Publications by authors named "Bianca Rocca"

83 Publications

The Key Contribution Of Platelet And Vascular Arachidonic Acid Metabolism To The Pathophysiology Of Atherothrombosis.

Cardiovasc Res 2021 Jan 23. Epub 2021 Jan 23.

Department of Bioethics and Safety, Section of Pharmacology, Catholic University School of Medicine, Rome, Italy.

Arachidonic acid is one of the most abundant and ubiquitous ω-6 polyunsaturated fatty acid, present in esterified form in the membrane phospholipids of all mammalian cells and released from phospholipids by several phospholipases in response to various activating or inhibitory stimuli. Arachidonic acid is the precursor of a large number of enzymatically- and non-enzymatically-derived, biologically active autacoids, including prostaglandins (PGs), thromboxane (TX) A2, leukotrienes, and epoxyeicosatetraenoic acids (collectively called eicosanoids), endocannabinoids and isoprostanes, respectively. Eicosanoids are local modulators of the physiological functions and pathophysiological roles of blood vessels and platelets. For example, the importance of cyclooxygenase (COX)-1-derived TXA2 from activated platelets in contributing to primary hemostasis and atherothrombosis is demonstrated in animal and human models by the bleeding complications and cardioprotective effects associated with low-dose aspirin, a selective inhibitor of platelet COX-1. The relevance of vascular COX-2-derived prostacyclin (PGI2) in endothelial thromboresistance and atheroprotection is clearly shown by animal and human models and by the adverse cardiovascular effects exerted by COX-2 inhibitors in humans. A vast array of arachidonic acid-transforming enzymes, downstream synthases and isomerases, transmembrane receptors, and specificity in their tissue expression make arachidonic acid metabolism a fine-tuning system of vascular health and disease. Its pharmacological regulation is central in human cardiovascular diseases, as demonstrated by biochemical measurements and intervention trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvab003DOI Listing
January 2021

The ESC Working Group on Thrombosis.

Eur Heart J 2020 09;41(33):3130-3131

Privatklinik Lauterbacher Mühle am Ostersee, Iffeldorf, Germany and Ludwig-Maximilians Universität München, Munich, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehaa482DOI Listing
September 2020

Effect of Low-dose and Standard-dose Aspirin on PGE Biosynthesis Among Individuals with Colorectal Adenomas: A Randomized Clinical Trial.

Cancer Prev Res (Phila) 2020 Oct 27;13(10):877-888. Epub 2020 Jul 27.

Clinical & Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults ( = 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8-12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 ± 14.6 (mean ± S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (-4.7 ± 14.8) compared with no decrease (0.8 ± 11.8) in the placebo group ( = 0.015; mean duration of treatment = 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (-15%; = 0.018) or 325 mg/day (-28%; < 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1940-6207.CAPR-20-0216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541643PMC
October 2020

A randomized double-blind trial of 3 aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia.

Blood 2020 07;136(2):171-182

Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy.

Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2-dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019004596DOI Listing
July 2020

Increased von Willebrand factor levels in polycythemia vera and phenotypic differences with essential thrombocythemia.

Res Pract Thromb Haemost 2020 Mar 28;4(3):413-421. Epub 2020 Feb 28.

Servizio Malattie Emorragiche e Trombotiche Fondazione Policlinico Universitario "A. Gemelli" IRCCS Roma Italy.

Background: Acquired von Willebrand factor (VWF) deficiency was described in Philadelphia-negative myeloproliferative neoplasms, especially in essential thrombocythemia (ET). VWF phenotype in contemporary patients with polycythemia vera (PV) remains less explored.

Objectives: To characterize the VWF phenotype in PV and to compare VWF phenotype in PV with matched healthy subjects and ET patients.

Patients/methods: We studied 48 PV patients, treated according to current recommendations (hematocrit ≤ 45%, on low-dose aspirin prophylaxis); 48 healthy and 41 subjects with ET, all sex, age, and blood group matched. We measured VWF antigen, activity, multimeric pattern, ADAMTS-13, and factor VIII (FVIII) antigen.

Results: In patients with PV, VWF antigen and activity were significantly higher than in healthy subjects (antigen: 119[96-137] vs 93[79-107] IU/dL; activity: 114[95-128] vs 90[79-107] IU/dL, respectively, medians and interquartile,  < 0.01), with normal multimeric distribution. ADAMTS-13 levels were similar between patients with PV and healthy subjects. FVIII levels were higher in PV than in healthy subjects (141[119-169] versus 98[88-123] IU/dL, respectively,  < 0.01). By multivariable analysis, JAK2-p.V617F allelic burden, erythrocyte count, and male sex significantly predicted VWF antigen and activity levels. As compared to patients with ET, patients with PV showed similar VWF antigen levels but approximately 40% higher activity (79[49-104] vs 112[93-125] IU/dL, respectively,  < 0.01).

