groups. LDL (mM) decreased from 3.2 ± 0.6 to 1.7 ± 0.7 with E10/S10 and from 3.0 ± 1.0 to 1.4 ± 0.5 with S80 treatment. Platelet function was evaluated by whole blood flow cytometry and turbidimetric aggregometry with agonist stimulation ex vivo before and after treatment. Neither treatment affected basal or adenosine diphosphate (ADP)- or thrombin-induced platelet P-selectin expression, or fibrinogen binding, or platelet-leukocyte aggregation. Similarly, neither treatment affected ADP-induced platelet aggregation. In conclusion, lipid lowering treatment with high dose simvastatin or low dose simvastatin plus ezetimibe did not exert any substantial inhibitory effects on the basal or agonist-stimulated activity of circulating platelets in patients with stable CAD and type 2 diabetes or impaired glucose tolerance.

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Kille, Alexander, Kilian Franke, Noé Corpataux, Julia Hromek, Christian M. Valina, Franz-Josef Neumann, Dietmar Trenk, Thomas G. Nührenberg et Willibald Hochholzer. « Impact of On-Clopidogrel Platelet Reactivity on Incidence of Peri-Interventional Bleeding in Patients Undergoing Transcatheter Aortic Valve Implantation ». Journal of Clinical Medicine 11, n^o 10 (19 mai 2022) : 2871. http://dx.doi.org/10.3390/jcm11102871.

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Dual anti-platelet therapy (DAPT) with clopidogrel and acetylsalicylic acid (ASA) has previously been recommended after transcatheter aortic valve implantation (TAVI) and is still the standard of care in patients who underwent coronary stent placement within 3 months prior to TAVI. This study sought to evaluate whether on-treatment platelet reactivity is a predictor for the occurrence of bleeding events after TAVI. This study enrolled 484 patients undergoing TAVI from November 2013 until April 2018. Patients were either on long-term DAPT with clopidogrel and ASA or received loading doses of both drugs before TAVI, reflecting the standard of care at the time of the patient’s enrollment. Platelet reactivity was determined by multi-electrode impedance aggregometry before TAVI, at days 1 and 5 thereafter. Peri-interventional bleeding was assessed up to 5 days following TAVI and coded according to BARC-classification. Bleeding events were seen in 199 (41.1%) patients. The most frequent were BARC 2 bleeding cases (24.2%), followed by BARC 1 (6.0%), BARC 3b (5.2%), and BARC 3a (4.5%) cases. Low on-clopidogrel platelet reactivity before TAVI was present in 243 patients, of which 44.4% had a bleeding event. In contrast, the incidence of bleeding was 30.5% in the 95 patients with high on-clopidogrel platelet reactivity. Multivariate logistic regression analysis identified low/normal/high on-clopidogrel platelet reactivity (OR: 0.533; CI: 0.309–0.917; p = 0.023) and use of oral anticoagulation (OR: 1.766; CI: 1.209–2.581; p = 0.003) as strongest predictors for peri-interventional bleeding events. These findings support current recommendations advocating against the routine use of dual antiplatelet therapy following TAVI.

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Čolić, Mirko D., Branko M. Čalija, Bratislav M. Milosavljević, Aleksandra G. Grdinić, Lazar G. Angelkov, Dragan Ž. Sagić, Peter Kruzliak, Jelena M. Marinković, Rade M. Babić et Igor B. Mrdović. « Low On-Treatment Platelet Reactivity Predicts Long-Term Risk of Bleeding After Elective PCI ». Journal of Interventional Cardiology 28, n^o 6 (décembre 2015) : 531–43. http://dx.doi.org/10.1111/joic.12251.

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Cuisset, Thomas, Charlotte Grosdidier, Anderson Diendonné Loundou, Jacques Quilici, Marie Loosveld, Laurence Camoin, Mathieu Pankert et al. « Clinical Implications of Very Low On-Treatment Platelet Reactivity in Patients Treated With Thienopyridine ». JACC : Cardiovascular Interventions 6, n^o 8 (août 2013) : 854–63. http://dx.doi.org/10.1016/j.jcin.2013.04.009.

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Wadowski, Patricia P., Silvia Lee, Christoph W. Kopp, Renate Koppensteiner, Simon Panzer et Thomas Gremmel. « Low Levels of High-Density Lipoprotein Cholesterol Are Linked to Impaired Clopidogrel-Mediated Platelet Inhibition ». Angiology 69, n^o 9 (26 février 2018) : 786–94. http://dx.doi.org/10.1177/0003319718760074.

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Low high-density lipoprotein cholesterol (HDL-C) levels are an independent predictor of ischemic events in patients with atherosclerotic cardiovascular disease. This may in part be due to decreased clopidogrel-mediated platelet inhibition in patients with low HDL-C. We investigated the association of HDL-C with on-treatment platelet reactivity to adenosine diphosphate (ADP) in 314 patients on dual antiplatelet therapy with clopidogrel and aspirin undergoing angioplasty and stenting. Platelet P-selectin expression was assessed by flow cytometry, and platelet aggregation was determined by the VerifyNow P2Y12 assay and the Impact-R. High-density lipoprotein cholesterol levels were inversely associated with P-selectin expression and the VerifyNow P2Y12 assay (both P ≤ .01). Moreover, we found a positive correlation of HDL-C with surface coverage by the Impact-R ( P = .003). Patients with low HDL-C (≤35 mg/dL) exhibited a significantly higher P-selectin expression in response to ADP and higher platelet aggregation by the VerifyNow P2Y12 assay and the Impact-R than patients with normal HDL-C (>35 mg/dL; all P < .05). High on-treatment residual platelet reactivity by the VerifyNow P2Y12 assay occurred significantly more frequently in patients with low HDL-C levels than in those with normal HDL-C (47.4% vs 30.1%, P = .01). In conclusion, low HDL-C is linked to impaired clopidogrel-mediated platelet inhibition after angioplasty and stenting.

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Boinska, Joanna, Marek Koziński, Michał Kasprzak, Michał Ziołkowski, Jacek Kubica et Danuta Rość. « Diurnal Oscillations of Fibrinolytic Parameters in Patients with Acute Myocardial Infarction and Their Relation to Platelet Reactivity : Preliminary Insights ». Journal of Clinical Medicine 11, n^o 23 (30 novembre 2022) : 7105. http://dx.doi.org/10.3390/jcm11237105.

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There is limited information about diurnal changes in fibrinolysis parameters after acute myocardial infarction (AMI) and their relationship with on-treatment platelet reactivity. The aim of this study was to assess tissue plasminogen activator (t-PA), plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin (α2-AP) activity, and plasmin–antiplasmin (PAP) complexes in 30 AMI patients taking dual antiplatelet therapy (DAPT), i.e., acetylsalicylic acid and clopidogrel. Fibrinolytic parameters were assessed at four time points (6 a.m., 10 a.m., 2 p.m., and 7 p.m.) on the third day after AMI using immunoenzymatic methods. Moreover, platelet reactivity was measured using multiple-electrode aggregometry, to assess potential differences in fibrinolytic parameters in low/high on-aspirin platelet reactivity and low/high on-clopidogrel platelet reactivity subgroups of patients. We detected significant diurnal oscillations in t-PA and PAI-1 levels in the whole study group. However, PAP complexes and α2-AP activity were similar at the analyzed time points. Our study reveals a potential impact of DAPT on the time course of fibrinolytic parameters, especially regarding clopidogrel. We suggest the presence of diurnal variations in t-PA and PAI-1 concentrations in AMI patients, with the highest levels midmorning, regardless of platelet reactivity. Significantly elevated levels of PAI-1 during the evening hours in clopidogrel-resistant patients may increase the risk of thrombosis.

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Johnston, Lisa, Ana Holley, Michael Chen-Xu, Ali Al-Sinan, Peter Larsen et Scott Harding. « PM156 Does Low on Treatment Platelet Reactivity Identify Acs Patients At Increased Risk of Bleeding ? » Global Heart 9, n^o 1 (mars 2014) : e93-e94. http://dx.doi.org/10.1016/j.gheart.2014.03.1547.

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Mărginean, Alina, Claudia Bănescu, Alina Scridon et Minodora Dobreanu. « Anti-platelet Therapy Resistance – Concept, Mechanisms and Platelet Function Tests in Intensive Care Facilities ». Journal of Critical Care Medicine 2, n^o 1 (1 janvier 2016) : 6–15. http://dx.doi.org/10.1515/jccm-2015-0021.

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AbstractIt is well known that critically ill patients require special attention and additional consideration during their treatment and management. The multiple systems and organ dysfunctions, typical of the critical patient, often results in different patterns of enteral absorption in these patients. Anti-platelet drugs are the cornerstone in treating patients with coronary and cerebrovascular disease. Dual anti-platelet therapy with aspirin and clopidogrel is the treatment of choice in patients undergoing elective percutaneous coronary interventions and is still widely used in patients with acute coronary syndromes. However, despite the use of dual anti-platelet therapy, some patients continue to experience cardiovascular ischemic events. Recurrence of ischemic events is partly attributed to the fact that some patients have poor inhibition of platelet reactivity despite treatment. These patients are considered low- or nonresponders to therapy. The underlying mechanisms leading to resistance are not yet fully elucidated and are probably multifactorial, cellular, genetic and clinical factors being implicated. Several methods have been developed to asses platelet function and can be used to identify patients with persistent platelet reactivity, which have an increased risk of thrombosis. In this paper, the concept of anti-platelet therapy resistance, the underlying mechanisms and the methods used to identify patients with low responsiveness to anti-platelet therapy will be highlighted with a focus on aspirin and clopidogrel therapy and addressing especially critically ill patients.

