Publications by authors named "William A E Parker"

33 Publications

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium.

Nat Rev Cardiol 2022 Jan 13. Epub 2022 Jan 13.

Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.
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http://dx.doi.org/10.1038/s41569-021-00665-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8757397PMC
January 2022

A randomised controlled trial to assess the antithrombotic effects of aspirin in type 1 diabetes: role of dosing and glycaemic control.

Cardiovasc Diabetol 2021 12 17;20(1):238. Epub 2021 Dec 17.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Background: The enhanced thrombotic milieu in diabetes contributes to increased risk of vascular events. Aspirin, a key antiplatelet agent, has inconsistent effects on outcomes in diabetes and the best dosing regimen remains unclear. This work investigated effects of aspirin dose and interaction with glycaemia on both the cellular and protein components of thrombosis.

Methods: A total of 48 participants with type 1 diabetes and 48 healthy controls were randomised to receive aspirin 75 or 300 mg once-daily (OD) in an open-label crossover study. Light transmittance aggregometry and fibrin clot studies were performed before and at the end of each treatment period.

Results: Aspirin demonstrated reduced inhibition of collagen-induced platelet aggregation (PA) in participants with diabetes compared with controls, although the higher dose showed better efficacy. Higher aspirin dose facilitated clot lysis in controls but not individuals with diabetes. Collagen-induced PA correlated with glycaemic control, those in the top HbA1c tertile having a lesser inhibitory effect of aspirin. Threshold analysis suggested HbA1c levels of > 65 mmol/mol and > 70 mmol/mol were associated with poor aspirin response to 75 and 300 mg daily doses, respectively. Higher HbA1c was also associated with longer fibrin clot lysis time.

Conclusions: Patients with diabetes respond differently to the antiplatelet and profibrinolytic effects of aspirin compared with controls. In particular, those with elevated HbA1c have reduced inhibition of PA with aspirin. Our findings indicate that reducing glucose levels improves the anti-thrombotic action of aspirin in diabetes, which may have future clinical implications.

Trial Registration: EudraCT, 2008-007875-26, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2008-007875-26 .
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http://dx.doi.org/10.1186/s12933-021-01427-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684134PMC
December 2021

Ticagrelor monotherapy in CKD: better safety at what price?

Eur Heart J 2021 12;42(45):4694-4696

Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.

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http://dx.doi.org/10.1093/eurheartj/ehab607DOI Listing
December 2021

Aspirin dosing for atherosclerotic cardiovascular disease: should we be more ADAPTABLE?

Cardiovasc Res 2021 08;117(10):e123-e125

Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK.

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http://dx.doi.org/10.1093/cvr/cvab251DOI Listing
August 2021

Ticagrelor: clinical development and future potential.

Rev Cardiovasc Med 2021 Jun;22(2):373-394

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, S10 2RX Sheffield, UK.

Platelets participate centrally in atherothrombosis, resulting in vessel occlusion and ischaemia. Consequently, optimisation of antiplatelet regimens has the potential to further reduce the residual burden of morbidity and mortality associated with atherosclerosis. Ticagrelor is a potent oral platelet P2Y receptor antagonist that (1) inhibits a central amplification pathway of platelet activation directly as well as via an active metabolite, (2) has a rapid onset and offset of antiplatelet action that remains consistent in the circulation during twice-daily administration and is amenable to reversal, (3) has inverse agonist properties, and (4) demonstrates pleiotropic effects that contribute to anti-thrombotic, anti-inflammatory and vasodilatory properties. These advantageous characteristics of ticagrelor have translated to beneficial clinical outcomes in patients with acute coronary syndromes or ischaemic stroke, during prolonged maintenance therapy in specific high-risk populations, and following percutaneous coronary intervention but not definitively following coronary artery bypass graft surgery or in peripheral artery disease patients. Novel innovative strategies aim to reduce the risk of bleeding during dual antiplatelet therapy via shortening the duration of treatment and replacing the standard-of-care with ticagrelor monotherapy. In cases where aspirin is an essential component in secondary prevention, dose modification when combined with ticagrelor may hypothetically provide desirable clinical outcomes following appropriate clinical assessment as predicted by pharmacological studies. Overall, the future management of acute coronary syndromes could potentially involve the dichotomisation of antithrombotic therapies, whereby only those with high-risk of ischaemia, without a high-risk of bleeding, receive ticagrelor plus very-low-dose aspirin, while ticagrelor monotherapy is administered to the remaining majority.
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http://dx.doi.org/10.31083/j.rcm2202044DOI Listing
June 2021

Coagulopathy and sepsis: Pathophysiology, clinical manifestations and treatment.

