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Aims Atherothrombotic events are influenced by systemic hypercoagulability and fibrinolytic activity. The present study evaluated thrombogenicity indices and their prognostic implications according to disease acuity. Methods and results From the consecutive patients undergoing percutaneous coronary intervention (PCI), those with thrombogenicity indices (n = 2705) were grouped according to disease acuity [acute myocardial infarction (AMI) vs. non-AMI]. Thrombogenicity indices were measured by thromboelastography (TEG). Blood samples for TEG were obtained immediately after insertion of the PCI sheath, and TEG tracing was performed within 4 h post-sampling. Major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) were evaluated for up to 4 years. Compared with non-AMI patients, AMI patients had higher platelet-fibrin clot strength [maximal amplitude (MA): 66.5 ± 7.8 vs. 65.3 ± 7.2 mm, P < 0.001] and lower fibrinolytic activity [clot lysis at 30 min (LY30): 0.9 ± 1.8% vs. 1.1 ± 1.9%, P < 0.001]. Index AMI presentation was associated with MA [per one-mm increase: odds ratio (OR): 1.024; 95% confidence interval (CI): 1.013–1.036; P < 0.001] and LY30 (per one% increase: OR: 0.934; 95% CI: 0.893–0.978; P = 0.004). The presence of high platelet-fibrin clot strength (MA ≥68 mm) and low fibrinolytic activity (LY30 < 0.2%) was synergistically associated with MACE occurrence. In the multivariable analysis, the combined phenotype of ‘MA ≥ 68 mm’ and ‘LY30 < 0.2%’ was a major predictor of post-PCI MACE in the AMI group [adjusted hazard ratio (HR): 1.744; 95% CI: 1.135–2.679; P = 0.011], but not in the non-AMI group (adjusted HR: 1.031; 95% CI: 0.499–2.129; P = 0.935). Conclusion AMI occurrence is significantly associated with hypercoagulability and impaired fibrinolysis. Their combined phenotype increases the risk of post-PCI atherothrombotic event only in AMI patients. These observations may support individualized therapy that targets thrombogenicity for better outcomes in patients with AMI. Clinical Trial Registration Gyeongsang National University Hospital (G-NUH) Registry, NCT04650529.

Background Guideline-recommended dual antiplatelet therapy (DAPT; aspirin plus prasugrel/ticagrelor) for 12 months in acute coronary syndrome (ACS) patients increases bleeding, with East Asians (EAs) exhibiting higher bleeding and lower ischemic risk, compared with non-East Asians (nEAs). We sought to compare DAPT “de-escalation” strategies in EA and nEA populations. Methods A systematic review and meta-analysis of randomized controlled trials assessing reduction of DAPT intensity or duration in ACS patients undergoing percutaneous coronary intervention, in EA and nEA, was performed using a random-effects model. Results Twenty-three trials assessed reduction of DAPT intensity (n = 12) or duration (n = 11). Overall, reduced DAPT intensity attenuated major bleeding (odds ratio [OR]: 0.78, 95% confidence interval [CI]: 0.65–0.94, p = 0.009), without impacting net adverse cardiovascular events (NACE) or major adverse cardiovascular events (MACE). In nEA, this increased MACE (OR: 1.20, 95% CI: 1.09–1.31, p Conclusion In EA, reduction of DAPT intensity or duration can minimize bleeding, without safety concerns. In nEA, reduction of DAPT intensity may incur an ischemic penalty, while DAPT abbreviation has no overall benefit.

OBJECTIVE To analyze the impact of modern glucose-monitoring strategies on glycemic and patient-related outcomes in individuals with type 2 diabetes (T2D) and recent myocardial infarction (MI) and assess cost effectiveness. RESEARCH DESIGN AND METHODS LIBERATES was a multicenter two-arm randomized trial comparing self-monitoring of blood glucose (SMBG) with intermittently scanned continuous glucose monitoring (isCGM), also known as flash CGM, in individuals with T2D and recent MI, treated with insulin and/or a sulphonylurea before hospital admission. The primary outcome measure was time in range (TIR) (glucose 3.9–10 mmol/L/day) on days 76–90 post-randomization. Secondary and exploratory outcomes included time in hypoglycemia, hemoglobin A1c (HbA1c), clinical outcome, quality of life (QOL), and cost effectiveness. RESULTS Of 141 participants randomly assigned (median age 63 years; interquartile range 53, 70), 73% of whom were men, isCGM was associated with increased TIR by 17 min/day (95% credible interval −105 to +153 min/day), with 59% probability of benefit. Users of isCGM showed lower hypoglycemic exposure ( CONCLUSIONS Compared with SMBG, isCGM in T2D individuals with MI marginally increases TIR and significantly reduces hypoglycemic exposure while equally improving HbA1c, explaining its cost effectiveness. Studies are required to understand whether these glycemic differences translate into longer-term clinical benefit.