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Bonello, Laurent. « Personalised Antiplatelet Therapy – Whether to Choose Genotype or Phenotype ». European Cardiology Review 6, n^o 4 (2010) : 45. http://dx.doi.org/10.15420/ecr.2010.8.2.45.

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A significant proportion of patients do not achieve optimal platelet reactivity inhibition after a loading dose of clopidogrel. The large interindividual variability in clopidogrel responsiveness is related to several factors, including the genetic polymorphism of hepatic cytochromes 2C19 2*, which has recently been highlighted by a US Food and Drug Administration (FDA) warning. In fact, patients exhibiting reduced clopidogrel metabolism and/or low clopidogrel responsiveness (i.e. high on-treatment platelet reactivity) have an increased rate of thrombotic events following percutaneous coronary intervention. In this article, current knowledge on this important clinical issue is summarised. While the future of genetic testing remains undetermined, several trials are under way to demonstrate the potential utility of platelet reactivity testing with P2Y12-ADP receptor antagonists.

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Aradi, Dániel, Lisa Gross, Dietmar Trenk, Tobias Geisler, Béla Merkely, Róbert Gábor Kiss, András Komócsi et al. « Platelet reactivity and clinical outcomes in acute coronary syndrome patients treated with prasugrel and clopidogrel : a pre-specified exploratory analysis from the TROPICAL-ACS trial ». European Heart Journal 40, n^o 24 (24 avril 2019) : 1942–51. http://dx.doi.org/10.1093/eurheartj/ehz202.

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Abstract Aims The value of platelet function testing (PFT) in predicting clinical outcomes and guiding P2Y12-inhibitor treatment is uncertain. In a pre-specified sub-study of the TROPICAL-ACS trial, we assessed ischaemic and bleeding risks according to high platelet reactivity (HPR) and low platelet reactivity (LPR) to ADP in patients receiving uniform prasugrel vs. PFT-guided clopidogrel or prasugrel. Methods and results Acute coronary syndrome patients with PFT done 14 days after hospital discharge were included with prior randomization to uniform prasugrel for 12 months (control group, no treatment modification) vs. early de-escalation from prasugrel to clopidogrel and PFT-guided maintenance treatment (HPR: switch-back to prasugrel, non-HPR: clopidogrel). The composite ischaemic endpoint included cardiovascular death, myocardial infarction, or stroke, while key safety outcome was Bleeding Academic Research Consortium (BARC) 2–5 bleeding, from PFT until 12 months. We identified 2527 patients with PFT results available: 1266 were randomized to the guided and 1261 to the control group. Before treatment adjustment, HPR was more prevalent in the guided group (40% vs. 15%), while LPR was more common in control patients (27% vs. 11%). Compared to control patients without HPR on prasugrel (n = 1073), similar outcomes were observed in guided patients kept on clopidogrel [n = 755, hazard ratio (HR): 1.06 (0.57–1.95), P = 0.86] and also in patients with HPR on clopidogrel switched to prasugrel [n = 511, HR: 0.96 (0.47–1.96), P = 0.91]. In contrast, HPR on prasugrel was associated with a higher risk for ischaemic events in control patients [n = 188, HR: 2.16 (1.01–4.65), P = 0.049]. Low platelet reactivity was an independent predictor of bleeding [HR: 1.74 (1.18–2.56), P = 0.005], without interaction (Pint = 0.76) between study groups. Conclusion Based on this substudy of a randomized trial, selecting prasugrel or clopidogrel based on PFT resulted in similar ischaemic outcomes as uniform prasugrel therapy without HPR. Although infrequent, HPR on prasugrel was associated with increased risk of ischaemic events. Low platelet reactivity was a strong and independent predictor of bleeding both on prasugrel and clopidogrel.

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Larsen, Sanne, Erik Grove, Steen Kristensen et Anne-Mette Hvas. « Reduced antiplatelet effect of aspirin is associated with low-grade inflammation in patients with coronary artery disease ». Thrombosis and Haemostasis 109, n^o 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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Mark, Gwenda, et 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, n^o 1 (janvier 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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Trenk, Dietmar, Karsten Schrör, Meinrad Gawaz, Steen D. Kristensen, Robert F. Storey, Kurt Huber et Jolanta M. Siller-Matula. « How to improve the concept of individualised antiplatelet therapy with P2Y12 receptor inhibitors – is an algorithm the answer ? » Thrombosis and Haemostasis 113, n^o 01 (2015) : 37–52. http://dx.doi.org/10.1160/th14-03-0238.

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SummaryWithin the past decade, high on-treatment platelet reactivity (HTPR) on clopidogrel and its clinical implications have been frequently discussed. Although it has been previously assumed that HTPR is a phenomenon occurring only in patients treated with clopidogrel, recent data show that HTPR might also occur during treatment with prasugrel or ticagrelor in the acute phase of ST-elevation myocardial infarction. Moreover, it has been postulated that there is a therapeutic window for P2Y12 receptor blockers, thus indicating that HTPR is associated with thrombotic events whereas low on-treatment platelet reactivity (LTPR) is associated with bleeding events. The current paper focuses on tools to identify risk factors for HTPR (pharmacogenomic testing, clinical scoring and drug-drug interactions) and on the use of platelet function testing in order to identify patients who might not respond adequately to clopidogrel. The majority of recent clinical randomised trials have not supported the hypothesis that platelet function testing and tailored antiplatelet therapy are providing a favourable clinical outcome. These trials, mainly performed in low-to-moderate risk patients, will be reviewed and discussed. Finally, an algorithm based on current knowledge is suggested, which might be of use for design of clinical trials.

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Trenk, Dietmar, Karsten Schrör, Meinrad Gawaz, Steen D. Kristensen, Robert F. Storey, Kurt Huber et Jolanta M. Siller-Matula. « How to improve the concept of individualised antiplatelet therapy with P2Y12 receptor inhibitors – is an algorithm the answer ? » Thrombosis and Haemostasis 113, n^o 01 (janvier 2015) : 37–52. http://dx.doi.org/10.1160/th14-13-0238.

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SummaryWithin the past decade, high on-treatment platelet reactivity (HTPR) on clopidogrel and its clinical implications have been frequently discussed. Although it has been previously assumed that HTPR is a phenomenon occurring only in patients treated with clopidogrel, recent data show that HTPR might also occur during treatment with prasugrel or ticagrelor in the acute phase of ST-elevation myocardial infarction. Moreover, it has been postulated that there is a therapeutic window for P2Y12 receptor blockers, thus indicating that HTPR is associated with thrombotic events whereas low on-treatment platelet reactivity (LTPR) is associated with bleeding events. The current paper focuses on tools to identify risk factors for HTPR (pharmacogenomic testing, clinical scoring and drug-drug interactions) and on the use of platelet function testing in order to identify patients who might not respond adequately to clopidogrel. The majority of recent clinical randomised trials have not supported the hypothesis that platelet function testing and tailored antiplatelet therapy are providing a favourable clinical outcome. These trials, mainly performed in low-to-moderate risk patients, will be reviewed and discussed. Finally, an algorithm based on current knowledge is suggested, which might be of use for design of clinical trials.

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Vargová, Katarína, Ádám László, Tamás Masszi, Gábor Kerecsen, István Préda, Róbert Gábor Kiss, Bernát János Béres et Emese Tóth-Zsámboki. « Analysis of platelet α2-adrenergic receptor activity in stable coronary artery disease patients on dual antiplatelet therapy ». Thrombosis and Haemostasis 100, n^o 05 (2008) : 829–38. http://dx.doi.org/10.1160/th08-03-0158.

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SummaryCombined antiplatelet therapy reduces recurrent atherothrombotic events in stable coronary disease patients; however, high residual platelet reactivity measured ex vivo still raises concerns as a condition related to treatment failure. Alpha-2 adrenoceptor enhances platelet reactivity and might contribute to this phenomenon. For the present study, 121 stable angina patients on standard dual antiplatelet therapy (75 mg clopidogrel and 100 mg acetylsalicylic acid) were recruited. Born aggregometry was performed with adenosine diphosphate (ADP),collagen and epnephrine. To verify platelet adrenergic activity, potentiation by low-dose epinephrine and inhibition by selective alpha-2 receptor blocker atipamezole were determined. To assess the P2Y12-specific residual activity, cangrelor was used. Plasma norepinephrine, soluble CD40-ligand, high-sensitivity-C-reactive protein (hsCRP) - and in 24 subjects platelet P-selectin positivity were measured. Epinephrine - at very low concentration (10-9g/ml) - significantly potentiates (1.25 µM ADP: 26.5% vs. 43%; 5 µM ADP: 53% vs. 64.5%; collagen: 17% vs 42%, p<0.001) while atipamezole inhibits ADP- and collagen-induced platelet aggregations (1.25 µM ADP: 26.5% vs. 23%; 5 µM ADP: 53% vs. 47%;collagen:17% vs.11%,p<0.001).Patients with high adrenergic activity have significantly increased baseline ADP- and collagen-induced platelet aggregation. Based on cangrelor’s efficacy, these patients have significantly more residual P2Y12 activity as well.HsCRP and soluble CD40-ligand levels were similar.In conclusion, stable coronary heart disease patients with prominent adrenoceptor activity in vitro have significantly increased platelet aggregability and more functional P2Y12 receptor, indicating poor inhibitory response to thienopyridines.Therefore,platelet adrenergic receptor represents a considerable, dynamic factor of high residual platelet reactivity and might contribute to cardiovascular events indicating failure of antiplatelet therapy.