Blood Rev 2021 11 25;50:100864. Epub 2021 Jun 25.

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

Sepsis is a complex syndrome with a high incidence, increasing by 8.7% annually over the last 20 years. Coagulopathy is a leading factor associated with mortality in patients with sepsis and range from slight thrombocytopenia to fatal disorders, such as disseminated intravascular coagulation (DIC). Platelet reactivity increases during sepsis but prospective trials of antiplatelet therapy during sepsis have been disappointing. Thrombocytopenia is a known predictor of worse prognosis during sepsis. The mechanisms underlying thrombocytopenia in sepsis have yet to be fully understood but likely involves decreased platelet production, platelet sequestration and increased consumption. DIC is an acquired thrombohemorrhagic syndrome, resulting in intravascular fibrin formation, microangiopathic thrombosis, and subsequent depletion of coagulation factors and platelets. DIC can be resolved with treatment of the underlying disorder, which is considered the cornerstone in the management of this syndrome. This review presents the current knowledge on the pathophysiology, diagnosis, and treatment of sepsis-associated coagulopathies.
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http://dx.doi.org/10.1016/j.blre.2021.100864DOI Listing
November 2021

Differential effect of clopidogrel and ticagrelor on leukocyte count in relation to patient characteristics, biomarkers and genotype: a PLATO substudy.

Platelets 2021 Jun 2:1-7. Epub 2021 Jun 2.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.

Inflammation plays a key role in cardiovascular disease by contributing to atherothrombosis. The PLATelet inhibition and patient Outcomes (PLATO) study (NCT00391872) compared ticagrelor to clopidogrel in patients with acute coronary syndromes and demonstrated fewer cardiovascular events with ticagrelor but lower white blood cell counts (WBC) with clopidogrel. In this further analysis of the PLATO biomarker substudy, we assessed associations between WBC and clinical characteristics, biomarker levels, and polymorphisms.On-treatment mean (SD) WBC in the clopidogrel group was mildly reduced at each stage of follow-up compared with either the ticagrelor group (1 month: 7.27 (2.1) and 7.67 (2.23) x10/L for clopidogrel and ticagrelor, respectively; < .001) or following cessation of clopidogrel (7.23 (1.97) x10/L, at 6 months vs 7.56 (2.28) x10/L after treatment cessation; < .001). This occurred independently of baseline biomarkers and genotype (where known). Adjusting for clinical characteristics and other biomarkers, no significant interaction was detected between clinical risk factors and the observed effect of clopidogrel on WBC.Clopidogrel weakly suppresses WBC, independent of clinical characteristics, baseline inflammatory biomarker levels, and genotype. Further work is required to determine the mechanism for this effect and whether it contributes to clopidogrel's efficacy as well as therapeutic interaction with anti-inflammatory drugs.
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http://dx.doi.org/10.1080/09537104.2021.1934667DOI Listing
June 2021

Platelets and the Endothelium: Active Participants in Severe COVID-19 Infection.

JACC Basic Transl Sci 2021 Mar 22;6(3):219-221. Epub 2021 Mar 22.

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

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http://dx.doi.org/10.1016/j.jacbts.2021.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987542PMC
March 2021

Prevention of stroke in patients with chronic coronary syndromes or peripheral arterial disease.

Eur Heart J Suppl 2020 Nov 6;22(Suppl M):M26-M34. Epub 2020 Dec 6.

Cardiovascular Research Unit, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.