Background Patients with severe aortic stenosis (AS) are at risk of both bleeding and thrombotic events. The high shear and flow rates across the stenotic aortic valve (AV) degrade von Willebrand factor high molecular weight multimers increasing bleeding risk, but can also lead to platelet activation. The overall effect on thrombotic and endogenous fibrinolytic status remains unclear. We aimed to assess the relationship between AS severity and thrombotic and fibrinolytic profile. Materials and methods In a prospective, observational study, thrombotic and thrombolytic status was assessed in venous blood taken from patients with severe AS using the Global Thrombosis Test. This point-of-care technique measures the time for occlusive thrombus formation under high shear (OT), and the time for spontaneous lysis of the thrombus (LT). We related these parameters to indices of AS severity. Results and conclusions Our cohort comprised of 86 patients (age 79 ± 9 years, 58% male), of whom 25% were on single and 28% on dual antiplatelet medication, 47% on no antithrombotic therapy, and 1% on oral anticoagulation. Lysis time was inversely related to AV peak (r = −0.242, P = 0.04) and mean (r = −0.286, P = 0.012) gradients. The severity of AS, by gradient or valve area, was not related to OT, although OT was inversely related to platelet count (r = −0.248, P = 0.029). Heterogeneity in antithrombotic medications may have masked a relationship between AS severity and OT. We report that increasing severity of AS is related to more effective endogenous fibrinolysis, which may contribute to the increased propensity to bleeding.

Background Impaired endogenous fibrinolysis is a risk factor for recurrent cardiovascular events in patients with acute coronary syndrome (ACS). Ongoing inflammation is also an adverse prognostic risk factor. While inflammatory markers are elevated in patients presenting with ST-segment elevation myocardial infarction (STEMI), whether there is a direct relationship between markers of inflammation at presentation, and the effectiveness of endogenous fibrinolysis in this setting, is unclear. Our study aimed to assess the relationship between markers of inflammation, coagulation and fibrinolysis, in patients with STEMI. Material and methods We conducted a prospective, observational study in consecutive patients presenting with STEMI. Blood was drawn on admission after dual antiplatelet therapy loading, but before administration of anticoagulants. The sample was immediately tested to assess endogenous fibrinolysis using the point-of-care Global Thrombosis Test. In addition, blood samples were tested for leucocyte and neutrophil count, neutrophil-to-leucocyte ratio (NLR), platelet-to-leucocyte ratio (PLR), fibrinogen, standard coagulation markers and high sensitivity C-reactive protein (hs-CRP). Results and conclusions The cohort consisted of 129 patients (aged 66 ± 13 years, 78% male). Whole blood endogenous fibrinolysis time correlated with fibrinogen (r = 0.300, P = 0.001) and hs-CRP (r = 0.236, P = 0.011). Hs-CRP correlated with fibrinogen (r = 0.631, P < 0.001). There was no relationship between whole blood lysis time and leucocyte count, NLR, PLR, international normalised ratio or activated partial thromboplastin time. The effectiveness of endogenous fibrinolysis in whole blood is related to fibrinogen and hs-CRP levels. Our findings strengthen the evidence for bi-directional cross talk between coagulation, fibrinolysis and inflammatory pathways, providing mechanistic insights that could help guide pharmacological strategies to treat hypofibrinolysis.

This abstract has been withdrawn. Please see: https://doi.org/10.1093/cvr/cvac183

Choosing an antiplatelet strategy in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) at high bleeding risk (HBR), undergoing post-percutaneous coronary intervention (PCI), is complex. We used a unique open-source approach (crowdsourcing) to document if practices varied across a small, global cross-section of antiplatelet prescribers in the post-PCI setting.Five-hundred and fifty-nine professionals from 70 countries (the 'crowd') completed questionnaires containing single- or multi-option and free form questions regarding antiplatelet clinical practice in post-PCI NSTE-ACS patients at HBR. A threshold of 75% defined 'agreement'. There was strong agreement favouring monotherapy with either aspirin or a P2YThe crowdsourcing methodology showed potential as a tool to assess current practice and variation on a global scale and to achieve a broad demographic representation. These preliminary results indicate a high degree of variation with respect to duration of DAPT, monotherapy drug of choice following DAPT and how thrombotic and bleeding risk are assessed. Further investigations should concentrate on interrogating practice variation between key demographic groups.

