Endogenous Fibrinolysis : An Important Mediator of Thrombus Formation and Cardiovascular Risk

© 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. PUBLISHED BY ELSEVIER INC.Most acute cardiovascular events are attributable to arterial thrombosis. Plaque rupture or erosion stimulates platelet activation, aggregation, and thrombosis, whilst simultaneously activating enzymatic processes that mediate endogenous fibrinolysis to physiologically maintain vessel patency. Interplay between these pathways determines clinical outcome. If proaggregatory factors predominate, the thrombus may propagate, leading to vessel occlusion. However, if balanced by a healthy fibrinolytic system, thrombosis may not occur or cause lasting occlusion. Despite abundant evidence for the fibrinolytic system regulating thrombosis, it has been overlooked compared with platelet reactivity, partly due to a lack of techniques to measure it. We evaluate evidence for endogenous fibrinolysis in arterial thrombosis and review techniques to assess it, including biomarkers and global assays, such as thromboelastography and the Global Thrombosis Test. Global assays, simultaneously assessing proaggregatory and fibrinolytic pathways, could play a role in risk stratification and in identifying impaired fibrinolysis as a potential target for pharmacological modulation.Peer reviewedFinal Published versio

Adjunctive therapies to reduce thrombotic events in patients with a history of myocardial infarction : role of vorapaxar

© 2015 Farag et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) LicenseAcute myocardial infarction (AMI) is generally attributed to coronary atherothrombotic disease. Platelet activation is essential for thrombus formation and is thus an important target for pharmacological intervention to prevent and treat AMI. Despite contemporary treatment with dual antiplatelet therapy, including acetylsalicylic acid and adenosine diphosphate receptor antagonists, patients with prior AMI remain at increased risk of future thrombotic events. This has stimulated the search for more potent antithrombotic agents. Among these is the oral protease-activated receptor-1 antagonist vorapaxar, which represents a new oral antiplatelet agent to reduce thrombotic risk in patients with atherothrombotic disease. The TRACER and the TRA 2°P-TIMI 50 trials concluded that vorapaxar in addition to standard therapy reduced ischemic adverse cardiac events. A remarkable benefit was observed in patients with stable atherosclerotic disease, particularly those with a previous history of AMI. Although favorable effects were seen in reduction of adverse cardiac events, this was associated with excess major and intracranial bleeding, particularly in patients at high risk of bleeding and those with a history of stroke or transient ischemic attack. Currently, the lack of a reliable individualized risk stratification tool to assess patients for thrombotic and bleeding tendencies in order to identify those who might gain most net clinical benefit has led to limited use of vorapaxar in clinical practice. Vorapaxar may find a niche as an adjunct to standard care in patients at high risk of thrombotic events and who are at low risk of bleeding.Peer reviewe

Nitrates for the Management of Acute Heart Failure Syndromes, A Systematic Review

© The Author(s) 2016Intravenous nitrates are widely used in the management of acute heart failure syndrome (AHFS) yet with lack of robust evidence to support their use. We therefore sought to analyze all randomized studies that evaluated the effects of nitrates on clinical outcomes in patients with AHFS. In total, 15 relevant trials comparing nitrates and alternative interventions in 1824 patients were identified. All but 3 were conducted before 1998. No trials demonstrated a beneficial effect on mortality, apart from 1 trial reporting a reduction in mortality, which was related to the time of treatment. Retrospective review suggests that there is a lack of data to draw any firm conclusions concerning the use of nitrates in patients with AHFS. More studies are needed to evaluate the safety and efficacy of these agents in the modern era of guideline-directed use of heart failure therapy.Peer reviewedFinal Accepted Versio

A rare cause of myocardial infarction with non-obstructive coronary arteries-case report of ST-segment elevation myocardial infarction caused by a mediastinal mass

© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction ST-segment elevation myocardial infarction (STEMI) is attributable to an occluded coronary artery in almost 90% of patients. Accordingly, restoration of coronary perfusion as early as possible, preferably with primary percutaneous coronary intervention, is the recommended treatment by the European Society of Cardiology, to maximise myocardial salvage. However, not all cases of STEMI are because of coronary artery occlusion. ST-segment elevation myocardial infarction that occurs in the absence of obstructive coronary artery disease on angiography has been termed myocardial infarction with non-obstructive coronary arteries (MINOCA). Case A 44-year-old man was admitted with retrosternal chest pain radiating to the left arm and jaw, and electrocardiogpresentation raphy showed extensive anterior ST-segment elevation. Emergency coronary angiography showed all three coronary arteries were patent with Thrombolysis in Myocardial Infarction-3 flow and no evidence of dissection or thrombus. The ST-elevation and pain resolved spontaneously. Troponin-T level rose from <3 ng/L on arrival to 549 ng/L at 12 h. Subsequent cardiac magnetic resonance imaging (MRI) showed a structurally normal heart (without late gadolinium enhancement) but detected an incidental large, lobulated (90 * 31 * 71 mm) mediastinal mass containing multiple cysts in the anterior mediastinum with inflammation and oedema of the parietal pericardium. Tissue biopsy confirmed Hodgkin's lymphoma and the patient was initiated on chemotherapy. Discussion Some 3% of ST-segment myocardial infarctions occur in the absence of obstructive coronary disease (MINOCA), is more frequent in younger patients. Cardiac MRI is a useful tool to both identify some of the potential causes of MINOCA and also to confirm the diagnosis of infarction. Some 26% of MINOCA patients have significant biochemical evidence of myocardial injury but have a normal cardiac MRI. This case illustrates a very rare cause of myocardial infarction in a young patient with unobstructed coronary arteries, and highlights the need in such cases for further detailed imaging of the myocardium and thorax to establish the diagnosis and initiate appropriate treatment.Peer reviewedFinal Published versio

Spontaneous Coronary Artery Dissection : The Phantom Menace

Articles © The authorsWe present a case of a 66-year-old lady with chest pain, without dynamic 12-lead electrocardiographic (ECG) changes and normal serial troponin. Coronary angiography revealed a linear filing defect in the first obtuse marginal branch of the circumflex artery indicating coronary artery dissection, with superadded thrombus. She was managed medically with dual antiplatelet therapy and has responded well. Spontaneous coronary artery dissection (SCAD) is a rare cause of cardiac chest pain, which can be missed without coronary angiography. Unlike most other lesions in patients with unstable symptoms, where coronary intervention with stenting is recommended, patients with SCAD generally fare better with conservative measures than with intervention, unless there is hemodynamic instability.Peer reviewe

Low-grade endotoxaemia and platelets : A deadly aggregation

This article has been accepted for publication in European Heart Journal. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020.Peer reviewe

Impaired thrombolytic status predicts adverse cardiac events in patients undergoing primary percutaneous coronary intervention

This document is the Accepted Manuscript version of the following article: C. Christopoulos, M. Faraf, K. Sullican, D. Wellsted, and D. A. Gorog, 'Impaired thrombolytic status predicts adverse cardiac events in patients undergoing primary percutaneous coronary intervention', Thrombosis and Haemostasis, Issue 3: 457-470, 2017. Under embargo. Embargo end date: 1 March 2018. The Version of Record is available online at doi: https://doi.org/10.1160/TH16-09-0712.Antithrombotic medications reduce thrombosis but increase bleeding. Identification of ST-elevation myocardial infarction (STEMI) patients at risk of recurrent thrombosis could allow targeted treatment with potent antithrombotic medications, with less potent agents in others, to reduce bleeding. Conventional platelet function tests assess platelet reactivity only, yet there is increasing evidence that endogenous thrombolytic potential determines outcome following thrombus initiation. We investigated whether assessing both platelet reactivity and endogenous thrombolysis, could identify STEMI patients at high-risk of recurrent thrombotic events. Thrombotic status was assessed in STEMI patients, before and after primary percutaneous coronary intervention (PPCI), at discharge and at 30 days; with 12 months' follow-up. The time to form an occlusive thrombus under high shear (occlusion time, OT), and time to restore flow by endogenous thrombolysis (lysis time, LT) was measured using the point-of-care Global Thrombosis Test (GTT) in the cardiac catheterisation laboratory. Impaired endogenous thrombolysis (prolonged LT ≥ 3000 s), seen in 13 % patients pre-PPCI, was related to major adverse cardiac events, MACE (HR: 3.31, 95 %CI: 1.02-10.78, p = 0.045), driven by cardiovascular death (HR: 4.17, 95 %CI: 0.99-17.51, p = 0.05). Enhanced (rapid) endogenous thrombolysis (LT < 1000 s) was associated with spontaneous reperfusion, ST-segment resolution and Thrombolysis In Myocardial Infarction 3 flow pre-PPCI. Baseline OT was shorter in those with MACE (especially recurrent myocardial infarction and stroke) than those without (253 ± 150 s vs 354 ± 134 s, p=0.017). Endogenous thrombolysis, when impaired, is associated with increased cardiovascular risk, and when enhanced, with spontaneous reperfusion. Endogenous thrombolysis may be a novel target for pharmacological intervention, and allow targeting of potent antithrombotic medications to high-risk patients.Peer reviewedFinal Accepted Versio