Conclusions: Patients with PV show increased VWF and FVIII levels, predicted by JAK2-p.V617F burden and erythrocyte count. At variance with ET, acquired VWF defect was not observed in PV. High VWF/FVIII levels may sustain the thrombotic diathesis of PV and may be investigated as biomarkers for risk stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/rth2.12315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086469PMC
March 2020

Highlights from the 2019 International Aspirin Foundation Scientific Conference, Rome, 28 June 2019: benefits and risks of antithrombotic therapy for cardiovascular disease prevention.

Ecancermedicalscience 2020 13;14:998. Epub 2020 Jan 13.

Unit of Cardiology, Department of Medicine, Karolinska University Hospital, 171 76 Stockholm, Sweden.

At the 2019 International Aspirin Foundation Scientific Conference 'Benefits and Risks of Antithrombotic Therapy for Cardiovascular Disease Prevention', held in Rome, Italy, international experts sought to discuss and debate the optimal antithrombotic strategy for the secondary prevention of cardiovascular disease (CVD) and to seek agreement around dosing and target populations for aspirin use in primary disease prevention. Getting the best evidence to support real-life decisions in the clinic can be complex, and individualising management in order to balance both the risks and benefits of different disease prevention strategies appears to be the best approach. It is hoped that future decision-making tools and biomarkers will help direct treatments at those most likely to benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3332/ecancer.2020.998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032943PMC
January 2020

Antithrombotic therapy in patients with acute coronary syndrome complicated by cardiogenic shock or out-of-hospital cardiac arrest: a Joint Position Paper from the European Society of Cardiology (ESC) Working Group on Thrombosis, in association with the Acute Cardiovascular Care Association (ACCA) and European Association of Percutaneous Cardiovascular Interventions (EAPCI).

Eur Heart J Cardiovasc Pharmacother 2020 02 12. Epub 2020 Feb 12.

Department of Pharmacology, Catholic University School of Medicine, Rome, Italy.

Timely and effective antithrombotic therapy is critical to improving outcome, including survival, in patients with acute coronary syndrome (ACS). Achieving effective platelet inhibition and anticoagulation, with minimal risk, is particularly important in high-risk ACS patients, especially those with cardiogenic shock (CS) or those successfully resuscitated following out-of-hospital cardiac arrest (OHCA), who have a 30-50% risk of death or a recurrent ischaemic event over the subsequent 30 days. There are unique challenges to achieving effective and safe antithrombotic treatment in this cohort of patients that are not encountered in most other ACS patients. This position paper focuses on patients presenting with CS or immediately post-OHCA, of presumed ischaemic aetiology, and examines issues related to thrombosis and bleeding risk. Both the physical and pharmacological impacts of CS, namely impaired drug absorption, metabolism, altered distribution and/or excretion, associated multiorgan failure, co-morbidities and co-administered treatments such as opiates, targeted temperature management, renal replacement therapy and circulatory or left ventricular assist devices, can have major impact on the effectiveness and safety of antithrombotic drugs. Careful attention to the choice of antithrombotic agent(s), route of administration, drug-drug interactions, therapeutic drug monitoring and factors that affect drug efficacy and safety, may reduce the risk of sub- or supra-therapeutic dosing and associated adverse events. This paper provides expert opinion, based on best available evidence, and consensus statements on optimising antithrombotic therapy in these very high-risk patients, in whom minimising the risk of thrombosis and bleeding is critical to improving outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ehjcvp/pvaa009DOI Listing
February 2020

Aspirin in the primary prevention of cardiovascular disease in diabetes mellitus: A new perspective.

Diabetes Res Clin Pract 2020 Feb 8;160:108008. Epub 2020 Jan 8.

Institute of Pharmacology, Catholic University School of Medicine, and Fondazione Policlinico Universitario "A. Gemelli" Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.