INTRODUCTION Atrial fibrillation (AF) is frequent after any cardiac surgery, but evidence suggests it may have no significant impact on survival if sinus rhythm (SR) is effectively restored early after the onset of the arrhythmia. In contrast, management of preoperative AF is often overlooked during or after cardiac surgery despite several proposed protocols. This study sought to evaluate the impact of preoperative AF on mortality in patients undergoing isolated surgical aortic valve replacement (AVR). METHODS We performed a retrospective, single-center study involving 2628 consecutive patients undergoing elective, primary isolated surgical AVR from 2008 to 2018. A total of 268/2628 patients (10.1%) exhibited AF before surgery. The effect of preoperative AF on mortality was evaluated with univariate and multivariate analyses. RESULTS Short-term mortality was 0.8% and was not different between preoperative AF and SR cohorts. Preoperative AF was highly predictive of long-term mortality (median follow-up of 4 years [Q1-Q3 2-7]; hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.79-2.79, p

A high incidence of thrombosis in hospitalised patients with COVID-19 was identified early during the pandemic. Accurately quantifying thrombotic risk may assist prognosis and guide appropriate thromboprophylaxis. Observational studies have estimated the rate of thrombosis in both hospitalised and non-hospitalised patients with COVID-19, and how this corresponds to the severity of illness. In this review, we provide an overview of the incidence and prevalence of arterial and venous thrombotic events in patients with COVID-19 and highlight the limitations in the studies to date. Asymptomatic individuals with COVID-19 and those with mild symptoms are at very low risk of thrombotic complications. However, rates of thrombosis are substantially increased in hospitalised patients, and are strikingly high in those patients who are critically-ill requiring treatment on the intensive care unit and especially those requiring extracorporeal membrane oxygenation. Clinicians managing such patients need to be aware of these risks and take appropriate steps with respect to thromboprophylaxis and heightened clinical vigilance. Large prospective observational studies will more accurately quantify thrombotic rate, and randomized controlled trials are currently investigating optimal thromboprophylactic strategies.

Patients supported with extracorporeal membrane oxygenation (ECMO) experience a very high frequency of bleeding and ischaemic complications, including stroke and systemic embolism. These patients require systemic anticoagulation, mainly with unfractionated heparin (UFH) to prevent clotting of the circuit and reduce the risk of arterial or venous thrombosis. Monitoring of UFH can be very challenging. While most centres routinely monitor the activated clotting time and activated partial thromboplastin time (aPTT) to assess UFH, measurement of anti-factor Xa (anti-Xa) level best correlates with heparin dose, and appears to be predictive of circuit thrombosis, although aPTT may be a better predictor of bleeding. Although monitoring of prothrombin time, platelet count and fibrinogen is routinely undertaken to assess haemostasis, there is no clear guidance available regarding the optimal test.Additional tests, including antithrombin level and thromboelastography, can be used for risk stratification of patients to try and predict the risks of thrombosis and bleeding. Each has their specific role, strengths and limitations. Increased thrombin generation may have a role in predicting thrombosis. Acquired von Willebrand syndrome is frequent with ECMO, contributing to bleeding risk and can be detected by assessing the von Willebrand factor activity-to-antigen ratio, while the platelet function analyser can be used in urgent situations to detect this, with a high negative predictive value. Tests of platelet aggregation can aid in the prediction of bleeding.To personalise management, a selection of complementary tests to collectively assess heparin-effect, coagulation, platelet function and platelet aggregation is proposed, to optimise clinical outcomes in these high-risk patients. ispartof: THROMBOSIS AND HAEMOSTASIS vol:122 issue:04 pages:480-491 ispartof: location:Germany status: published

Importance The arrest and the post-arrest period are an incredibly emotionally traumatic time for family and friends of the affected individual. There is a need to assess prognosis early in the patient pathway to offer objective, realistic and non-emotive information to the next-of-kin regarding the likelihood of survival. Objective To present a systematic review of the clinical risk scores available to assess patients on admission following out-of-hospital cardiac arrest (OHCA) which can predict in-hospital mortality. Evidence review A systematic search of online databases Embase, MEDLINE and Cochrane Central Register of Controlled Trials was conducted up until 20th November 2020. Findings Out of 1,817 initial articles, we identified a total of 28 scoring systems, with 11 of the scores predicting mortality following OHCA included in this review. The majority of the scores included arrest characteristics (initial rhythm and time to return of spontaneous circulation) as prognostic indicators. Out of these, the 3 most clinically-useful scores, namely those which are easy-to-use, comprise of commonly available parameters and measurements, and which have high predictive value are the OHCA, NULL-PLEASE, and rCAST scores, which appear to perform similarly. Of these, the NULL-PLEASE score is the easiest to calculate and has also been externally validated. Conclusions Clinicians should be aware of these risk scores, which can be used to provide objective, nonemotive and reproducible information to the next-of-kin on the likely prognosis following OHCA. However, in isolation, these scores should not form the basis for clinical decision-making.