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Mutschlechner, David, Maximilian Tscharre, Patricia P. Wadowski, Joseph Pultar, Constantin Weikert, Silvia Lee, Beate Eichelberger, Simon Panzer, Thomas Perkmann et Thomas Gremmel. « Growth Differentiation Factor 15 Is Associated with Platelet Reactivity in Patients with Acute Coronary Syndrome ». Journal of Clinical Medicine 12, n^o 4 (17 février 2023) : 1627. http://dx.doi.org/10.3390/jcm12041627.

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Bleeding events in patients with acute coronary syndrome (ACS) are a risk factor for adverse outcomes, including mortality. We investigated the association of growth differentiation factor (GDF)-15, an established predictor of bleeding complications, with on-treatment platelet reactivity in ACS patients undergoing coronary stenting receiving prasugrel or ticagrelor. Platelet aggregation was measured by multiple electrode aggregometry (MEA) in response to adenosine diphosphate (ADP), arachidonic acid (AA), thrombin receptor-activating peptide (TRAP, a protease-activated receptor-1 (PAR-1) agonist), AYPGKF (a PAR-4 agonist) and collagen (COL). GDF-15 levels were measured using a commercially available assay. GDF-15 correlated inversely with MEA ADP (r = −0.202, p = 0.004), MEA AA (r = −0.139, p = 0.048) and MEA TRAP (r = −0.190, p = 0.007). After adjustment, GDF-15 was significantly associated with MEA TRAP (β = −0.150, p = 0.044), whereas no significant associations were detectable for the other agonists. Patients with low platelet reactivity in response to ADP had significantly higher GDF-15 levels (p = 0.005). In conclusion, GDF-15 is inversely associated with TRAP-inducible platelet aggregation in ACS patients treated with state-of-the-art antiplatelet therapy and significantly elevated in patients with low platelet reactivity in response to ADP.

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Edelstein, Leonard C., Lukas M. Simon, Raul Teruel Montoya, Michael Holinstat, Edward Chen, Angela Bergeron Woodley, Xiango Kong et al. « Racial Differences In Thrombin-Induced Human Platelet PAR4 Reactivity ». Blood 122, n^o 21 (15 novembre 2013) : 1054. http://dx.doi.org/10.1182/blood.v122.21.1054.1054.

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Abstract Compared to white patients, black patients have worse outcomes after acute coronary events, but there is a paucity of literature considering racial differences in platelet function. Thrombin is an especially potent in vivo platelet agonist, and no work has considered racial differences in thrombin-induced platelet aggregation. Using PAR1- and PAR4- activation peptides (APs), we recently reported that platelets from healthy black subjects (n = 70) demonstrated greater aggregation to the PAR4-AP than platelets from white subjects (n = 84) (p = 5.15 x 10-8). There was no racial difference to PAR1-AP, ADP or CRP. The goal of the current study was to determine if this racial difference in PAR4-AP-mediated platelet reactivity was also observed with thrombin and to investigate responsible molecular and genetic mechanism(s). A detailed dose-response study (4 blacks and 3 whites) revealed that when thrombin signaling was restricted to PAR4 by inhibiting PAR1 with BMS-200261, platelets from black subjects aggregated faster than platelets from white subjects at low concentrations of thrombin. No PAR1-AP-induced aggregation occurred in the presence of BMS-200261. A subsequent replication study (an additional 5 blacks and 5 whites) again showed platelets from black subjects aggregated faster than white subjects in the absence of PAR1 signaling (p = 3.56x10-5). DNA from all 154 subjects was genotyped for 5 million SNPs (HumanOmni5 array) and principal component analysis revealed that the genotypes segregated into two distinct groups that correlated perfectly with subject self-identified race. Gene expression profiling on leukocyte-depleted platelets from all 154 subjects revealed numerous differentially expressed (DE) RNAs associated with both race and PAR4 reactivity. The gene encoding phosphatidylcholine transfer protein (PC-TP), PCTP, showed the strongest correlation with race (p = 10-23; q = 10-20) and with PAR4 reactivity (p = 3.4x10-8; q = 3.5x10-4). PC-TP protein was higher in platelets from blacks (p = 3.8x10-6) and levels correlated with reactivity to PAR4-AP (r = 0.249, p = 0.002). Pctp has been knocked out in mice, but we found that wild type mouse platelets express little or no Pctp protein, consistent with mouse platelet RNA data from Rowley et al (Blood 2011). However, a specific PC-TP inhibitor resulted in a reduced aggregation response to PAR4-AP, but not PAR1-AP. Transfection of a siRNA against PCTP reduced both PCTP mRNA and PC-TP protein levels, and inhibited Ca+ release in a megakaryocytic cell line, Meg-01 in response to PAR4-AP but not PAR1-AP. A racial difference in platelet Ca+ release in response to PAR4-AP treatment was also observed (p = 0.02). Platelet microRNA (miRNA) profiling from all 154 subjects also revealed numerous DE miRNAs associated with both race and PAR4 reactivity. Target prediction analysis indicated that miR-376c is a candidate for regulating PCTP expression. qRT-PCR of all 154 subjects indicated that miR-376c levels are expressed higher in platelets from whites (p = 1.47 x10-4; q = 1.38 x10-3), and are inversely correlated with PCTP mRNA (r = -0.214; p = 0.008), PC-TP protein (r = -0.211; p = 0.009) and PAR4 reactivity (r = -0.161; p = 0.049). Transfection of megakaryocytic cell lines or cord blood CD34+ derived megakaryocytes with the pre-miR-376c precursor or LNA-miR-376c inhibitor resulted in decreased (P<0.01) or increased PCTP (p = 0.0003), respectively. Co-transfection of the miRNA precursor or inhibitor with a luciferase vector containing the PCTP 3’UTR indicated the regulation was dependent on the predicted miR-376c target site. In summary, we have uncovered a racial difference in thrombin-induced PAR4 platelet activation. This finding has potential clinical significance because PAR4 is the primary means by which thrombin activates platelets in the presence of vorapaxar (a PAR1 inhibitor in clinical trials), and the risks and benefits of vorapaxar by race are unknown. This racial difference in platelet activation is mediated, in part, by PC-TP, a novel protein in platelet biology. Our data also supports racial differences in miRNA expression, one of which (miR-376c) regulates PC-TP expression. These results indicate a genomic contribution to platelet function that differs by race, emphasize a need to consider race effects when developing anti-thrombotic drugs and raise the possibility that PC-TP inhibition might be a useful anti-thrombotic strategy. Disclosures: No relevant conflicts of interest to declare.

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Mărginean, Alina, Valeriu Moldovan et Mihai Mărginean. « High-on-Aspirin Residual Platelet Reactivity Evaluated Using the Multiplate® Point-of-Care Device ». Acta Medica Marisiensis 62, n^o 1 (1 mars 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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Huang, Shengshi, Wouter van der Heijden, Isaie J. Reuling, Jun Wan, Qiuting Yan, Romy M. W. de Laat - Kremers, Andre J. Van der Ven et al. « Functional changes in hemostasis during asexual and sexual parasitemia in a controlled human malaria infection ». PLOS ONE 17, n^o 7 (15 juillet 2022) : e0271527. http://dx.doi.org/10.1371/journal.pone.0271527.

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Decreased platelet count is an early phenomenon in asexual Plasmodium falciparum parasitemia, but its association with acute or long-term functional changes in platelets and coagulation is unknown. Moreover, the impact of gametocytemia on platelets and coagulation remains unclear. We investigated the changes in platelet number and function during early asexual parasitemia, gametocytemia and convalescence in 16 individuals participating in a controlled human malaria infection study, and studied its relationship with changes in total and active von Willebrand factor levels (VWF) and the coagulation system. Platelet activation and reactivity were determined by flow cytometry, and the coagulation system was assessed using different representative assays including antigen assays, activity assays and global functional assays. Platelet count was decreased during asexual blood stage infection but normalized during gametocytemia. Platelet P-selectin expression was slightly increased during asexual parasitemia, gametocytemia and at day 64. In contrast, platelet reactivity to different agonists remained unchanged, except a marked decrease in reactivity to low dose collagen-related peptide-XL. Thrombin generation and antigen assays did not show a clear activation of the coagulation during asexual parasitemia, whereas total and active VWF levels were markedly increased. During gametocytemia and on day 64, the endogenous thrombin potential, thrombin peak and velocity index were increased and prothrombin conversion and plasma prothrombin levels were decreased. We conclude that the decreased platelet count during asexual parasitemia is associated with increased active VWF levels (i.e. endothelial activation), but not platelet hyperreactivity or hypercoagulability, and that the increased platelet clearance in asexual parasitemia could cause spontaneous VWF-platelet complexes formation.

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Leng, Xing-Hong, Wei Zhang, Bernhard Nieswandt, Jose A. Lopez et Paul F. Bray. « Effects of Estrogen Replacement Therapies on Mouse Platelet Funcion. » Blood 104, n^o 11 (16 novembre 2004) : 3893. http://dx.doi.org/10.1182/blood.v104.11.3893.3893.