Stroke is a common and devastating condition caused by atherothrombosis, thromboembolism, or haemorrhage. Patients with chronic coronary syndromes (CCS) or peripheral artery disease (PAD) are at increased risk of stroke because of shared pathophysiological mechanisms and risk-factor profiles. A range of pharmacological and non-pharmacological strategies can help to reduce stroke risk in these groups. Antithrombotic therapy reduces the risk of major adverse cardiovascular events, including ischaemic stroke, but increases the incidence of haemorrhagic stroke. Nevertheless, the net clinical benefits mean antithrombotic therapy is recommended in those with CCS or symptomatic PAD. Whilst single antiplatelet therapy is recommended as chronic treatment, dual antiplatelet therapy should be considered for those with CCS with prior myocardial infarction at high ischaemic but low bleeding risk. Similarly, dual antithrombotic therapy with aspirin and very-low-dose rivaroxaban is an alternative in CCS, as well as in symptomatic PAD. Full-dose anticoagulation should always be considered in those with CCS/PAD and atrial fibrillation. Unless ischaemic risk is particularly high, antiplatelet therapy should not generally be added to full-dose anticoagulation. Optimization of blood pressure, low-density lipoprotein levels, glycaemic control, and lifestyle characteristics may also reduce stroke risk. Overall, a multifaceted approach is essential to best prevent stroke in patients with CCS/PAD.
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http://dx.doi.org/10.1093/eurheartj/suaa165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916419PMC
November 2020

Recovery of platelet reactivity following cessation of either aspirin or ticagrelor in patients treated with dual antiplatelet therapy following percutaneous coronary intervention: a GLOBAL LEADERS substudy.

Platelets 2020 Dec 26:1-6. Epub 2020 Dec 26.

Department of Cardiology, Golden Jubilee National Hospital, Glasgow, UK.

Cessation of one component of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) has been associated with increased risk of ischemic events but it is uncertain whether discontinuation of aspirin is preferable to discontinuation of the oral P2Y inhibitor. The GLOBAL LEADERS study compared two antiplatelet strategies following PCI, cessation of aspirin at 1 month with continued ticagrelor monotherapy for 23 months versus standard DAPT for 12 months followed by aspirin monotherapy for a further 12 months. We assessed recovery of platelet reactivity after withdrawal of either aspirin or ticagrelor at 1 month and 12 months, respectively, in this study. Platelet aggregation (PA) was assessed before cessation of DAPT ('baseline') and after 2, 7, and 14 days post-cessation using Multiplate whole-blood aggregometry with collagen, thrombin-receptor-activating peptide (TRAP), adenosine diphosphate (ADP) and arachidonic acid (AA) as agonists. Following cessation of aspirin at 1 month, there was marked recovery of PA induced by AA (baseline [mean ± SD]: 11.1 ± 7.4 U vs. 14 days: 64.9 ± 19.6 U, < .0001) and collagen (37.4 ± 22.9 U vs. 79.8 ± 13.8 U, < .0001), whereas PA induced by ADP (18.6 ± 6.6 vs. 69.1 ± 20.5, < .0001) and collagen (34.4 ± 18.7 U vs. 43.0 ± 21.0, = .0018) recovered following cessation of ticagrelor at 12 months. There were no significant changes in TRAP-induced PA in either group. In conclusion, cessation of either component of DAPT leads to substantial increase in platelet reactivity with differential effects on different pathways of platelet activation when aspirin or the P2Y inhibitor is stopped. Further work is required to determine which patients receive net benefit from long-term continuation of DAPT.
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http://dx.doi.org/10.1080/09537104.2020.1863937DOI Listing
December 2020

Computed tomography chest imaging offers no advantage over chest X-ray in the initial assessment of gestational trophoblastic neoplasia.

Br J Cancer 2021 03 16;124(6):1066-1071. Epub 2020 Dec 16.

Department of Automatic Control and Systems Engineering, The University of Sheffield, Mappin Street, Sheffield, S1 3JD, UK.