Although the improved control of hyperglycaemia and other cardiovascular risk factors was associated with a parallel decline of atherosclerotic cardiovascular disease (ASCVD) and death in both type 1 (T1) and type 2 (T2) diabetes mellitus (DM), the burden of death and hospitalization for ASCVD remains significantly higher by about 2-fold versus the matched non-DM population. Life style interventions, such as physical activity and healthy diet, and drugs, such as statins and low-dose aspirin, may have beneficial effects by targeting one or multiple pathways responsible for accelerated atherosclerosis and its thrombotic complications. The debate on the benefit-risk balance of primary cardiovascular prevention with aspirin has been especially vivacious over the past two years, following the publication of three large randomized, placebo-controlled, primary prevention trials in different settings, spanning from healthy elderly to DM subjects. The aim of this review is to discuss the pathophysiological, pharmacological and clinical evidence supporting the appropriate use of low-dose aspirin in DM, within the context of the current multifactorial approach to primary cardiovascular prevention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.diabres.2020.108008DOI Listing
February 2020

From the Choice of a Regimen to the Choice of an Intensity: Changing Perspective in the Antithrombotic Therapy of Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention.

Cardiovasc Drugs Ther 2020 02;34(1):143-144

Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10557-019-06903-yDOI Listing
February 2020

Antithrombotic therapy and revascularisation strategies in people with diabetes and coronary artery disease.

Eur J Prev Cardiol 2019 Dec;26(2_suppl):92-105

Leicester Real World Evidence Unit, Leicester Diabetes Centre, UK.

Background: Diabetes mellitus, largely type 2, affects nearly 10% of the global adult population according to the World Health Organization. Diabetes is an independent risk factor for atherosclerotic cardiovascular diseases, including coronary artery disease. Diabetes patients experience a two to three-fold increased incidence of coronary artery disease, despite improved metabolic control and management of other cardiovascular risk factors.

Discussion: Platelet abnormalities and activation as well as reduced antiplatelet drug responsiveness characterise diabetes mellitus. Mechanisms linking diabetes to platelet and vascular abnormalities, atherogenesis and atherosclerotic cardiovascular disease are still only partially known, highlighting the unique complexity of the pro-atherogenic clinical scenario and its treatment. Consistently, a higher residual cardiovascular risk characterises patients with diabetes compared with those without, in spite of improved antiplatelet and antithrombotic treatment combinations. Randomised clinical trials aimed at optimising antiplatelet treatment specifically in patients with diabetes are lacking, both in acute and chronic coronary artery disease settings. Thus, patients with diabetes are treated with regimens validated in studies including only variable proportions of diabetes patients. Myocardial revascularisation appears to confer a comparable relative benefit between diabetes patients and patients without diabetes, and generally coronary artery bypass grafting has a better outcome in diabetes mellitus versus peripheral coronary intervention. New glucose-lowering drugs have been shown to reduce the incidence of major cardiovascular events in secondary prevention. Type 1 diabetes mellitus remains less explored than type 2 in this context.

Conclusion: Diabetes-tailored antithrombotic strategies in acute and chronic coronary artery disease remain an unmet clinical need, requiring ad-hoc trials and precision pharmacological strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2047487319880045DOI Listing
December 2019

Measurement of Thromboxane Biosynthesis in Health and Disease.

Front Pharmacol 2019 30;10:1244. Epub 2019 Oct 30.

Department of Pharmacology, Catholic University School of Medicine, Rome, Italy.

Thromboxane (TX) A is a chemically unstable lipid mediator involved in several pathophysiologic processes, including primary hemostasis, atherothrombosis, inflammation, and cancer. In human platelets, TXA is the major arachidonic acid derivative the cyclooxygenase (COX)-1 pathway. Assessment of platelet TXA biosynthesis can be performed through measurement of serum TXB, an index of platelet COX-1 activity, as well as through measurement of urinary enzymatic metabolites, a non-invasive index of platelet activation. This article reviews the main findings of four decades of clinical investigation based on these analytical approaches, focusing on the measurement of TXA metabolites to characterize the pathophysiologic role of transiently or persistently enhanced platelet activation and to describe the clinical pharmacology of COX-1 inhibition in health and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2019.01244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832017PMC
October 2019

In vivo thromboxane-dependent platelet activation is persistently enhanced in subjects with impaired glucose tolerance.

Diabetes Metab Res Rev 2020 02 15;36(2):e3232. Epub 2019 Nov 15.

Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy.

Background: Impaired glucose tolerance (IGT) is associated with increased cardiovascular morbidity and mortality. Enhanced thromboxane (TX)-dependent platelet activation plays a pivotal role in atherothrombosis and characterizes type 2 diabetes mellitus (DM). Whether this also pertains to IGT is currently unknown. We investigated whether TXA -dependent platelet activation, as reflected by 11-dehydro-TXB (TXM) urinary excretion, is comparably abnormal in IGT as in DM, is persistent over long-term follow-up, changes as a function of metabolic disease progression, and is influenced by food intake.