© 2020 Elsevier Inc. All rights reserved. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1016/j.amjcard.2020.12.014

OBJECTIVES: Severe coronavirus disease 2019 is associated with an extensive pneumonitis and frequent coagulopathy. We sought the true prevalence of thrombotic complications in critically ill patients with severe coronavirus disease 2019 on the ICU, with or without extracorporeal membrane oxygenation. DESIGN: We undertook a single-center, retrospective analysis of 72 critically ill patients with coronavirus disease 2019-associated acute respiratory distress syndrome admitted to ICU. CT angiography of the thorax, abdomen, and pelvis were performed at admission as per routine institution protocols, with further imaging as clinically indicated. The prevalence of thrombotic complications and the relationship with coagulation parameters, other biomarkers, and survival were evaluated. SETTING: Coronavirus disease 2019 ICUs at a specialist cardiorespiratory center. PATIENTS: Seventy-two consecutive patients with coronavirus disease 2019 admitted to ICU during the study period (March 19, 2020, to June 23, 2020). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All but one patient received thromboprophylaxis or therapeutic anticoagulation. Among 72 patients (male:female = 74%; mean age: 52 ± 10; 35 on extracorporeal membrane oxygenation), there were 54 thrombotic complications in 42 patients (58%), comprising 34 pulmonary arterial (47%), 15 peripheral venous (21%), and five (7%) systemic arterial thromboses/end-organ embolic complications. In those with pulmonary arterial thromboses, 93% were identified incidentally on first screening CT with only 7% suspected clinically. Biomarkers of coagulation (e.g., D-dimer, fibrinogen level, and activated partial thromboplastin time) or inflammation (WBC count, C-reactive protein) did not discriminate between patients with or without thrombotic complications. Fifty-one patients (76%) survived to discharge; 17 (24%) patients died. Mortality was significantly greater in patients with detectable thrombus (33% vs 10%; p = 0.022). CONCLUSIONS: There is a high prevalence of thrombotic complications, mainly pulmonary, among coronavirus disease 2019 patients admitted to ICU, despite anticoagulation. Detection of thrombus was usually incidental, not predicted by coagulation or inflammatory biomarkers, and associated with increased risk of death. Systematic CT imaging at admission should be considered in all coronavirus disease 2019 patients requiring ICU.

Mechanical thrombectomy is now well - established first - line treatment for selected patients with large artery occlusions of the anterior circulation. However, number of technical and procedural issues remains open to assure optimal outcomes in majority of patients including those suffering from posterior circulation perfusion defects. This brief review addresses some of the open issues and refers to the ongoing trials to close the existing knowledge gaps.

PURPOSE: Out-of-hospital cardiac arrest (OHCA) carries a very high mortality rate even after successful cardiopulmonary resuscitation. Currently, information given to relatives about prognosis following resuscitation is often emotive and subjective, and varies with clinician experience. We aimed to validate the NULL-PLEASE score to predict survival following OHCA.METHODS: A multicenter cohort study was conducted, with retrospective and prospective validation in consecutive unselected patients presenting with OHCA. The NULL-PLEASE score was calculated by attributing points to the following variables: Nonshockable initial rhythm, Unwitnessed arrest, Long low-flow period, Long no-flow period, pH 7.0 mmol/L, End-stage renal failure, Age ≥85 years, Still resuscitation, and Extracardiac cause. The primary outcome was in-hospital death.RESULTS: We assessed 700 patients admitted with OHCA, of whom 47% survived to discharge. In 300 patients we performed a retrospective validation, followed by prospective validation in 400 patients. The NULL-PLEASE score was lower in patients who survived compared with those who died (0 [interquartile range 0-1] vs 4 [interquartile range 2-4], P < .0005) and strongly predictive of in-hospital death (C-statistic 0.874; 95% confidence interval, 0.848-0.899). Patients with a score ≥3 had a 24-fold increased risk of death (odds ratio 23.6; 95% confidence interval, 14.840-37.5; P < .0005) compared with those with lower scores. A score ≥3 has a 91% positive predictive value for in-hospital death, while a score CONCLUSION: The easy-to-use NULL-PLEASE score predicts in-hospital mortality with high specificity and can help clinicians explain the prognosis to relatives in an easy-to-understand, objective fashion, to realistically prepare them for the future.