Background: The International Federation of Gynaecology and Obstetrics (FIGO) score identifies gestational trophoblastic neoplasia (GTN) patients as low- or high-risk of single-agent chemotherapy resistance (SACR). Computed tomography (CT) has greater sensitivity than chest X-ray (CXR) in detecting pulmonary metastases, but effects upon outcomes remain unclear.

Methods: Five hundred and eighty-nine patients underwent both CXR and CT during GTN assessment. Treatment decisions were CXR based. The number of metastases, risk scores, and risk category using CXR versus CT were compared. CT-derived chest assessment was evaluated as impact upon treatment decision compared to patient outcome, incidence of SACR, time-to-normal human chorionic gonadotrophin hormone (TNhCG), and primary chemotherapy resistance (PCR).

Results: Metastasis detection (p < 0.0001) and FIGO score (p = 0.001) were higher using CT versus CXR. CT would have increased FIGO score in 188 (31.9%), with 43 re-classified from low- to high-risk, of whom 23 (53.5%) received curative single-agent chemotherapy. SACR was higher when score (p = 0.044) or risk group (p < 0.0001) changed. Metastases on CXR (p = 0.019) but not CT (p = 0.088) lengthened TNhCG. Logistic regression analysis found no difference between CXR (area under the curve (AUC) = 0.63) versus CT (AUC = 0.64) in predicting PCR.

Conclusions: CT chest would improve the prediction of SACR, but does not influence overall treatment outcome, TNhCG, or prediction of PCR. Lower radiation doses and cost mean ongoing CXR-based assessment is recommended.
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http://dx.doi.org/10.1038/s41416-020-01206-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961138PMC
March 2021

Aspirin after PCI: in the twilight of its years?

Platelets 2020 10 15;31(7):831-833. Epub 2020 Jul 15.

Cardiovascular Research Unit, University of Sheffield , Sheffield, UK.

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http://dx.doi.org/10.1080/09537104.2020.1793927DOI Listing
October 2020

New Antithrombotic Drugs in Acute Coronary Syndrome.

J Clin Med 2020 Jun 30;9(7). Epub 2020 Jun 30.

Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2RX, UK.

In recent years, much progress has been made in the field of antithrombotic drugs in acute coronary syndrome (ACS) treatment, as reflected by the introduction of the more potent P2Y12-inhibitors prasugrel and ticagrelor, and novel forms of concomitant anticoagulation, such as fondaparinux and bivalirudin. However, despite substantial improvements in contemporary ACS treatment, there remains residual ischemic risk in this group and hence the need for even more effective antithrombotic drugs, while balancing antithrombotic efficacy against bleeding risk. This review discusses recently introduced and currently developed antiplatelet and anticoagulant drugs in ACS treatment.
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http://dx.doi.org/10.3390/jcm9072059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408919PMC
June 2020

Glimpsing Into the miRe of Ischemia Reperfusion Injury.

Transplantation 2020 09;104(9):1769-1771

Heart & Lung Transplant Unit, Northern General Hospital, Sheffield, United Kingdom.

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http://dx.doi.org/10.1097/TP.0000000000003371DOI Listing
September 2020

Prolonged enoxaparin therapy compared with standard-of-care antithrombotic therapy in opiate-treated patients undergoing primary percutaneous coronary intervention.

Platelets 2021 May 16;32(4):555-559. Epub 2020 Jun 16.

Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK.

A novel enoxaparin regimen consisting of intra-arterial bolus (0.75 mg/kg) followed by intravenous infusion (0.75 mg/kg/6 hours) has been developed as a possible solution to the delayed absorption of oral P2Y inhibitors in opiate-treated ST-elevation myocardial infarction (STEMI) patients undergoing primary angioplasty. We aimed to study the feasibility of this regimen as an alternative to standard-of-care treatment (SOC) with unfractionated heparin ± glycoprotein IIb/IIIa antagonist (GPI). One hundred opiate-treated patients presenting with STEMI and accepted for primary angioplasty were randomized (1:1) to either enoxaparin or SOC. Fifty patients were allocated enoxaparin (median age 61, 40% females) and 49 allocated SOC (median age 62, 22% females). One developed stroke before angiography and was withdrawn. One SOC patient had a gastrointestinal bleed resulting in 1 g drop in hemoglobin and early cessation of GPI infusion. Two enoxaparin patients had transient minor bleeding: one transient gingival bleed and one episode of coffee ground vomit with no hemoglobin drop or hemodynamic instability. Two SOC and no enoxaparin group patients had acute stent thrombosis. These preliminary data support further study of this novel 6-hour enoxaparin regimen in opiate-treated PPCI patients.
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http://dx.doi.org/10.1080/09537104.2020.1779925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352377PMC
May 2021