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Abstract Clinical trials of hormone replacement therapy (HRT) have demonstrated an increase in stroke and myocardial infarction despite the beneficial changes in LDL and HDL cholesterols, and it has been suggested that HRT may adversely affect thrombosis and/or inflammation. Platelets participate in both of these processes and play a central role in thrombosis formation in high shear arterial vasculature. The effects of HRT on platelet function have been controversially reported, probably due to different hormone regimes used (e.g. different estrogenic compounds, different dosages and routes of administration). We used a murine model of menopause to test the hypothesis that HRT alters platelet reactivity. Bilaterally ovariectomized female littermates were treated with various estrogen regimes or matching placebo for 21 days. Three estrogen replacement therapy (ERT) regimes were studied: 1) oral conjugated equine estrogen (CEE) vs. placebo (n=5 pairs), 2) oral 17-beta estradiol (E2) vs. placebo (n=4 pairs), and 3) subcutaneously implanted E2 (SQ E2) vs. placebo (n=8 pairs). Washed platelets were used to focus on intrinsic platelet reactivity in the absence of plasma coagulation factors. Platelet reactivity was assessed by flow cytometric quantification of agonist-induced fibrinogen binding. Oral CEE, but not oral E2 enhanced the platelet response to collagen-related-peptide (CRP) (P<0.001 and P=0.87 for oral CEE and oral E2, respectively). This enhancement of platelet function was agonist specific since neither oral CEE (P=0.862) nor oral E2 (P=0.917) affected the platelet response to thrombin. We also tested whether the route of hormone administration affected platelet function. SQ E2 induced a condition different from that of oral E2: the platelet response to thrombin was enhanced (P=0.028), but only to low (<10 mU/ml), not high concentrations of thrombin. In contrast to oral E2, SQ E2 caused a reduction in CRP-induced platelet fibrinogen binding (P=0.030). Platelet surface expression of GPVI was reduced in response to SQ E2 (P<0.001), and the level of GPVI correlated with CRP-induced platelet fibrinogen binding (P<0.0001). In conclusion: 1) the effects of different estrogen replacement therapies on platelet function differ significantly, perhaps explaining some of the conflicts in the literature, 2) the effects of ERT on platelet function are dependent upon the ERT preparations and routes, 3) the effects of ERT on platelet function are agonist and agonist dose-dependent, and 4) SQ E2 induces lower platelet GPVI expression, most likely explaining the reduced response to CRP. A potential practical consequence of our findings is that oral E2 may be less prothrombotic than either oral CEE or transdermal E2.

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Nurden, Alan. « GPVI : the inside story ». Blood 114, n^o 9 (27 août 2009) : 1723–24. http://dx.doi.org/10.1182/blood-2009-06-226225.

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The search is on for natural regulators of platelet reactivity. In this issue of Blood, Trifiro and colleagues confirm that the low frequency isoform of platelet GPVI (VIb) attenuates ligand-mediated signal transduction and dampens down platelet reactivity with collagen while not affecting GPVI receptor copy number.

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Gross, Lisa, David Jochheim, Tobias Nitschke, Moritz Baquet, Martin Orban, Lesca Holdt, Magda Zadrozny et al. « Platelet Reactivity and Early Outcomes after Transfemoral Aortic Valve Implantation ». Thrombosis and Haemostasis 118, n^o 10 (20 septembre 2018) : 1832–38. http://dx.doi.org/10.1055/s-0038-1670658.

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AbstractBeyond thromboembolic events, peri-procedural bleeding remains one of the most frequent complications after transcatheter aortic valve implantation (TAVI). The majority of TAVI patients receive a dual anti-platelet treatment (DAPT) regimen. This analysis from the EVERY-TAVI register database aimed to analyse whether the level of on-treatment adenosine diphosphate-induced platelet reactivity predicts early outcomes at 30 days after TAVI. A total of 146 consecutive TAVI patients on DAPT who underwent platelet function testing with the Multiplate analyser were included here. Definition of bleeding events was done according to the Valve Academic Research Consortium-2 (VARC-2) classification. In our cohort, a status of low platelet reactivity (LPR, ≤ 18 units) was observed in 79 patients (54%), while high platelet reactivity (HPR, ≥ 46 units) was present in 18 patients (12%). At 30-day follow-up, the incidence of VARC-2 bleeds was 45.6% (n = 36) in LPR patients and 23.9% (n = 16) in patients without LPR (hazard ratio [HR] 2.10, 95% confidence interval [CI], 1.17–3.79; p = 0.01). In age-adjusted multivariate analysis, a status of LPR was independently associated with VARC-2 bleeding events (HRadj, 2.06, 95% CI, 1.14–3.71; p = 0.02). HPR was not associated with the 30-day risk of death, stroke, or myocardial infarction (p ≥ 0.43). In summary, presence of LPR was associated with bleeding events in patients undergoing TAVI while presence of HPR was not associated with ischaemic outcomes at 30 days. The value of platelet function testing for bleeding risk prediction and for a possible guidance of anti-thrombotic treatment in the elderly TAVI population warrants further investigation.

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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 et Tobias Bonten. « Effect of aspirin intake at bedtime versus on awakening on circadian rhythm of platelet reactivity ». Thrombosis and Haemostasis 112, n^o 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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Khan, Dalia, Joanne Mitchell, Rekha Rana, Neline Kriek, Amanda Unsworth, Tanya Sage, Michael Laffan et al. « Prospective Study Reveals Increased Platelet Function Associated with Multiple Myeloma and Its Treatment ». Blood 136, Supplement 1 (5 novembre 2020) : 21. http://dx.doi.org/10.1182/blood-2020-140821.

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Background: Multiple Myeloma (MM) is a rare incurable bone marrow cancer characterised by a malignant proliferation of plasma cells. MM is usually preceded by a premalignant and benign Monoclonal Gammopathy of Undetermined Significance (MGUS). The incidence of arterial and venous thrombosis in MM is substantially higher than in the normal population, however the cause of this increased thrombosis risk and the impact of MM on platelet function is unclear. Treatments for both newly diagnosed and relapsed/refractory patients with MM include Immunomodulatory drugs (IMiDs) such as thalidomide/lenalidomide-based combinations. These treatments improve considerably patient outcomes, however iMiD treatment also increases the risk of thrombotic complications in these patients. Aims: In this prospective study we explored the impact of MM and its treatment on platelet function. Methods: High throughput functional analysis was performed using platelets from normal healthy controls (n=31) and patients with MGUS (n=18), smouldering multiple myeloma (SMM, n= 20), and MM (26). The MM group was further divided into 3 treatment cohorts; (1) no treatment, (2) treatment with proteasome inhibitor (PI) and dexamethasone (Dex), and (3) treatment with PI, Dex, immunomodulatory drug (iMiD) and direct oral anticoagulant. Platelet aggregation and activation (fibrinogen binding and P-selectin exposure) were measured in response to a concentration range of agonists including ADP, the thrombin receptor agonist TRAP-6, collagen, collagen-related peptide (CRP), a thromboxane receptor agonist U46619 and epinephrine. Cereblon protein was detected in platelet protein extracts by immunoblot analysis. Results: Consistent with previous reports, modestly increased VWF and factor VIII levels were detected in MM patients, but no additional differences in coagulation parameters were detected in patient groups compared to normal healthy controls (other than expected due to anticoagulant usage). Platelet aggregation in response to each agonist was increased significantly in the MM patient group compared to the normal healthy controls, suggesting that platelet reactivity is elevated in MM patients through a common mechanism that is shared by different activation pathways or the involvement of multiple mechanisms. P-selectin exposure on platelets from MM patients was not significantly different from normal healthy donors, indicating that enhanced platelet reactivity in MM is specifically through modulation of integrin αIIbβ3 activation, fibrinogen binding and therefore enhanced aggregation. The effects of treatment on platelet function in patients on iMiD vs. non iMiD treatment were assessed. In the iMiD treatment group, patient platelets aggregated in response to lower concentrations of ADP, collagen, epinephrine and CRP in samples taken post-treatment compared to those taken before and during treatment. This demonstrates an increased sensitivity to platelet activation in these patients induced by treatment. Immunoblot analysis revealed that platelets contain cereblon, a therapeutic target of lenalidomide. The potential direct effects of iMiDs on platelets in vitro was therefore explored. Lenalidomide treatment (10mM) increased the ability of platelets to aggregate in response to low concentrations of each agonist tested when compared to normal controls. Conclusions: Platelet reactivity is increased in multiple myeloma and increased further upon iMiD treatment. The presence of the key therapeutic target for iMiDs in platelets and the ability of lenalidomide to modulate platelet function directly, reveals new avenues for investigation to determine the underlying mechanism of action. Disclosures Laffan: CSL: Consultancy; Pfizer: Consultancy; Sobi: Consultancy; Roche: Consultancy; LFB: Consultancy; Shire: Consultancy; Octapharma: Consultancy; Bayer: Speakers Bureau; Roche-Chugai: Speakers Bureau; Takeda: Speakers Bureau; Leo-Pharma: Speakers Bureau; Pfizer: Speakers Bureau. Shapiro:Bayer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Chugai/Roche: Consultancy, Speakers Bureau; Shire/Takeda: Consultancy, Speakers Bureau. Thakurta:Oxford University: Other: visiting professor; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ramasamy:Takeda: Research Funding; Janssen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Amgen: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria; Takeda: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers squibb: Membership on an entity's Board of Directors or advisory committees. Gibbins:Bristol Myers Squibb: Research Funding; Arena Pharmaceuticals: Research Funding.