Methods: We prospectively investigated subjects with IGT (n = 48) and two control groups with DM diagnosed either less than 12 months (n = 60) or 12 months or more (n = 58).

Results: Baseline TXM excretion was comparable between subjects with IGT and DM, with no evidence of a circadian variation. During a 36-month follow-up, urinary TXM excretion was stable over time in the DM groups, while tended to increase in subjects with IGT. Increasing urinary TXM excretion over time was observed in the subjects who progressed to diabetes vs nonprogressors.

Conclusions: We conclude that TXA -dependent platelet activation was at least as high in IGT as in patients with DM and further increased over time, especially in those who progressed to overt diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dmrr.3232DOI Listing
February 2020

Obesity is associated with impaired responsiveness to once-daily low-dose aspirin and in vivo platelet activation.

J Thromb Haemost 2019 06 29;17(6):885-895. Epub 2019 Apr 29.

Istituto di Farmacologia, Università Cattolica, Rome, Italy.

Background: The prevalence and degree of obesity is rising worldwide, increases cardiovascular risk, modifies body composition and organ function, and potentially affects the pharmacokinetics and/or pharmacodynamics of drugs.

Objectives: To investigate the pharmacodynamics of once-daily low-dose aspirin in healthy obese subjects, and to assess whether body weight (BW) and body mass index (BMI) affect the pharmacology of aspirin.

Patients/methods: Otherwise healthy, obese (BMI > 30 kg/m ) subjects were studied before and after 3-4 weeks of 100-mg once-daily aspirin intake. Aspirin pharmacodynamics were assessed according to serum thromboxane (TX) B levels measured at 4 hours, 24 hours (i.e., posologic interval) and 48 hours after the last witnessed intake; age-matched and sex-matched non-obese controls were included. A previously calibrated pharmacokinetic/pharmacodynamic in silico model of aspirin was used to fit serum TXB data from obese subjects. At baseline, the major urinary TXA and prostacyclin metabolites, urinary isoprostane and plasma inflammatory biomarkers were measured.

Results: In 16 obese subjects (aged 47 ± 11 years; BMI of 39.4 ± 5.1 kg/m ), residual serum TXB values between 4 and 48 hours after aspirin intake were increased 3- to 5-fold as compared with controls. At 24 hours, the residual serum TXB level was log-linearly associated with body size over a wide range of BMI and BW values, without any apparent threshold. The in silico model predicted that reduced aspirin bioavailability would be inversely related to body size and rescued by 200 mg of aspirin once daily or 85 mg twice daily. Baseline urinary TXA metabolite, isoprostane and plasma C-reactive protein levels were significantly increased in obese subjects.

Conclusions: Obesity is associated with impaired aspirin responsiveness, largely because of body size. Impaired inhibition of platelet activation by conventional low-dose aspirin may affect antithrombotic efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.14445DOI Listing
June 2019

Characterization of aspirin esterase activity in health and disease: In vitro and ex vivo studies.

Biochem Pharmacol 2019 05 13;163:119-127. Epub 2019 Feb 13.

Centro Cardiologico Monzino, IRCCS, Milan, Italy.

Due to its ability to irreversibly inactivate platelet cyclooxygenase, low-dose aspirin (ASA) is the most widely used antithrombotic agent. Although, studies in specific types of patients with cardiovascular disease (CVD) have shown an incomplete inhibition of platelet's cyclooxygenase, which may increase the variability in drug response. Some aspects of ASA pharmacokinetics (PK) still need further investigation. In this study, we aimed to characterise the contribution of esterase enzymes to ASA hydrolysis in the peripheral blood and to assess their activity in 36 healthy subjects (Ctrl) and 77 CVD patients. To this aim, an in vitro assay testing esterase activity in parallel to a liquid chromatography-tandem mass spectrometry method simultaneously detecting ASA and its main metabolites salicylic (SA) and gentisic acids, have been developed. Michaelis-Menten constant (Km) calculation, ASA esterase isoforms characterisation, and ASA PK study were then achieved. The calculated Km identified plasma esterases as the enzymes with the higher affinity for the substrate compared to the RBC ones. Both rivastigmine and 4-bis-nitrophenyl phosphate inhibited plasma esterase activities, suggesting that acetylcholinesterase and carboxylesterase largely contribute to ASA hydrolysis. The feasibility of the method here developed has been explored in Ctrl and CVD patients. The effect of ASA treatment on enzyme activity was further evaluated on an age, sex and BMI matched subgroup of patients and Ctrl (n = 10 for each subgroup, on and off ASA). No overall variations were evidenced in both CVD and Ctrl groups, even when the effect of ASA treatment was tested. This result suggests the absence of any influence of disease state, drug treatments, and comorbidities on plasma esterase and the inability of ASA intake to induce esterase function. In conclusion, the method here developed allows a better characterisation of ASA esterase activity and could be helpful to define the PK-related determinants of ASA responsiveness in order to personalise regimen in specific pathological conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2019.02.014DOI Listing
May 2019

Very-low-dose twice-daily aspirin maintains platelet inhibition and improves haemostasis during dual-antiplatelet therapy for acute coronary syndrome.