Benefits and Challenges of Robotic Pelvic Surgery in a Cardiac Transplant Recipient.

Surg Innov 2020 Dec 11;27(6):697-698. Epub 2020 Jun 11.

The Heart & Lung Transplant Unit, Northern General Hospital, 7318Sheffield Teaching Hospitals NHS Foundation Trust, UK.

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http://dx.doi.org/10.1177/1553350620936007DOI Listing
December 2020

Pharmacology and potential role of selatogrel, a subcutaneous platelet P2Y receptor antagonist.

Expert Opin Emerg Drugs 2020 03 17;25(1):1-6. Epub 2020 Feb 17.

Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.

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http://dx.doi.org/10.1080/14728214.2020.1729121DOI Listing
March 2020

Opiates and Clopidogrel Efficacy: Lost in Transit?

J Am Coll Cardiol 2020 01;75(3):301-303

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom; South Yorkshire Cardiothoracic Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.

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http://dx.doi.org/10.1016/j.jacc.2019.11.023DOI Listing
January 2020

Novel approaches to P2Y inhibition and aspirin dosing.

Platelets 2021 Jan 19;32(1):7-14. Epub 2020 Jan 19.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield , Sheffield, UK.

Aspirin and P2Y inhibitors remain commonly prescribed antiplatelet drugs in the treatment of atherothrombotic conditions. Despite established benefits of dual antiplatelet therapy (DAPT) in the setting of acute coronary syndromes, there remains residual ischemic risk in this group and the problem of bleeding complications is an ongoing issue. DAPT with aspirin and ticagrelor has now been studied in other patient groups such as those with concurrent diabetes and stable coronary artery disease, and those undergoing elective percutaneous coronary intervention (PCI). Recent trials of ticagrelor monotherapy have suggested this may have benefits over standard-of-care in some settings, such as PCI, but not in others such as peripheral arterial disease or stroke. A novel subcutaneously administered P2Y inhibitor, selatogrel, has shown powerful, rapid and consistent effect in a phase 2 study. Aspirin dosing remains an area of investigation, particularly in the setting of DAPT. A novel regimen of very-low-dose twice-daily aspirin has hypothetical advantages in pharmacodynamic and pharmacokinetic effects, maintaining antiplatelet effect whilst reducing potentially harmful peak-trough variation.
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http://dx.doi.org/10.1080/09537104.2020.1714574DOI Listing
January 2021

Aspirin, clopidogrel and prasugrel monotherapy in patients with type 2 diabetes mellitus: a double-blind randomised controlled trial of the effects on thrombotic markers and microRNA levels.

Cardiovasc Diabetol 2020 01 7;19(1). Epub 2020 Jan 7.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Background: Despite increased atherothrombotic risk in type 2 diabetes mellitus, (T2DM) the best preventative antithrombotic strategy remains undetermined. We defined the effects of three antiplatelet agents on functional readout and biomarker kinetics in platelet activation and coagulation in patients with T2DM.

Materials And Methods: 56 patients with T2DM were randomised to antiplatelet monotherapy with aspirin 75 mg once daily (OD), clopidogrel 75 mg OD or prasugrel 10 mg OD during three periods of a crossover study. Platelet aggregation (PA) was determined by light-transmittance aggregometry and P-selectin expression by flow cytometry. Markers of fibrin clot dynamics, inflammation and coagulation were measured. Plasma levels of 14 miRNA were assessed by quantitative polymerase chain reactions.