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Wiśniewski, Adam. « Multifactorial Background for a Low Biological Response to Antiplatelet Agents Used in Stroke Prevention ». Medicina 57, n^o 1 (10 janvier 2021) : 59. http://dx.doi.org/10.3390/medicina57010059.

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Effective platelet inhibition is the main goal of the antiplatelet therapy recommended as a standard treatment in the secondary prevention of non-embolic ischemic stroke. Acetylsalicylic acid (aspirin) and clopidogrel are commonly used for this purpose worldwide. A low biological response to antiplatelet agents is a phenomenon that significantly reduces the therapeutic and protective properties of the therapy. The mechanisms leading to high on-treatment platelet reactivity are still unclear and remain multifactorial. The aim of the current review is to establish the background of resistance to antiplatelet agents commonly used in the secondary prevention of ischemic stroke and to explain the possible mechanisms. The most important factors influencing the incidence of a low biological response were demonstrated. The similarities and the differences in resistance to both drugs are emphasized, which may facilitate the selection of the appropriate antiplatelet agent in relation to specific clinical conditions and comorbidities. Despite the lack of indications for the routine assessment of platelet reactivity in stroke subjects, this should be performed in selected patients from the high-risk group. Increasing the detectability of low antiaggregant responders, in light of its negative impact on the prognosis and clinical outcomes, can contribute to a more individualized approach and modification of the antiplatelet therapy to maximize the therapeutic effect in the secondary prevention of stroke.

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Wiśniewski, Adam. « Multifactorial Background for a Low Biological Response to Antiplatelet Agents Used in Stroke Prevention ». Medicina 57, n^o 1 (10 janvier 2021) : 59. http://dx.doi.org/10.3390/medicina57010059.

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Effective platelet inhibition is the main goal of the antiplatelet therapy recommended as a standard treatment in the secondary prevention of non-embolic ischemic stroke. Acetylsalicylic acid (aspirin) and clopidogrel are commonly used for this purpose worldwide. A low biological response to antiplatelet agents is a phenomenon that significantly reduces the therapeutic and protective properties of the therapy. The mechanisms leading to high on-treatment platelet reactivity are still unclear and remain multifactorial. The aim of the current review is to establish the background of resistance to antiplatelet agents commonly used in the secondary prevention of ischemic stroke and to explain the possible mechanisms. The most important factors influencing the incidence of a low biological response were demonstrated. The similarities and the differences in resistance to both drugs are emphasized, which may facilitate the selection of the appropriate antiplatelet agent in relation to specific clinical conditions and comorbidities. Despite the lack of indications for the routine assessment of platelet reactivity in stroke subjects, this should be performed in selected patients from the high-risk group. Increasing the detectability of low antiaggregant responders, in light of its negative impact on the prognosis and clinical outcomes, can contribute to a more individualized approach and modification of the antiplatelet therapy to maximize the therapeutic effect in the secondary prevention of stroke.

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Gruttemeier, Julia, Yves Cottin, Hermann Yao, Emmanuel De Maistre, Maud Maza, Laurent Bonello, Marc Laine et al. « Impact of Platelet Reactivity in ACS Patients on Clinical Outcomes with Triple Antithrombotic Therapy ». Journal of Clinical Medicine 10, n^o 8 (8 avril 2021) : 1565. http://dx.doi.org/10.3390/jcm10081565.

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Optimal antithrombotic therapy after percutaneous coronary intervention (PCI) in patients on oral anticoagulants (OAC) remains a clinical conundrum. In fact, combining an OAC with dual antiplatelet therapy (triple antithrombotic therapy, TAT) increases the risk of bleeding. Clopidogrel is the only thienopyridine recommended in TAT patients. Whether its response plays a relevant role in this setting remains uncertain. We aimed to evaluate the level of platelet reactivity inhibition (PRI) achieved by oral TAT in Acute Coronary Syndrome (ACS) patients undergoing PCI and its relationship with outcomes. We performed a multicenter prospective observational study and assessed PRI by vasodilator-stimulated phosphoprotein (VASP) index following a loading dose of clopidogrel. The primary endpoint was the incidence of major adverse cerebral or cardiovascular events (MACCE) at six months based on High on Treatment Platelet Reactivity (HTPR, VASP > 50%). The secondary endpoint was the incidence of bleeding at six months based on Low on Treatment Platelet Reactivity (LTPR, VASP < 16%). 491 patients were followed up for six months: 7.7% experienced MACCE and 17.3% experienced bleeding. There was no significant relationship between HTPR and MACCE, neither between LTPR and bleeding. Vitamin-K antagonist (VKA) treatment was associated with more MACCE and bleeding events, and the majority of events occurred within the first months. VASP index failed to predict outcomes in post-ACS patients with TAT. We confirm that direct acting OAC should be prioritized over VKA in TAT regimen.

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Chae, Hyojin, Myungshin Kim, Yoon-Seok Koh, Byung-Hee Hwang, Min-Kyu Kang, Yonggoo Kim, Hae-il Park et Kiyuk Chang. « Feasibility of a Microarray-Based Point-of-CareCYP2C19Genotyping Test for Predicting Clopidogrel On-Treatment Platelet Reactivity ». BioMed Research International 2013 (2013) : 1–5. http://dx.doi.org/10.1155/2013/154073.

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Clopidogrel is a prodrug which is converted into active metabolite by cytochrome P450 isoenzyme,CYP2C19. Numerous polymorphisms ofCYP2C19are reported, and a strong link exists between loss-of-function (LOF) or gain-of-function polymorphisms, clopidogrel metabolism, and clinical outcome. Hence, a fully automated point-of-care CYP2C19 genotyping assay is more likely to bring personalized antiplatelet therapy into real practice. We assessed the feasibility of the Verigene 2C19/CBS Nucleic Acid Test, a fully automated microarray-based assay, compared to bidirectional sequencing, and performed VerifyNow P2Y12 assay to evaluate the effect ofCYP2C19polymorphisms on on-treatment platelet reactivity in 57 Korean patients treated with clopidogrel after percutaneous coronary intervention. The Verigene 2C19/CBS assay identified *2, *3, and *17 polymorphisms with 100% concordance to bidirectional sequencing in 180 minutes with little hands-on time. Patients were classified into 4 groups: extensive (*1/*1;n=12, 21.1%), intermediate (*1/*2, *1/*3;n=33, 57.9%), poor (*2/*2, *2/*3, and *3/*3;n=11, 19.3%), and ultrarapid metabolizers (*1/*17;n=1, 1.8%). The prevalence of theCYP2C19 *2, *3, and *17 alleles was 36.0%, 12.3%, and 0.9%. Platelet reactivity showed gene dose response according to the number ofCYP2C19LOF allele. In conclusion, the Verigene 2C19/CBS assay gave accurateCYP2C19genotype results which were in well match with the differing on-treatment platelet reactivity.

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Raab, Stefanie, Korbinian Nepomuk Kropp, Alexander Steinle, Gerd Klein, Lothar Kanz, Hans-Georg Kopp et Helmut R. Salih. « Platelet-Derived Proteases ADAM10 and ADAM17 Impair NK Cell Immunosurveillance of Metastasizing Tumor Cells By Diminishing NKG2D Ligand Surface Expression ». Blood 124, n^o 21 (6 décembre 2014) : 4164. http://dx.doi.org/10.1182/blood.v124.21.4164.4164.

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Abstract Introduction: NK cells are cytotoxic lymphocytes the reactivity of which is governed by the principles of ‘missing-self’ and “induced-self’ recognition. This implies that cells with low or absent expression of MHC class I and/or stress-induced expression of ligands for activating receptors like NKG2D (NKG2DL) are preferentially eliminated by NK cells. We and others reported previously that NKG2DL undergo proteolytic cleavage (i.e. shedding) which promotes evasion from NKG2D-mediated tumor immunosurveillance. Notably, the reactivity of NK cells is also influenced by various other components of the hematopoietic system, and we and others provided evidence for the involvement of platelets in tumor immune evasion including impairment of NKG2D-mediated immune surveillance (e.g., Kopp et al., Cancer Res 2009, Raab et al., Blood 2013 122:3488). Here we extend our recent findings and provide further data how platelets affect immunostimulatory NKG2D-NKG2DL interaction. Methods: Tumor cells were incubated with platelets from healthy donors or treated with platelet-derived soluble factors (releasate) obtained by stimulation of platelets with known platelet agonists including ADP and thrombin. NKG2DL and ADAM10 as well as ADAM17 surface expression on tumor cells and platelets, respectively, was measured by FACS, while release of NKG2DL was determined by ELISA. ADAM10 and 17 protein levels were assessed by immunoblotting. NK cell lysis of tumor cells in the presence or absence of coating platelets or platelet releasate was determined by chromium release assays. Results: We found that interaction of platelets with tumor cells resulted in substantially reduced NKG2DL expression on the surface of the malignant cells, which was paralleled by enhanced release of soluble NKG2DL. Similar albeit weaker effects were observed upon treatment of tumor cells with platelet releasate, indicating that platelet-derived factors mediate NKG2DL shedding from the tumor cell surface. Notably, ADAM10 and ADAM17, the known sheddases of NKG2DL, were found to be expressed on the platelet surface, and sheddases could also be detected in platelet releasate, pointing to an involvement in platelet-mediated NKG2DL shedding. Diminished NKG2DL surface expression resulted in reduced NKG2D-mediated NK cell cytotoxicity as revealed by blocking experiments using NKG2D antibody and F(ab)2 fragments specific for the modulated NKG2DL. Conclusion: We propose that induction of NKG2DL shedding constitutes a novel mechanism by which the interaction of platelets with metastasizing tumor cells impairs NK cell immunosurveillance. Disclosures No relevant conflicts of interest to declare.