Platelets 2019 13;30(2):148-157. Epub 2019 Feb 13.

a Department of Infection, Immunity and Cardiovascular Disease , University of Sheffield , Sheffield , United Kingdom.

Higher aspirin doses may be inferior in ticagrelor-treated acute coronary syndrome (ACS) patients and reducing bleeding risk whilst maintaining antithrombotic benefits could improve outcomes. We characterized the pharmacodynamics of a novel dual-antiplatelet-therapy regimen consisting of very-low-dose twice-daily (BD) aspirin with standard-dose ticagrelor. A total of 20 ticagrelor-treated ACS patients entered a randomized crossover to take aspirin 20 mg BD (12-hourly) during one 14-day period and 75 mg once-daily (OD) in the other. After 14 days of treatment, serum thromboxane (TX)B and light-transmittance aggregometry were assessed pre- and 2 h post-morning-dose, bleeding time was measured post-dose, and TXA and prostacyclin stable metabolites were measured in urine collected 2 h post-morning-dose. Data are expressed as mean ± SD. After 14 days treatment, serum TXB levels were significantly greater 2 h post-dosing with aspirin 20 mg BD vs. 75 mg OD (3.0 ± 3.6 ng/mL vs. 0.8 ± 1.9 ng/mL; p = 0.018) whereas pre-dosing levels were not significantly different (3.5 ± 4.1 ng/mL vs. 2.5 ± 3.1 ng/mL, p = 0.23). 1-mmol/L arachidonic acid-induced platelet aggregation was similarly inhibited by both regimens pre-dose (8.5 ± 14.3% vs. 5.1 ± 3.6%, p = 0.24) and post-dose (8.7 ± 14.2% vs. 6.6 ± 5.3%; p = 0.41). Post-dose bleeding time was shorter with 20 mg BD (680 ± 306 s vs. 834 ± 386 s, p = 0.02). Urinary prostacyclin and TX metabolite excretion were not significantly different. In conclusion, compared to aspirin 75 mg OD, aspirin 20 mg BD provided consistent inhibition of platelet TXA release and aggregation, and improved post-dose hemostasis, in ticagrelor-treated ACS patients. Further studies are warranted to assess whether this regimen improves the balance of clinical efficacy and safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09537104.2019.1572880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425913PMC
April 2019

Pathophysiology of Thrombosis in Peripheral Artery Disease.

Curr Vasc Pharmacol 2020 ;18(3):204-214

Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy.

Under physiological conditions, peripheral arteries release endogenous vascular-protective and antithrombotic agents. Endothelial cells actively synthesize vasoactive mediators, which regulate vascular tone and platelet reactivity thus preventing thrombosis. Atherosclerosis disrupts homeostasis and favours thrombosis by triggering pro-thrombotic responses in the vessels, platelet activation, aggregation as well as vasoconstriction, phenomena that ultimately lead to symptomatic lumen restriction or complete occlusion. In the present review, we will discuss the homeostatic role of arterial vessels in releasing vascular-protective agents, such as nitric oxide and prostacyclin, the role of pro- and anti-thrombotic vascular receptors as well as the contribution of circulating platelets and coagulation factors in triggering the pro-thrombotic response(s). We will discuss the pathological consequences of disrupting the protective pathways in the arteries and the pharmacological interventions along these pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1570161117666190206234046DOI Listing
October 2020

Aspirin inhibits cancer stem cells properties and growth of glioblastoma multiforme through Rb1 pathway modulation.

J Cell Physiol 2019 Jan 30. Epub 2019 Jan 30.

Department of Biomedical Sciences, Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy.