The introduction of transcatheter aortic valve implantation (TAVI) has revolutionised the management of aortic stenosis (AS), with procedure numbers rapidly increasing. Although there has been enth...

Studies using whole blood platelet aggregometry as a laboratory research tool, provided important insights into the mechanism and modulators of platelet aggregation. Subsequently, a number of point-of-care (POC) platelet function tests (PFTs) were developed for clinical use, based on the concept that an individual’s thrombotic profile could be assessed in vitro by assessing the response to stimulation of platelet aggregation by specific, usually solo agonists such as adenosine diphosphate (ADP), collagen and thrombin. However, adjusting antiplatelet medication in order to improve the results of such POC PFTs has not translated into a meaningful reduction in cardiovascular events, which may be attributable to important differences between the POC PFT techniques and in vivo conditions, including patient-to-patient variability. Important limitations of most tests include the use of citrate-anticoagulated blood. Citrate directly and irreversibly diminishes platelet function and even after recalcification, it may result in altered platelet aggregation in response to ADP, epinephrine or collagen, and interfere with thrombin generation from activated platelets. Furthermore, most tests do not employ flowing blood and therefore do not assess the effect of high shear forces on platelets that initiate, propagate and stabilize arterial thrombi. Finally, the effect of endogenous thrombolysis, due to fibrinolysis and dislodgement, which ultimately determines the outcome of a thrombotic stimulus, is mostly not assessed. In order to accurately reflect an individual’s predisposition to arterial thrombosis, future tests of thrombotic status which overcome these limitations should be used, to improve cardiovascular risk prediction and to guide pharmacotherapy.

Morphine is routinely used for pain relief in patients with acute myocardial infarction. However, it was documented that morphine decreases the bioavailability and antiplatelet effect of P2Y 12 receptor inhibitors. Multiple strategies to overcome this undesirable interaction are currently under investigation; they include the follwing: administration of crushed ticagrelor tablets, co-administration of metoclopramide, bridging with intravenous antiplatelet agents, or replacement of morphine with other analgesic. Adequately powered randomised trials examining the clinical consequences of concomitant use of morphine and P2Y 12 receptor inhibitors are still lacking.

© The Author(s) 2021. Published on behalf of the European Society of Cardiology. All rights reserved. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1093/eurheartj/ehab479

Whilst there is a clear clinical benefit of oral anticoagulation (OAC) in patients with atrial fibrillation (AF) and venous thromboembolism (VTE) in reducing the risks of thromboembolism, major bleeding events (especially intracranial bleeds) may still occur and be devastating. The decision to initiate and continue anticoagulation is often based on a careful assessment of both the thromboembolism and bleeding risk. The more common and validated bleeding risk factors have been used to formulate bleeding risk stratification scores, but thromboembolism and bleeding risk factors often overlap. Also, many factors that increase bleeding risk are transient and modifiable, such as variable international normalized ratio values, surgical procedures, vascular procedures, or drug–drug and food–drug interactions. Bleeding risk is also not a static ‘one off’ assessment based on baseline factors but is dynamic, being influenced by ageing, incident comorbidities, and drug therapies. In this Consensus Document, we comprehensively review the published evidence and propose a consensus on bleeding risk assessments in patients with AF and VTE, with the view to summarizing ‘best practice’ when approaching antithrombotic therapy in these patients. We address the epidemiology and size of the problem of bleeding risk in AF and VTE, review established bleeding risk factors, and summarize definitions of bleeding. Patient values and preferences, balancing the risk of bleeding against thromboembolism are reviewed, and the prognostic implications of bleeding are discussed. We propose consensus statements that may help to define evidence gaps and assist in everyday clinical practice.

The first international guidance on antithrombotic therapy in the elderly came from the European Society of Cardiology Working Group on Thrombosis in 2015. This same group has updated its previous report on antiplatelet and anticoagulant drugs for older patients with acute or chronic coronary syndromes, atrial fibrillation, or undergoing surgery or procedures typical of the elderly (transcatheter aortic valve implantation and left atrial appendage closure). The aim is to provide a succinct but comprehensive tool for readers to understand the bases of antithrombotic therapy in older patients, despite the complexities of comorbidities, comedications and uncertain ischaemic- vs. bleeding-risk balance. Fourteen updated consensus statements integrate recent trial data and other evidence, with a focus on high bleeding risk. Guideline recommendations, when present, are highlighted, as well as gaps in evidence. Key consensus points include efforts to improve medical adherence through deprescribing and polypill use; adoption of universal risk definitions for bleeding, myocardial infarction, stroke and cause-specific death; multiple bleeding-avoidance strategies, ranging from gastroprotection with aspirin use to selection of antithrombotic-drug composition, dosing and duration tailored to multiple variables (setting, history, overall risk, age, weight, renal function, comedications, procedures) that need special consideration when managing older adults.