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Ding, Peng, Yujie Wei, Nana Chen et Huiliang Liu. « Validation of a New ELISA-Based Vasodilator-Associated Stimulated Phosphoprotein Phosphorylation Assay to Assess Platelet Reactivity Index in a Chinese Population ». Clinical and Applied Thrombosis/Hemostasis 24, n^o 3 (23 janvier 2017) : 452–61. http://dx.doi.org/10.1177/1076029616689300.

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The level of platelet reactivity during P2Y12-adenosine diphosphate receptor antagonist is associated with ischemic and bleeding risks following percutaneous coronary intervention in acute coronary syndrome. Determining platelet reactivity inhibition may be valuable for confirming effective platelet inhibition for individual patients and identifying patients at risk of bleeding. The enzyme-linked immunosorbent assay (ELISA)-based vasodilator-stimulated phosphoprotein (VASP) assay offers unique advantages over other methods and has not been used in the Chinese population. We enrolled 10 healthy volunteers and 54 patients with acute coronary syndrome. The volunteers received no treatment, and patients were administered a loading dose of clopidogrel or ticagrelor. The platelet reactivity index (PRI) was measured using flow cytometry (FC)-VASP and ELISA-VASP at baseline and 8-hour postloading dose. Blood samples of healthy volunteers and clopidogrel- or ticagrelor-treated patients were frozen and stored for 1, 2, and 4 weeks after initial activation. All frozen samples were tested using ELISA-VASP. The PRI assessed by FC-VASP and ELISA-VASP correlated well showing a high degree of consistency in identifying high or low on-treatment platelet reactivity. No significant time-dependent changes in PRI results were observed in frozen samples stored up to 4 weeks compared to nonfrozen samples. The PRI of ticagrelor-treated patients was lower than that of clopidogrel-treated patients. The ELISA-VASP effectively assesses the PRI, and results obtained from frozen specimens are unaffected by storage and shipment prior to assay. Ticagrelor was superior to clopidogrel in decreasing the PRI.

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Orban, M., S. Massberg et D. Sibbing. « Potent P2Y12 receptor inhibitors in patients with acute coronary syndrome ». Hämostaseologie 33, n^o 01 (2013) : 9–15. http://dx.doi.org/10.5482/hamo-12-12-0022.

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SummaryBlood platelets are highly activated in the setting of an acute coronary syndrome (ACS). This fact mandates the need for potent platelet inhibition in ACS patients and especially in patients undergoing a percutaneous coronary intervention (PCI). The 2nd generation thienopyridine clopidogrel has been the standard of treatment in the past. Due to its pharmacological properties including a delayed onset of action, a large response variability and an insufficient antiplatelet action in some patients (low responsiveness or high on-treatment platelet reactivity), there was a need to develop, to study and to introduce more potent agents with a fast, reliable and potent antiplatelet action. With the 3rd generation thienopyridine prasugrel and with ticagrelor two potent agents for antiplatelet treatment of ACS patients are available now. Both drugs have demonstrated their superiority compared to clopidogrel in terms of thrombotic risk reduction in large-scale randomized trials. However, for these agents and in line with the expectations towards a more potent anti platelet treatment regimen, a higher risk for bleeding was observed for prasugrel and ticagrelor. Further on, the new anti platelet agents have their own and characteristic contraindications and numerous issues to be considered in clinical practice.This review aims to provide an overview on the state of the art P2Y12 receptor directed inhibition in ACS patients with a focus on patients undergoing a coronary stenting procedure.

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Wal, Françoise, Danielle Joseph, Lhousseine Touqui et B. Boris Vargaftig. « PAF-Acether May Not Mediate the Third Pathway of Platelet Aggregation since Self-Desensitization Reduces the Effects of Low Thrombin but Enhances Those of Convulxin ». Thrombosis and Haemostasis 53, n^o 01 (1985) : 099–104. http://dx.doi.org/10.1055/s-0038-1661245.

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SummaryPAF-acether (platelet-activating factor) was hypothesized as the mediator of the ADP and thromboxane-independent activation of platelets induced by thrombin (Thr) and by the snake venom glycoprotein convulxin (Cx). Aspirinized rabbit platelets self-desensitized to PAF-acether were less responsive to low amounts of Thr, as expected if PAF-acether would be formed, but were hyper-reactive to Cx, in contradiction with its hypothesized mediating role. Aggregation by higher concentrations of Thr overcame inhibition. Experiments with ADP-depleted platelets showed that secretion is neither involved with desensitization to PAF-acether nor with hyper-reactivity to Cx. Those effects required the presence of PAF-acether in the platelet suspension and persisted when transformation of PAF-acether into its recognized metabolite alkyl-acyl-glycerophosphorylcholine was inhibited. The ADP and thromboxane-independent activation of rabbit platelets by low and medium concentrations of Thr may be accounted for by platelet formation of PAF-acether, but overall the contrasting effects of platelet desensitization to PAF-acether on responsiveness to Thr and to Cx suggest that the third pathway of aggregation requires other explanations.

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Walenga, Jeanine M., Margaret Prechel, Walter P. Jeske, Meredith K. McDonald, James M. Daikur et Wasimul Haque. « Novel Single Agents with Combined Anti-Coagulant and Anti-Platelet Activities : Potential Treatment Option for the Management of HIT. » Blood 106, n^o 11 (16 novembre 2005) : 1884. http://dx.doi.org/10.1182/blood.v106.11.1884.1884.

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Abstract A recently introduced series of antithrombotic agents brings the novel characteristic of dual anti-coagulant and anti-platelet actions in one molecule. These low molecular weight, synthetic, serine protease inhibitors, depending on structural modifications, have variable ratios of both anti-thrombin and anti-platelet activities. Studies have shown that these agents produce stronger antithrombotic actions relative to single targeted therapeutic agents (O. Iqbal #P0521 and D. Hoppensteadt #OR335, ISTH meeting Sydney, Australia August 2005). Heparin-induced thrombocytopenia (HIT) is an adverse effect of heparin in which both thrombin generation and platelet activation augment hypercoagulable and inflammatory states leading to a high probability of developing severe thrombosis. Current guidelines for patients who have HIT recommend the use of a direct thrombin inhibitor (DTI) to prevent or treat associated thrombosis. Clinical trial data, as well as practice outcomes, show that DTI treatment alone is not sufficient to overcome the pathology and resultant thrombosis in all HIT patients. Thus, more optimal treatment options are needed. A focus of treatment on inhibiting both platelet and coagulation activation is logical based on the pathophysiology of HIT. This study was undertaken to determine if the novel CanAm series of agents may have a role in the management of patients with HIT. Eight agents (MC45301, MC45308, CA207, CA216, CA234, CA247, CA250, CA254) with varying ratios of anticoagulant/anti-platelet activities were studied using the 14C-serotonin release assay (SRA) and flow cytometry for the detection of platelet P-selectin expression and platelet microparticle generation. The DTI argatroban, the FXa inhibitor fondaparinux, and the platelet GPIIb/IIIa receptor antagonist eptifibatide were included for comparison. Both cross-reactivity to HIT antibodies and amelioration of HIT antibody-induced platelet activation were assessed. In the absence of heparin, at 1-100 μg/ml none of the CanAm agents caused platelet activation in the presence of serum from patients with HIT (n=12) ruling out cross-reactivity with HIT antibodies. None of the comparator drugs showed cross reactivity with HIT antibodies. In the presence of heparin (0.1 U/ml) and serum from patients with HIT (n=12), the CanAm agents were able to inhibit all platelet activation responses at concentrations of 10–100 μg/ml. In comparison, the DTI and FXa inhibitor were not able to inhibit the HIT antibody/heparin induced platelet activation with any HIT serum. The GPIIb/IIIa inhibitor, however, showed a concentration-dependent inhibition of the platelet activities with complete blockade at 1 μg/ml, suggesting the importance of platelet activation inhibition for the treatment of HIT. Thus, compared to mono-therapeutic agents such as DTIs and fondaparinux, the dual-acting CanAm agents not only lack cross reactivity with HIT antibodies, but they have the added ability to block the antibody-induced platelet activation that occurs during an acute episode of HIT. A dual-acting anticoagulant/anti-platelet drug may, therefore, be of more value than single targeted anti-thrombin drugs for the management of HIT and associated thrombosis.

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Bordeaux, Bryan C., Rehan Qayyum, Lisa R. Yanek, Dhananjay Vaidya, Lewis C. Becker, Nauder Faraday et Diane M. Becker. « Effect of Obesity on Platelet Reactivity and Response to Low-Dose Aspirin ». Preventive Cardiology 13, n^o 2 (avril 2010) : 56–62. http://dx.doi.org/10.1111/j.1751-7141.2009.00058.x.