Morphine Analgesia Pre-PPCI Is Associated with Prothrombotic State, Reduced Spontaneous Reperfusion and Greater Infarct Size

Schattauer GmbH Stuttgart.The emergency management of ST-elevation myocardial infarction (STEMI) involves treatment with dual-antiplatelet therapy (DAPT) and primary percutaneous coronary intervention (PPCI). Pain is generally treated with opiates, which may delay gastric transit and reduce DAPT absorption. We sought to assess the effect of morphine on reperfusion, infarct size and thrombotic status in 300 patients presenting for PPCI. Morphine was given in a non-randomized fashion as required by emergency teams en route to the heart attack centre. All patients received DAPT and PPCI according to standard care, with optional glycoprotein IIb/IIIa inhibitor (GPI) use. Patients were assessed for ST-segment resolution, coronary flow, thrombotic status and peak troponin. Patients receiving morphine (n = 218; 72.7%) experienced less spontaneous ST-segment resolution pre-PPCI, lower rate of TIMI 2/3 flow in the infarct-related artery pre-PPCI and higher peak troponin level post-PPCI (median [interquartile range]; 1,906 [1,002-4,398] vs. 1,268 [249-2,920] ng/L; p = 0.016) than those who did not. Patients receiving morphine exhibited significantly enhanced platelet reactivity and impaired endogenous fibrinolysis on arrival, compared with no-morphine patients. Morphine administration was an independent predictor of failure of spontaneous ST-segment resolution after adjustment for other variables (odds ratio: 0.26; confidence interval: 0.08-0.84; p = 0.025). Among patients receiving GPI, there was no difference in pre-PPCI flow or peak troponin according to morphine use, suggesting that the adverse effects of morphine relate to delayed DAPT absorption, which may be overcome by GPI. Our hypothesis-generating data suggest that morphine use in STEMI is associated with enhanced platelet reactivity, reduced spontaneous myocardial reperfusion (pre-PPCI) and larger infarct size, and these adverse effects may be influenced by GPI use. CLINICAL TRIAL REGISTRATION:  URL: http://www.clinicaltrials.gov. Unique identifier: NCT02562690.Peer reviewedFinal Accepted Versio

Is There Long-Term Clinical Equipoise Between CABG and PCI for Isolated Left Anterior Descending Artery Disease?

© 2023 Society for Cardiovascular Angiography and Interventions Foundation. Published by Elsevier Inc. on behalf of the Society for Cardiovascular Angiography and Interventions Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Rationale and design of "Can Very Low Dose Rivaroxaban (VLDR) in addition to dual antiplatelet therapy improve thrombotic status in acute coronary syndrome (VaLiDate-R)" study : A randomised trial modulating endogenous fibrinolysis in patients with acute coronary syndrome

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of Very Low Dose Rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. The VaLiDate-R study (ClinicalTrials.gov Identifier: NCT03775746, EudraCT: 2018-003299-11) is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time > 2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.Peer reviewedFinal Published versio