Interest in the use of mechanical circulatory support for patients presenting with cardiogenic shock is growing rapidly. The Impella (Abiomed Inc), a microaxial, continuous-flow, short-term, ventricular assist device (VAD), requires meticulous postimplantation management. Because systemic anticoagulation is needed to prevent pump thrombosis, patients are exposed to increased bleeding risk, further aggravated by sepsis, thrombocytopenia, and high shear stress-induced acquired von Willebrand syndrome. The precarious balance between bleeding and thrombosis in percutaneous VAD-supported cardiogenic shock patients is often the main reason that patient outcomes are jeopardized, and there is a lack of data addressing optimal anticoagulation management strategies during percutaneous VAD support. Here, we present a parallel anti-Factor Xa/activated partial thromboplastin time-guided anticoagulation algorithm and discuss pitfalls of heparin monitoring in critically ill patients. This review will guide physicians toward a more standardized (anti)coagulation approach to tackle device-related morbidity and mortality in this critically ill patient group.

© 2020 American Society for Clinical Pharmacology and Therapeutics. This is the peer reviewed version of the following article: Impact of pre-admission morphine on re-infarction 1 in patients with STEMI 2 treated with PPCI: a meta-analysis, which has been published in final form at https://doi.org/10.1002/cpt.1798 purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

Background Taxus baccata, also known as English yew, is a poison that causes cardiac arrhythmias and can result in death from cardiogenic shock. Case summary A 49-year-old gentleman was admitted following yew ingestion with suicidal intent. He was bradycardic at 30 b.p.m. and hypotensive on arrival. Electrocardiography revealed complete heart block with broad complex ventricular escape rate of 30 b.p.m. Bedside echocardiography revealed severe global impairment of right and left ventricular systolic function. Urgent temporary transvenous pacing was instituted, and the patient was considered for veno-arterial extracorporeal membrane oxygenation. Unfortunately, he deteriorated rapidly and cardiorespiratory arrest ensued, and despite prolonged in-hospital resuscitation, the patient died. Post-mortem examination revealed small needle-shaped plant leaves together with seeds found in the stomach. Ante mortem serum sample analysis sent to the Royal Botanical Gardens and revealed the presence of taxine Type B alkaloids in the patient’s blood. Discussion Yew poisoning is a rare occurrence, and there is currently no effective antidote. Treatment involves supportive management, comprising prolonged effective cardiopulmonary resuscitation, pacing, and mechanical cardiac support. This case illustrates the importance of prompt recognition of yew poisoning, alongside early consideration of pacing and mechanical cardiac support. Due to the rarity of this cause of heart block, and since patients may not always volunteer a history of yew ingestion, yew poisoning is something that physicians should be aware of and this should be considered in the differential diagnosis in patients with unexpected heart block. Serum analysis for taxine alkaloids can be used to confirm the diagnosis.

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.

Highlights •Endogenous fibrinolysis is a natural defense against lasting arterial thrombotic occlusion. •Impaired fibrinolysis is detectable with global assays in a number of patients with ACS and CVD. •Impaired fibrinolysis is a strong, independent and novel marker of cardiovascular risk. •Future trials of pharmacotherapy to enhance chronic fibrinolytic status are required to reduce cardiovascular risk.

BACKGROUND: Raised lipoprotein(a) [Lp(a)] is a cardiovascular risk factor common in patients with refractory angina. The apolipoprotein(a) component of Lp(a) exhibits structural homology with plasminogen and can enhance thrombosis and impair fibrinolysis. OBJECTIVES: The objective of the study was to assess the effect of lipoprotein apheresis on markers of thrombosis and fibrinolysis in patients with high Lp(a). METHODS: In a prospective, single-blind, crossover trial, 20 patients with refractory angina and raised Lp(a) > 50 mg/dL were randomized to three months of weekly lipoprotein apheresis or sham. Blood taken before and after apheresis/sham was assessed using the Global Thrombosis Test, to assess time taken for in vitro thrombus formation (occlusion time) and endogenous fibrinolysis (lysis time), as well as von Willebrand Factor, fibrinogen, D-dimer, thrombin/anti-thrombin III complex, prothrombin fragments 1 + 2, and thrombin generation assays. RESULTS: Lp(a) was significantly reduced by apheresis (100.2 [interquartile range {IQR}, 69.6143.0] vs 24.8 [17.2,34.0] mg/dL, P = .0001) but not by sham (P = .0001 between treatment arms). Apheresis prolonged occlusion time (576 ± 116 s vs 723 ± 142 s, P