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Kostyak, John C., Carol A. Dangelmaier, Benjamin R. Mauri, Akruti Patel et Satya P. Kunapuli. « Severely Impaired Platelet Function Due to a Novel Mutation of P2Y12 from a Human Subject with No History of Bleeding ». Blood 132, Supplement 1 (29 novembre 2018) : 1130. http://dx.doi.org/10.1182/blood-2018-99-113015.

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Abstract Platelets mediate hemostasis through amplifying an initial stimulus and aggregating at a site of injury. The identification of bleeding phenotypes in humans has the potential to reveal new insight into the mechanisms behind platelet signaling, as well as pinpoint new potential therapeutic targets. In fact, the study of bleeding disorders in human subjects has led to the identification of a number of disease states and proteins important to platelet functional responsiveness. We have recently identified a human subject (PDS25) with a platelet functional disorder that has a normal CBC, and no history of bleeding diathesis. However, platelets from PDS25 have virtually no response to even high concentrations of 2-MeSADP, even though P2Y12 protein expression appears unaltered (Figure 1). Further, platelet reactivity to high doses of agonist for other receptors, such as PAR-4 and GPVI, is normal. Low concentrations of these agonists, which typically rely on feedback for platelet reactivity, elicit an inhibited response using platelets from PDS25 compared to platelets from a healthy control. Consistently, Rap1b activity (Figure 2) was reduced in platelets from PDS25, while VASP phosphorylation was enhanced, suggesting that signaling from the P2Y12 receptor was interrupted by the heterozygous mutation. To determine whether it is the receptor or a downstream signaling component that is dysfunctional and because shape change in response to 2-MeSADP is normal in platelets from PDS25, we co-stimulated 2-MeSADP treated platelets with epinephrine to initiate signaling through Gz, which is very similar to Gi. We found that the response of platelets from PDS25 to 2-MeSADP can be rescued with the addition of epinephrine, suggesting that the signaling components downstream of Gi/zare intact. These data suggest that the aberrant reactivity observed in platelets from PDS25 is due to the P2Y12 receptor. Therefore, we performed a genetic analysis of P2Y12 from PDS25, which revealed a heterozygous mutation of D121N within the conserved DRY motif (Figure 3). We are currently evaluating how this heterozygous mutation confers such a strong phenotype. Disclosures No relevant conflicts of interest to declare.

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Berglund, Ulf, Lars Wallentin et Henning von Schenck. « Platelet Function and Plasma Fibrinogen and their Relations to Gender, Smoking Habits, Obesity and Beta-Blocker Treatment in Young Survivors of Myocardial Infarction ». Thrombosis and Haemostasis 60, n^o 01 (1988) : 021–24. http://dx.doi.org/10.1055/s-0038-1647627.

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SummarySeventy-three (58 men and 15 women) survivors of myocardial infarction below 45 years of age and 73 healthy matched controls were investigated regarding in vitro platelet aggregability to ADP and collagen, platelet sensitivity to prostacyclin and plasma levels of beta-thromboglobulin, platelet factor 4 and fibrinogen. The patients, studied 3-6 months after the acute event, had a reduced platelet sensitivity to prostacyclin. They did not differ from the controls regarding the other platelet function tests. Females had higher platelet reactivity than men. Smoking, obesity or beta- blocker treatment did not influence platelet function. The patients had higher fibrinogen levels than the controls. Gender did not influence, while smoking and obesity increased plasma fibrinogen. Patients on beta-blockade had lower fibrinogen levels than patients without this therapy. The high fibrinogen level and the low platelet sensitivity to prostacyclin might indicate an increased thrombotic liability in young myocardial infarction patients.

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Park, Ji Won, Barbora Piknova, Khanh Nghiem, Jay N. Lozier et Alan N. Schechter. « Nitrite Regulation Of Platelet Reactivity Under Physiological Conditions ». Blood 122, n^o 21 (15 novembre 2013) : 4739. http://dx.doi.org/10.1182/blood.v122.21.4739.4739.

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Nitric oxide (NO) is generated by serial reduction pathway of nitrate and nitrite or by activity of endogenous nitric oxide synthase (NOS), and modulates platelet function and hemostasis. We have shown by aggregometry and flow cytometric analysis of P-selectin that nitrite in the presence of erythrocytes inhibits platelet aggregation and activation after its reduction to NO at low oxygen tension [PLoS One. 2012; 7: e30380. 10.1371/journal.pone.0030380]. We then investigated how nitrite may affect overall clotting processes by regulating platelet function using thrombelastography (TEG), a method used to assess platelet function, fibrin clot formation, and fibrinolysis in blood and/or plasma. We measured the effect of NO donors and nitrite on three TEG parameters, reaction time (R, time to initial fibrin formation), α angle (velocity of clot growth) and maximum amplitude (MA, clot strength), in healthy volunteers. The NO donor (DEANONOate) inhibited all three TEG parameters in response to two independent platelet activators (ADP and AA), in platelet rich plasma (PRP) or whole blood diluted with plasma to yield 20% hematocrit (Hct) to model blood in the microcirculation in vivo. At DEANONOate concentrations ranging from 0-1 μM, R values were progressively prolonged from 1.9 to 3.6 (p=0.008), α angle was decreased from 17.8 to 9.5 (p=0.01) and maximum clot amplitude was reduced from 9.0 to 4.4 (p=0.001) in 20% Hct with ADP stimulation. In contrast, nitrite did not affect clotting parameters in PRP, but exhibited moderate inhibitory effects in 20% Hct at concentrations from 0-10 μM; R values were slightly prolonged from 1.6 to 2.7 (p=0.12), α angle was decreased from 21.8 to 12.8 (p=0.07) and maximum clot amplitude was reduced from 11.0 to 5.0 (p=0.02). This inhibitory effect of nitrite on clotting was greatly enhanced under hypoxic conditions (blood pO2 46.5±11.6 mmHg); R values from 1.4 to 4.0 (p=0.003), α angle from 21.7 to 7.8 (p=0.002), and maximum clot amplitude from 10.0 to 3.4 (p=0.0003). These results suggest that the nitrite effect may be greatest in the microcirculation and be important in differences between arterial and venous clotting. In conclusion, our results show TEG parameters indicate NO inhibition of platelet-mediated blood clotting and that the physiological effect of factors which determine NO bioavailability, such as reduction of blood and tissue nitrite, could be used to predict hemostasis. Disclosures: Schechter: National Institutes of Health: Dr. Alan Schechter is listed as a co-inventor on several patents issued to the National Institutes of Health for the use of nitrite salts for the treatment of cardiovascular diseases., Dr. Alan Schechter is listed as a co-inventor on several patents issued to the National Institutes of Health for the use of nitrite salts for the treatment of cardiovascular diseases. Patents & Royalties.

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Vijayan, Kadekuzhi V., Yan Liu, Tong-Tong Li et Paul F. Bray. « Non-Genomic Effects of Estradiol on Human Platelets : Regulation of Mitogen Activated Protein Kinase Activation and Enhanced Spreading and Aggregation. » Blood 104, n^o 11 (16 novembre 2004) : 2620. http://dx.doi.org/10.1182/blood.v104.11.2620.2620.

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Abstract 17β-estradiol or estrogen (E2) is a sex hormone that modulates platelet function and is widely used in hormone replacement therapy (HRT). We and others have previously demonstrated that human megakaryocytes and platelets posses estrogen receptors ERα and ERβ. HRT treatment augmented the bone marrow megakaryocytes without increasing other bone marrow cells, suggesting that E2 can modulate proliferation of megakaryocytes. Since mitogen activated protein kinases (MAPKs) are critical for 1) cell proliferation, 2) megakarytocyte differentiation and proplatelet formation and estrogen activates MAPK in other cell types, we hypothesized that estrogen regulates the activation of MAPK in human platelets. Signaling was studied using washed platelets from male and female subjects in response to varying concentrations of estrogen. Compared to the ethanol (vehicle) treated platelets, 1 nM E2 treated platelets for 60 seconds resulted in an enhanced activation of extracellular signal-regulated kinase 2 (ERK 2) and P38 but not Jun N-kinase (JNK). These results suggest that E2 can cause a non-genomic signaling in human platelets. The MEK inhibitors PD98059 and U0216 blocked the E2 effect, suggesting that the activation of ERK 2 was mediated through the upstream mitogen activated protein kinase kinase (MAPKK). Because E2 can modulate actin reorganization in other cell types and cell spreading is promoted by ERK 2 activation, we examined the effect of E2 on platelet spreading - a process not dependent on agonist stimulation. Compared to ethanol treated platelets, platelets preincubated with 100 nM E2 for 60 seconds and stained with rhodamine phallodine exhibited a ~60 % greater spreading at 5 and 15 minutes. This observation suggests that that E2 can cause rapid actin cytoskeletal reorganization in platelets. Since inhibition of ERK 2 activation blocks aggregation to low doses of thrombin and collagen, we examined a role for E2 in platelet aggregation. E2 alone did not induce platelet aggregation. However, E2 potentiated aggregation with low but not high doses of thrombin and collagen related peptide (CRP) (P=0.05 for 0.02 μg/ml thrombin and P<0.001 for 0.2 μg/ml CRP). Our data demonstrates that E2 can activate MAPK through a non-genomic mechanism and this activation correlates with greater platelet functions like spreading and aggregation. Our findings support a mechanism whereby a consistent non-genomic enhancement of platelet signaling and reactivity by E2 may underlie the increased cardiovascular events observed in recent randomized clinical trials with HRT.