Several clinical studies indicated that the daily use of aspirin or acetylsalicylic acid reduces the cancer risk via cyclooxygenases (Cox-1 and Cox-2) inhibition. In addition, aspirin-induced Cox-dependent and -independent antitumor effects have also been described. Here we report, for the first time, that aspirin treatment of human glioblastoma cancer (GBM) stem cells, a small population responsible for tumor progression and recurrence, is associated with reduced cell proliferation and motility. Aspirin did not interfere with cell viability but induced cell-cycle arrest. Exogenous prostaglandin E significantly increased cell proliferation but did not abrogate the aspirin-mediated growth inhibition, suggesting a Cox-independent mechanism. These effects appear to be mediated by the increase of p21 and p27 , associated with a reduction of Cyclin D1 and Rb1 protein phosphorylation, and involve the downregulation of key molecules responsible for tumor development, that is, Notch1, Sox2, Stat3, and Survivin. Our results support a possible role of aspirin as adjunctive therapy in the clinical management of GBM patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcp.28194DOI Listing
January 2019

The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: Implementation of the serum thromboxane B assay as an evaluation tool of different aspirin dosing regimens in the clinical setting.

Blood Cancer J 2018 06 1;8(6):49. Epub 2018 Jun 1.

Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy.

Once-daily (od), low-dose aspirin (75-100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A production, without inhibiting vascular prostacyclin biosynthesis. Second, whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen. Considering that the primary study end point is serum TXB, a surrogate biomarker of clinical efficacy, a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented. The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB as a reliable end point for dose-finding studies of novel aspirin regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41408-018-0078-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992153PMC
June 2018

Inhibitory mechanisms of very low-dose rivaroxaban in non-ST-elevation myocardial infarction.

Blood Adv 2018 03;2(6):715-730

Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany.

Very low-dose (VLD) factor Xa (FXa) inhibition, in combination with acetylsalicylic acid (ASA) and clopidogrel, is associated with improved outcomes in patients with acute coronary syndrome (ACS) with a tolerable bleeding risk profile. To date, there are no data documenting platelet inhibition and the anticoagulatory effects of VLD FXa inhibition on top of guideline-adherent dual-antiplatelet therapy (DAPT) in patients with ACS. Patients with non-ST-elevation myocardial infarction (NSTEMI) receiving oral DAPT (ASA + clopidogrel, n = 20; or ASA + ticagrelor, n = 20) were prospectively enrolled in a nonrandomized study. Coagulation- and platelet-dependent thrombin generation (TG), measured by means of the calibrated automated thrombogram, were significantly decreased after in vitro and in vivo addition of rivaroxaban. As shown by a total thrombus-formation analysis approach, rivaroxaban treatment led to a significantly decreased coagulation-dependent (AR-chip) thrombus formation in patients treated with ASA plus P2Y inhibitor (clopidogrel/ticagrelor), whereas the pure platelet-dependent (PL-chip) thrombus formation was not affected at all. Adjunctive rivaroxaban therapy was not associated with significant differences in platelet aggregation assessed by light-transmission aggregometry (LTA). Nevertheless, according to fluorescence-activated cell sorter analysis, VLD rivaroxaban treatment resulted in a significantly reduced expression of platelet HMGB-1, whereas P-selectin exposure was not affected. Furthermore, an enhanced effect of rivaroxaban on total thrombus formation and TG was observed in particular in clopidogrel nonresponder patients defined as adenosine 5'-diphosphate-induced LTA ≥40%. VLD rivaroxaban reduces thrombus formation and platelet-dependent TG in patients with ACS receiving DAPT, which can be of potential ischemic benefit. This trial was registered at www.clinicaltrials.gov as #NCT01417884.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2017013573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873232PMC
March 2018

Aspirin: 120 years of innovation. A report from the 2017 Scientific Conference of the International Aspirin Foundation, 14 September 2017, Charité, Berlin.

Ecancermedicalscience 2018 20;12:813. Epub 2018 Feb 20.

Faculty of Medicine and Health Sciences, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK.

Acetylsalicylic acid was first synthesised by Dr FeIix Hoffman on 10th August 1897 and Aspirin was born. It quickly became the best-known pain killer in the world and in the 120 years since this event, aspirin has continued to attract interest, innovation and excitement. Set within the walls of the preserved ruins of Rudolf Virchow's lecture hall at Charité, within Berlin's Museum of Medical History, the International Aspirin Foundation's 28th Scientific Conference served to facilitate international, multi-disease, multidisciplinary discussion about the current understanding of aspirin's mechanisms of action and its utility in modern medicine as well as ideas for future research into its multifaceted applications to enhance global health. In addition to the delegates in Berlin, 300 medical doctors at the 19th Annual Scientific Congress of the Chinese Society of Cardiology were able to join the cardiology sessions from Taiyuan, Shangxi province via a live streaming link to and from China. This led to useful discussion and allowed a truly international perspective to the meeting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3332/ecancer.2018.813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834311PMC
February 2018

More, More, More: Reducing Thrombosis in Acute Coronary Syndromes Beyond Dual Antiplatelet Therapy-Current Data and Future Directions.