Results: Of the 56 patients, 24 (43%) were receiving aspirin for primary prevention of ischaemic events and 32 (57%) for secondary prevention. Prasugrel was the strongest inhibitor of ADP-induced PA (mean ± SD maximum response to 20μmol/L ADP 77.6 ± 8.4% [aspirin] vs. 57.7 ± 17.6% [clopidogrel] vs. 34.1 ± 14.1% [prasugrel], p < 0.001), P-selectin expression (30 μmol/L ADP; 45.1 ± 21.4% vs. 27.1 ± 19.0% vs. 14.1 ± 14.9%, p < 0.001) and collagen-induced PA (2 μg/mL; 62.1 ± 19.4% vs. 72.3 ± 18.2% vs. 60.2 ± 18.5%, p < 0.001). Fibrin clot dynamics and levels of coagulation and inflammatory proteins were similar. Lower levels of miR-24 (p = 0.004), miR-191 (p = 0.019), miR-197 (p = 0.009) and miR-223 (p = 0.014) were demonstrated during prasugrel-therapy vs. aspirin. Circulating miR-197 was lower in those cardiovascular disease during therapy with aspirin (p = 0.039) or prasugrel (p = 0.0083).

Conclusions: Prasugrel monotherapy in T2DM provided potent platelet inhibition and reduced levels of a number of platelet-associated miRNAs. miR-197 is a potential marker of cardiovascular disease in this population. Clinical outcome studies investigating prasugrel monotherapy are warranted in individuals with T2DM. Trial registration EudraCT, 2009-011907-22. Registered 15 March 2010, https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011907-22/GB.
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http://dx.doi.org/10.1186/s12933-019-0981-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945631PMC
January 2020

Offset of ticagrelor prior to coronary artery bypass graft surgery for acute coronary syndromes: effects on platelet function and cellular adenosine uptake.

Platelets 2020 Oct 2;31(7):945-951. Epub 2020 Jan 2.

Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield , Sheffield, UK.

Ticagrelor is an antagonist of both platelet adenosine diphosphate (ADP) receptor P2Y and equilibrative nucleoside transporter-1. Optimal timing of ticagrelor cessation prior to coronary artery bypass grafting (CABG) remains unclear. We characterized the offset of ticagrelor's effects on platelets and cellular adenosine uptake in ticagrelor-treated patients (n = 13) awaiting CABG. Blood was drawn prior to CABG at multiple timepoints 2 to 120 (h) after the last dose of ticagrelor. Platelet function (n = 13) was assessed with multiple electrode aggregometry (MEA), expressed as arbitrary units (U) derived from area-under-the-curve (AUC) in response to ADP, and inhibition of adenosine uptake by high-performance liquid chromatography (n = 7). Mean±SD AUC was 20.3 ± 8.2 U (2 h post-ticagrelor), 33.0 ± 18.3U (24 h), 56.6 ± 30.6U (48 h), 61.4 ± 20.2U (72 h), 82.8 ± 24.2U (96 h) and 96.0 ± 15.3U (120 h). There was a significant difference between 72 h and 120 h ( = .007), but not between 96 h and 120 h ( > .99). By 96 h, all patients had AUC >31U, an accepted cutoff below which surgical bleeding risk is increased. Adenosine uptake showed no significant differences between the timepoints. These data suggest it takes 4 days for platelet reactivity to recover sufficiently after cessation of ticagrelor to avoid the excess risk of CABG-related bleeding. Discontinuing ticagrelor had no measurable effect on cellular adenosine uptake.
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http://dx.doi.org/10.1080/09537104.2019.1709631DOI Listing
October 2020

Combining DAPT with a PPI faces the acid test of real-world use.

Eur Heart J 2019 06;40(24):1971-1974

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.

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http://dx.doi.org/10.1093/eurheartj/ehz102DOI Listing
June 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.
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http://dx.doi.org/10.1080/09537104.2019.1572880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425913PMC
April 2019

Study of Two Dose Regimens of Ticagrelor Compared with Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease (STEEL-PCI).