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Galea, Vassiliki, Grigoris T. Gerotziafas, Mouna Sassi, Jawed Fareed, Jeanine M. Walenga et Ismail Elalamy. « Comparison of Seven Generic Enoxaparins with Lovenox® on In Vitro Cross-Reactivity with Antibodies From Heparin Induced Thrombocytopenia. » Blood 116, n^o 21 (19 novembre 2010) : 1105. http://dx.doi.org/10.1182/blood.v116.21.1105.1105.

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Abstract Abstract 1105 Introduction: Heparin induced thrombocytopenia (HIT) is the major complication of heparin treatment but is less frequent in patients treated with low molecular weight heparins (LMWHs) than with unfractionated heparin (UFH). Cross immunological reactions of LMWHs with HIT antibodies from patients treated with UFH is a common finding. The immunological profile is among the criteria for similarity of a generic LMWHs. The cross reactivity of generic LMWHs with HIT antibodies has yet to be compared with the innovator product. Aim: To compare the profile of platelet aggregation induced by HIT antibodies in the presence of Lovenoxâ or seven generic enoxaparins. Methods: Platelet activation by HIT antibodies in the presence of UFH (Héparine Choay, France), branded enoxaparin (Lovenox®) and 7 generics (Novex®, Enoxa®, Dilutol®, Versa®, Cutenox®, Loparin®, Fibrinox®) was assessed by Multiple Electrode Aggregometry (MEA, Multiplate, Dynabyte, Germany) according to previously published assay1. Briefly, whole blood (340 μl) from 5 individual healthy donors was incubated with pooled platelet poor plasma (200 μl) from well characterised HIT positive patients and 40 μl of UFH or Lovenox® or generic enoxaparins yielding a final concentration of 1 anti-Xa IU/ml. Platelet aggregation was recorded over 15 min and the area under the curve (AUC, AU*min) was determined. Results: UFH and branded enoxaparin showed high cross reactivity with HIT antibodies in 4 out of 5 experiments. All of the 7 generic enoxaparins gave also a high positive cross-reactivity but the intensity of platelet aggregation varied. The magnitude of the response was classified as follows: Versa® > Enoxa® > Lovenox® > Novex® > Fibrinox® > Cutenox® > Loparin® > Dilutol®. In one experiment Lovenox® showed border-line cross-reactivity with HIT antibodies. Among generic enoxaparins Versa® showed the same extent of cross reactivity as that of Lovenox®. The other generic enoxaparins did not cross react with HIT antibodies. Conclusions: This is the first study that provides key data on the comparison of in vitro cross reactivity with HIT antibodies of generic enoxaparins versus Lovenox®. In the presence of a cross-reactivity of the originator enoxaparin with heparin-PF4-IgG immune complex, there is also a cross-reactivity of the 7 studied generic enoxaparins. The intensity of cross-reactivity is an additional criterion for comparison of generic LMWHs and the originator one. The differences on the intensity of cross reactivity follow the same pattern in the case of border line cross reactivity of the originator enoxaparin. References 1. I. Elalamy, V. Galea, M. Hatmi, G. Gerotziafas. Heparin-Induced Multiple Electrode Aggregometry: A potential tool for improvement of Heparin-Induced Thrombocytopenia diagnosis. JTH 2009;7:1932-4. Figure 1. Cross-reactivity of branded and generic forms of enoxaparin. Whole blood platelet aggregation of a HIT positive patient with 4 different blood donors. Values of AUC are expressed as mean ± sd. *p<0.05 versus Lovenox®. Disclosures: No relevant conflicts of interest to declare.

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Farag, Sherif S., Heten Savoia, Cindy J. O'Malley et Katherine M. McGrath. « Lack of In Vitro Cross-Reactivity Predicts Safety of Low-Molecular Weight Heparins in Heparin-Induced Thrombocytopenia ». Clinical and Applied Thrombosis/Hemostasis 3, n^o 1 (janvier 1997) : 58–62. http://dx.doi.org/10.1177/107602969700300109.

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Alternative anticoagulation in patients with heparin-induced thrombocytopenia (HIT) is often problematic. The relatively high cross-reactivity rate reported for the low-molecular-weight heparins (LMWH) has discouraged their use in this setting. This study has investigated the safety of using the LMWH Fragmin, based on a negative heparin-dependent platelet aggregation test using the latter, in patients with proven HIT. Fifty-three evaluable patients with clinical and laboratory evidence of HIT were evaluated for cross-reactivity with Fragmin using a Fragmin-dependent platelet aggregation test. In 20 of 38 patients who showed no in vitro cross-reactivity. Fragmin was substituted for unfractionated heparin. The outcome of these 20 patients was evaluated and compared to that of the remaining 33 patients, in whom anticoagulates were ceased or warfarin or Orgaran was used. Eighteen of 20 patients treated with Fragmin increased their platelet count by ≥50 x 109/l from a mean nadir of 57.9 ± 4.7 x 109/l within 2.8 ± 0.29 days following substitution of Fragmin for unfractionated heparin. Twenty-eight of the 33 remaining patients who did not receive Fragmin increased their platelet count by ≥50 x 109/l from a mean nadir of 53.0 ± 4.8 x 109/l within 3.0 ± 0.29 days. In seven patients (two treated with Fragmin), response could not be evaluated due to death within 36 h of cessation of heparin or discharge from hospital. The results indicate that in vitro cross-reactivity testing employing a heparin-dependent platelet aggregation assay can be safely used to select patients with HIT for further anticoagulation with LMWH. Key Words: Fragmin—Crossreactivity—Heparin-induced thrombocytopenia.

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Marcus, Aaron J., Joan HF Drosopoulos, Kim E. Olson, Ranjini Anand, Dana Leifer et Jorge R. Kizer. « Platelet Reactivity and CD39 Ectonucleotidase Activities in Cryptogenic Stroke ». Blood 120, n^o 21 (16 novembre 2012) : 3397. http://dx.doi.org/10.1182/blood.v120.21.3397.3397.

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Abstract Abstract 3397 Background: In the US, 795,000 patients are diagnosed with stroke annually. Of the 90% of strokes that are ischemic, a substantial number are of unknown etiology. In younger adults, the proportion of such cryptogenic strokes exceeds 40%. Cryptogenic stroke patients have an increased prevalence of interatrial shunts (IAS), which can be found in as many as 60% of cases as compared to 26% for the general population. Yet, percutaneous closure of such defects has not been found to reduce the recurrence rate as compared with medical therapy. Hypercoagulable disorders have also been implicated in the pathogenesis of premature ischemic strokes, but their occurrence in cryptogenic stroke series is modest, leaving many such strokes unexplained. We hypothesized that cryptogenic stroke may in part represent a disorder of enhanced platelet reactivity. An understanding of the responsiveness of platelets from young cryptogenic stroke patients to a broad panel of agonists is required because platelet reactivity to a single agonist or a thromboxane measurement does not provide sufficient information about platelet reactivity. CD39/NTPDase1, the ecto-enzyme on endothelial cells and leukocytes, is responsible for control of adenine nucleotide levels in the local vascular microenvironment, and, therefore, blood fluidity. CD39 rapidly metabolizes ATP and ADP released from activated platelets and other cells, thereby abolishing the prothrombotic cascade of platelet activation and recruitment. Methods: We sought to determine whether platelet activation and recruitment, markers of platelet activation, and CD39 enzymatic activity are increased in younger patients with unexplained stroke. To this end, we evaluated such platelet-related measures in a subsample (n=167 subjects) participating in the THrombophilia In Cryptogenic stroKe (THICK) study, a prospective case-control study evaluating the prothrombotic determinants of unexplained stroke. Cases consisted of patients, ages 18–64, referred to Weill Cornell Medical Center for evaluation of cryptogenic stroke, whereas controls were stroke-free volunteers within the same age range recruited at our center and the surrounding area. Cryptogenic stroke was defined according to modified TOAST criteria. Results: Cases (n=99) were similar in age (median 45 years old), sex (51% women), and race-ethnic composition (8% African American) as compared with controls (n=68). They also had similar prevalences of hypertension (18%), diabetes (7%), dyslipidemia (40%), and current smoking (6%). Cases had over twice the prevalence of IAS (56%) as controls (24%). Extensive testing for humoral prothrombotic disorders revealed a potential explanation for stroke in only half of the patients. We developed a Broad Range Aggregometry System to study profiles of platelet reactivity to multiple agonists, and classified patient responsiveness based on their reactivity to these agonists. We have also been able to make a laboratory diagnosis of aspirin non-responsiveness in these patients and controls. In addition, in stroke subjects, trends to higher total ADPase activity were observed on lymphocytes (p=0.09) and PMN (p=0.09), while ATPase activities were similar (p=0.81 and 0.68, respectively), as determined by our radio-TLC nucleotidase assay. Also, the ADPase to ATPase activity ratio was greater in the stroke patients than controls (p=0.003 for lymphocytes; p=0.13 for PMN). Cryptogenic stroke patients also displayed increased levels of platelet-monocyte aggregates (p=0.034) and the platelet activation marker CD63 (p=0.048), but not CD154 (p=0.183), as compared to controls (determined by FACS analyses). Conclusions: These findings support a potential role for enhanced platelet reactivity and a low threshold for platelet responsiveness in cryptogenic stroke patients. Disclosures: No relevant conflicts of interest to declare.

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