J Am Heart Assoc 2018 01 26;7(3). Epub 2018 Jan 26.

Postgraduate Medical School, University of Hertfordshire, United Kingdom

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.117.007754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850258PMC
January 2018

Antithrombotic Therapy in Atrial Fibrillation Associated with Valvular Heart Disease: Executive Summary of a Joint Consensus Document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, Endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE).

Thromb Haemost 2017 12 6;117(12):2215-2236. Epub 2017 Dec 6.

Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy.

Management strategies for patients with atrial fibrillation (AF) in association with valvular heart disease (VHD) have been less informed by randomized trials, which have largely focused on ‘non-valvular AF’ patients. Thromboembolic risk also varies according to valve lesion and may also be associated with CHA2DS2-VASc score risk factor components, rather than only the valve disease being causal. Given the need to provide expert recommendations for professionals participating in the care of patients presenting with AF and associated VHD, a task force was convened by the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group (WG) on Thrombosis, with representation from the ESC WG on Valvular Heart Disease, Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE) with the remit to comprehensively review the published evidence, and to produce a consensus document on the management of patients with AF and associated VHD, with up-to-date consensus statements for clinical practice for different forms of VHD, based on the principles of evidence-based medicine. This is an executive summary of a consensus document which proposes that the term ‘valvular AF’ is outdated and given that any definition ultimately relates to the evaluated practical use of oral anticoagulation (OAC) type, we propose a functional EHRA (Evaluated Heartvalves, Rheumatic or Artificial) categorization in relation to the type of OAC use in patients with AF, as follows: (1) EHRA (Evaluated Heartvalves, Rheumatic or Artificial) type 1 VHD, which refers to AF patients with ‘VHD needing therapy with a vitamin K antagonist (VKA)’ and (2) EHRA (Evaluated Heartvalves, Rheumatic or Artificial) type 2 VHD, which refers to AF patients with ‘VHD needing therapy with a VKA or a non-VKA oral anticoagulant also taking into consideration CHA2DS2-VASc score risk factor components.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH-17-10-0709DOI Listing
December 2017

Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: a joint consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE).

Europace 2017 Nov;19(11):1757-1758

Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy.

Atrial fibrillation (AF) is a major worldwide public health problem, and AF in association with valvular heart disease (VHD) is also common. However, management strategies for this group of patients have been less informed by randomized trials, which have largely focused on 'non-valvular AF' patients. Thrombo-embolic risk also varies according to valve lesion and may also be associated with CHA2DS2VASc score risk factor components, rather than only the valve disease being causal. Given marked heterogeneity in the definition of valvular and non-valvular AF and variable management strategies, including non-vitamin K antagonist oral anticoagulants (NOACs) in patients with VHD other than prosthetic heart valves or haemodynamically significant mitral valve disease, there is a need to provide expert recommendations for professionals participating in the care of patients presenting with AF and associated VHD. To address this topic, a Task Force was convened by the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Thrombosis, with representation from the ESC Working Group on Valvular Heart Disease, Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE) with the remit to comprehensively review the published evidence, and to publish a joint consensus document on the management of patients with AF and associated VHD, with up-to-date consensus recommendations for clinical practice for different forms of VHD. This consensus document proposes that the term 'valvular AF' is outdated and given that any definition ultimately relates to the evaluated practical use of oral anticoagulation (OAC) type, we propose a functional Evaluated Heartvalves, Rheumatic or Artificial (EHRA) categorization in relation to the type of OAC use in patients with AF, as follows: (i) EHRA Type 1 VHD, which refers to AF patients with 'VHD needing therapy with a Vitamin K antagonist (VKA); and (ii) EHRA Type 2 VHD, which refers to AF patients with 'VHD needing therapy with a VKA or a Non-VKA oral anticoagulant (NOAC)', also taking into consideration CHA2DS2VASc score risk factor components. This consensus document also summarizes current developments in the field, and provides general recommendations for the management of these patients based on the principles of evidence-based medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/eux240DOI Listing
November 2017

Antiplatelet Agents for the Treatment and Prevention of Coronary Atherothrombosis.

J Am Coll Cardiol 2017 Oct;70(14):1760-1776

Cardiovascular Science Institute-ICCC IIB-Sant Pau, CiberCV, Hospital de Sant Pau, Barcelona, Spain.