Aims Approximately 20% of ischaemic stroke patients exhibit spontaneous arterial recanalization, attributable to endogenous fibrinolysis, which strongly relates to improved functional outcome. The impact of oral anticoagulants on endogenous fibrinolysis is unknown. Our aim was to test the hypothesis that apixaban enhances endogenous fibrinolysis in non-valvular atrial fibrillation (NVAF). Methods and results In a prospective cross-sectional analysis, we compared endogenous fibrinolysis in NVAF patients (n = 180) taking aspirin, warfarin, or apixaban. In a prospective longitudinal study, patients were tested before and after apixaban (n = 80). Endogenous fibrinolysis was assessed using the Global Thrombosis Test (GTT) and thromboelastography (TEG). Endogenous fibrinolysis [measured by GTT lysis time (LT)] was shorter on apixaban compared with warfarin or aspirin [median 1850 (IQR 1591–2300) vs. 2758 (2014–3502) vs. 2135 (1752–2463) s, P Conclusion Apixaban enhances endogenous fibrinolysis, with maximal effect in those with impaired fibrinolysis pre-treatment. Apixaban-treated patients exhibit more favourable fibrinolysis profiles than those taking warfarin or aspirin. Whether apixaban may confer additional thrombotic risk reduction in NVAF patients with impaired fibrinolysis, compared to warfarin, merits further study.

A mismatch between myocardial oxygen demand and supply underlies the core principle behind myocardial ischaemia and the consequent presenting symptom of angina. Atherosclerosis is a disease of the arterial wall initiated by lipid retention, which starts in childhood and adolescence, followed by inflammatory response resulting in the formation of plaque. Plaques within the coronary arteries can progress and ultimately cause stenosis by reducing the arterial luminal diameter, resulting in myocardial ischaemia or myocardial infarction (MI). Lifestyle adjustments, pharmacological and interventional therapies can modify the progression and deterioration of chronic coronary syndromes. It is a low-cost test which requires little expertise, and is readily available in most hospitals. A resting echocardiogram is a non-invasive test which provides important information about cardiac function and anatomy. Myocardial perfusion scan (MPS) is a non-invasive nuclear medicine test which provides functional information of the myocardium using radioisotopes.

Patients with transient ST-elevation myocardial infarction (STEMI) or spontaneous resolution (SpR) of the ST-segment elevation on electrocardiogram could potentially represent a unique group of patients posing a therapeutic management dilemma. In this review, we discuss the potential mechanisms underlying SpR, its relation to clinical outcomes and the proposed management options for patients with transient STEMI with a focus on immediate versus early percutaneous coronary intervention. We performed a structured literature search of PubMed and Cochrane Library databases from inception to December 2020. Studies focused on SpR in patients with acute coronary syndrome were selected. Available data suggest that deferral of angiography and revascularization within 24–48 h in these patients is reasonable and associated with similar or perhaps better outcomes than immediate angiography. Further randomized trials are needed to elucidate the best pharmacological and invasive strategies for this cohort.

The occurrence of thrombotic complications, which can result in excess mortality and morbidity, represent an imbalance between the pro-thrombotic and fibrinolytic equilibrium. The mainstay treatment of these complications involves the use of antithrombotic agents but despite advances in pharmacotherapy, there remains a significant proportion of patients who continue to remain at risk. Endogenous fibrinolysis is a physiological counter-measure against lasting thrombosis and may be measured using several techniques to identify higher risk patients who may benefit from more aggressive pharmacotherapy. However, the assessment of the fibrinolytic system is not yet accepted into routine clinical practice. In this review, we will revisit the different methods of assessing endogenous fibrinolysis (factorial assays, turbidimetric lysis assays, viscoelastic and the global thrombosis tests), including the strengths, limitations, correlation to clinical outcomes of each method and how we might integrate the assessment of endogenous fibrinolysis into clinical practice in the future.

Despite advancements in pharmacotherapy and interventional strategies, patients with acute coronary syndrome (ACS) remain at risk of recurrent thrombotic events. In addition to an enhanced tendency to thrombus formation, impairment in the ability to naturally dissolve or lyse a developing thrombus, namely impaired endogenous fibrinolysis, is responsible for a major part of this residual risk regardless of optimal antiplatelet medication. Global assessment of endogenous fibrinolysis, including a point-of-care assay, can identify patients with ACS at persistent high cardiovascular risk and might play an important role in allowing the personalisation of potent antithrombotic therapy to enhance fibrinolytic status, providing precision treatment of ACS to improve long-term outcome.