Circulation 2018 Jun 21. Epub 2018 Jun 21.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom & Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom

-Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndromes but has not been assessed in patients undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD). We compared the pharmacodynamic effects of ticagrelor and clopidogrel in this stable population. -180 aspirin-treated stable CAD patients, who were planned to undergo elective PCI in a single center, were randomized 1:1:1 to either a standard clopidogrel regimen or one of two regimens of ticagrelor, either 90mg (T90) or 60mg twice-daily (T60), both with 180mg loading dose. Cellular adenosine uptake was assessed, at the time of the procedure and pre- and post-dose at 1 month, by adding adenosine 1 μmol/L to aliquots of anticoagulated whole blood and mixing with a stop solution at 0, 15, 30 and 60 seconds then measuring residual plasma adenosine concentration by high-performance liquid chromatography. Systemic plasma adenosine concentration and platelet reactivity were assessed at the same timepoints. High-sensitivity troponin T (hsTnT) was measured pre- and 18-24 hours post-PCI. -174 patients underwent an invasive procedure, of which 162 patients received PCI (mean age 65 years, 18% female, 21% with diabetes mellitus). No effect on adenosine uptake was seen post-dose at 1 month for either ticagrelor dose compared with clopidogrel (residual adenosine at 15s, mean ± SD: clopidogrel 0.274 ± 0.101 μmol/L; T90 0.278 ± 0.134 μmol/L; T60 0.288 ± 0.149 μmol/L; P = 0.37). Similarly no effect of ticagrelor on in vitro adenosine uptake was seen at other timepoints, nor was plasma adenosine concentration affected (all P > 0.1). Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel (VerifyNow PRU, 1 month, mean ± SD: pre-dose, T60: 62 ± 47, T90: 40 ± 38, clopidogrel 181 ± 44; post-dose, T60: 34 ± 30, T90: 24 ± 21, clopidogrel 159 ± 57; all P < 0.0001 for ticagrelor vs clopidogrel). High platelet reactivity was markedly less with both T60 and T90 compared with clopidogrel (VerifyNow PRU>208, 1-month post-dose: 0%, 0% and 21%, respectively). Median (IQR) hsTnT increase was 16.9 (6.5-46.9) ng/l for clopidogrel, 22.4 (5.5-53.8) ng/L for T60 and 17.7 (8.1-43.5) ng/L for T90 (P = 0.95). There was a trend towards less dyspnea with T60 versus T90 (7.1% vs 19.0%; P = 0.09). -Maintenance therapy with T60 or T90 had no detectable effect on cellular adenosine uptake at 1 month, nor was there any effect on systemic plasma adenosine levels. Both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel but did not appear to affect troponin release following PCI. -URL: https://clinicaltrials.gov Unique Identifier: NCT02327624.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159686PMC
June 2018

Pharmacodynamic Effects of a 6-Hour Regimen of Enoxaparin in Patients Undergoing Primary Percutaneous Coronary Intervention (PENNY PCI Study).

Thromb Haemost 2018 Jul 6;118(7):1250-1256. Epub 2018 Jun 6.

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

Delayed onset of action of oral P2Y inhibitors in ST-elevation myocardial infarction (STEMI) patients may increase the risk of acute stent thrombosis. Available parenteral anti-thrombotic strategies, to deal with this issue, are limited by added cost and increased risk of bleeding. We investigated the pharmacodynamic effects of a novel regimen of enoxaparin in STEMI patients undergoing primary percutaneous coronary intervention (PPCI). Twenty patients were recruited to receive 0.75 mg/kg bolus of enoxaparin (pre-PPCI) followed by infusion of enoxaparin 0.75 mg/kg/6 h. At four time points (pre-anti-coagulation, end of PPCI, 2-3 hours into infusion and at the end of infusion), anti-Xa levels were determined using chromogenic assays, fibrin clots were assessed by turbidimetric analysis and platelet P2Y inhibition was determined by VerifyNow P2Y12 assay. Clinical outcomes were determined 14 hours after enoxaparin initiation. Nineteen of 20 patients completed the enoxaparin regimen; one patient, who developed no-reflow phenomenon, was switched to tirofiban after the enoxaparin bolus. All received ticagrelor 180 mg before angiography. Mean (± standard error of the mean) anti-Xa levels were sustained during enoxaparin infusion (1.17 ± 0.06 IU/mL at the end of PPCI and 1.003 ± 0.06 IU/mL at 6 hours), resulting in prolonged fibrin clot lag time and increased lysis potential. Onset of platelet P2Y inhibition was delayed in opiate-treated patients. No patients had thrombotic or bleeding complications. In conclusion, enoxaparin 0.75 mg/kg bolus followed by 0.75 mg/kg/6 h provides sustained anti-Xa levels in PPCI patients. This may protect from acute stent thrombosis in opiate-treated PPCI patients who frequently have delayed onset of oral P2Y inhibition.
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http://dx.doi.org/10.1055/s-0038-1657768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202933PMC
July 2018