Antiplatelet drugs provide first-line antithrombotic therapy for the management of acute ischemic syndromes (both coronary and cerebrovascular) and for the prevention of their recurrence. Their role in the primary prevention of atherothrombosis remains controversial because of the uncertain balance of the potential benefits and risks when combined with other preventive strategies. The aim of this consensus document is to review the evidence for the efficacy and safety of antiplatelet drugs, and to provide practicing cardiologists with an updated instrument to guide their choice of the most appropriate antiplatelet strategy for the individual patient presenting with different clinical manifestations of coronary atherothrombosis, in light of comorbidities and/or interventional procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2017.08.037DOI Listing
October 2017

Type 2 Diabetes, Obesity, and Aspirin Responsiveness.

J Am Coll Cardiol 2017 02 11;69(6):613-615. Epub 2017 Jan 11.

Department of Pharmacology, Catholic University School of Medicine, Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2016.11.049DOI Listing
February 2017

Patient-independent variables affecting the assessment of aspirin responsiveness by serum thromboxane measurement.

Thromb Haemost 2016 Oct 21;116(5):891-896. Epub 2016 Jul 21.

Bianca Rocca, MD, PhD, Istituto di Farmacologia, Università Cattolica, Largo F. Vito 1, 00168 Rome, Italy, Tel.: +39 06 30154253, E-mail:

The serum TXB (sTXB) assay reflects the pharmacodynamics of platelet inhibition by low-dose aspirin. However, different studies reported variable sTXB values. sTXB assay requires whole blood incubation at 37 °C as a condition for optimal thrombin generation, arachidonic acid release and its metabolism by platelet cyclooxygenase-1 to form TXA. Access to 37 °C incubation may be variably delayed, and different methods to quantitate sTXB may contribute to variable results between different Centers. We investigated whether delaying 37 °C incubation and/or analytical issues affect sTXB concentrations, biasing the assessment of aspirin responsiveness. Sixty-eight samples from 54 volunteers, on- and off-aspirin, were incubated at 37 °C immediately after sampling (reference sample) or after 5, 10, 15, 20, 30 or 60 minutes at room temperature (RT); 8 samples remained at RT 60 minutes, without subsequent incubation; 314 sera were measured by enzyme immunoassay (EIA) and liquid chromatography-tandem mass-spectrometry (LC/MS-MS) methods. sTXB concentrations decreased exponentially as a function of the delay before 37 °C incubation, ranging from 94 ± 11 % at 5 minutes to 23 ± 22 % of the reference sample after 60 minutes at RT. There was high agreement between EIA and LC/MS-MS. Moreover, we simulated the influence of a 15- or 30-minute delayed incubation on 300 sTXB2 measurements from previously-studied, aspirin-treated patients. Delayed incubation reduced the percentage of aspirin 'non-responders' by 22 % to 52 %, depending on the response threshold. In conclusion, a variable delay in the 37 °C incubation of blood samples may affect the assessment of platelet cyclooxygenase-1 inhibition by aspirin and confound the characterization of the determinants of aspirin responsiveness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1160/TH16-05-0349DOI Listing
October 2016

Aspirin, stroke and drug-drug interactions.

Vascul Pharmacol 2016 12 17;87:14-22. Epub 2016 Oct 17.

Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy. Electronic address:

Low-dose aspirin, alone or in combination, is recommended for the secondary prevention of acute non-cardioembolic ischemic stroke and transient ischemic attack, starting soon after the acute event. Clinically-relevant drug-drug interactions (DDIs) are a major concern of regulatory agencies and practicing physicians. Drug's pharmacodynamics and/or pharmacokinetics account for clinically-relevant DDIs that modify efficacy and/or safety of one or more of the co-administered drugs. Some non-steroidal anti-inflammatory drugs interact with aspirin pharmacodynamics by competing on the drug target, i.e. the platelet's cyclooxygenase-1 protein. Although the molecular mechanism(s) of this DDI and its effect on the degree of platelet inhibition in vitro and ex vivo are well unraveled, nevertheless, the extent to which this DDI impacts on long-term antithrombotic efficacy of aspirin in secondary prevention remains unclear. Aspirin pharmacokinetics does not involve critical cytochrome P450 enzymes nor efflux transporters, therefore clinically-relevant DDIs competing on pharmacokinetic pathways seem unlikely. The co-administration of antiplatelet drugs with serotonin storage reuptake inhibitors can create a synergistic effect with antiplatelet agents on platelet inhibition. Low-dose aspirin, alone or in combination with other antiplatelet agents, remains a cornerstone in treating cerebrovascular disorders. The relatively straightforward pharmacokinetics of aspirin limits DDIs, giving it a unique advantage over most antiplatelet drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vph.2016.10.006DOI Listing
December 2016