Equilibrative nucleoside transporter 1 gene polymorphisms and clinical outcomes following acute coronary syndromes: findings from the PLATelet inhibition and patient Outcomes (PLATO) study.

Platelets 2019 31;30(5):579-588. Epub 2018 May 31.

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

In the PLATelet inhibition and patient Outcomes (PLATO) study, the P2Y inhibitors ticagrelor and clopidogrel were compared in the treatment of acute coronary syndromes (ACS). Ticagrelor was shown to reduce occurrence of the primary end point - a composite of death from vascular causes, myocardial infarction, or stroke - compared to clopidogrel. Ticagrelor's pleiotropic effects on reuptake of adenosine via inhibition of equilibrative nucleoside transporter 1 (ENT1) have been hypothesized to contribute to this. Several polymorphisms of ENT1 are known to exist. We explored the interaction between ENT1 polymorphisms and clinical outcomes in ACS patients participating in the PLATO genetic substudy. Using genotyping data obtained in a genome-wide association study, the gene region encoding ENT1 was assessed and 94 polymorphisms were identified. After quality control filtering, data from 9943 participants were included. Subjects were divided into discovery (phase 1, n = 3970) and replication (phase 2, n = 5973) cohorts. Cox-regression analysis of the relationship between variants and seven efficacy and safety outcomes was performed in discovery, replication, and combined cohorts. Treatment-marker interactions were also determined. Although 35 variants were found with associations to the investigated outcomes reaching p < 0.05 in the discovery cohort, only one of these was replicated in phase 2 of the analysis and also reached the predetermined level of statistical significance in the combined data, taking into account the number of tests performed: the rare polymorphism rs141034817, with a frequency of 0.2%, was significantly associated with bleeding. Thirty-three treatment-marker interactions were found with a significance level of p < 0.05 in phase 1, but none was replicated in phase 2. We found no significant interaction between ENT1 genotype and clinical outcomes in ACS patients treated with ticagrelor or clopidogrel, apart from the association between a rare polymorphism and bleeding that requires further study. If ticagrelor's pleiotropic effects on adenosine uptake are clinically relevant, these do not appear to be significantly affected by variation in the ENT1 gene.
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http://dx.doi.org/10.1080/09537104.2018.1478404DOI Listing
November 2019

Secondhand Hypertrophy: A Rare Case of Genetically Based Pathology Developing Within a Transplanted Heart.

Transplantation 2018 09;102(9):e397-e398

The Heart & Lung Transplant Unit, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.

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http://dx.doi.org/10.1097/TP.0000000000002292DOI Listing
September 2018

Ticagrelor: agonising over its mechanisms of action.

Blood 2016 12;128(23):2595-2597

UNIVERSITY OF SHEFFIELD.

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http://dx.doi.org/10.1182/blood-2016-10-743930DOI Listing
December 2016

Choices for Potent Platelet Inhibition in Patients With Diabetes Mellitus.

Circulation 2016 Sep;134(11):793-6

From Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, United Kingdom (R.F.S., W.A.E.P.); and Directorate of Cardiology and Cardiothoracic Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom (R.F.S., W.A.E.P.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.023835DOI Listing
September 2016
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