The development of an obstructive luminal thrombus is pathological and considered a failure of endogenous fibrinolysis. The consequences may be fatal, or result in lasting downstream organ damage. Therefore, assessment of endogenous fibrinolytic status in an individual may identify those at risk of occlusive thrombus formation and provide prognostic information. Arterial thrombi are more platelet rich and more resistant to fibrinolysis than venous thrombi. Several recent studies using global tests of fibrinolysis in patients with acute coronary syndromes (ACS) have shown that despite dual antiplatelet therapy, patients with impaired fibrinolytic status have an increased risk of adverse cardiovascular events, compared with those with effective fibrinolytic function. Such data add significantly to the predictive value of established cardiovascular risk factors and conventional biomarkers. Most data reported have been obtained with the Global Thrombosis Test and the turbidimetric plasma clot lysis assay. A few small studies in patients with ischaemic stroke suggest a similar predictive role of fibrinolytic status assessment in these patients. Studies reporting an association between impaired fibrinolysis and future venous thrombotic events are limited, and in the form of case-control studies. Viscoelastic assays may have a role in the prediction of venous thromboembolic risk. Assays of fibrinolytic function should be used to obtain a more accurate risk of future thrombotic events, particularly in the setting of ACS. The availability of point-of-care tests helps facilitate this and should encourage future studies to assess personalised antithrombotic treatment combinations to optimise fibrinolytic status and reduce thrombosis risk.

Introduction: The COVID-19 pandemic has restricted availability of ICU resources. Symptomatic patients with coronary artery disease (CAD) normally considered surgical candidates have therefore required alternative revascularization with percutaneous coronary intervention (PCI). The UK-REVASC registry describes the demographics and in-hospital clinical outcomes of this novel patient cohort. Methods: From 1 st March to 31 st May 2020, anonymised data of 171 patients from 38 UK centres were enrolled in a prospective, observational registry. All were on surgical waiting lists or considered for surgery. Results: The demographics, procedural characteristics and outcomes are shown in Tables 1-3. A comparison with routine PCI British Cardiovascular Intervention Society (BCIS) data and UK isolated coronary bypass surgical data are listed, where available and appropriate. The median age was 68 (IQR 60-76) years. There was significantly more previous MI, PCI and CABG in the routine PCI database than in ReVasc Registry patients, perhaps suggesting a more acute presentation with accelerated symptoms in the test group. These were however complex patients with a mean SYNTAX Score (SS) of 27.8 (range 9-65) and >20x the number of LMS plus multi-vessel disease compared to the routine PCI group, which is reflected in a high use of adjunctive imaging. Radial access was very high at 94.1%. PCI success was 97.0%. Complete revascularization was achieved in 52% with the mean residual SS 1.42 (0-20) in these. There were 2 deaths, however the mortality rate was comparable with published surgical data. Furthermore, a 50% reduction in in-patient stay was observed. Conclusion: In this multi-centre UK registry, in-hospital outcomes following PCI for patients with complex coronary disease, who would typically be treated with CABG, compared well with the surgical data. This suggests that the role of PCI could be extended. Future longer term follow-up however is required and planned.

East Asian patients have reduced anti-ischemic benefits and increased bleeding risk during antithrombotic therapies compared with Caucasian patients. As potent P2Y12 receptor inhibitors (e.g., ticagrelor and prasugrel) and direct oral anticoagulants are commonly used in current daily practice, the unique risk–benefit trade-off in East Asians has been a topic of emerging interest. In this article, we propose updated evidence and future directions of antithrombotic treatment in East Asian patients.

Introduction Patients with diabetes mellitus (DM) are increased risk of myocardial infarction (MI) and following a MI, patients with DM have an increased risk of recurrent MI and cardiovascular (CV) death. Plasma turbidimetry studies show that hypofibrinolysis is a key abnormality in DM that may drive increased ischaemic risk. Such assays are cumbersome, require specialist expertise and do not provide information in a clinically-relevant timeframe. Assessment of fibrinolysis in whole blood, using a point-of-care assay, has revealed that in ACS patients, impaired fibrinolysis is predictive of adverse CV events. Whether this technique can identify residual risk in patients with DM, is unclear. Purpose It was our aim to compare thrombotic and endogenous fibrinolytic status between patients with and without DM, presenting with ACS. Methods We conducted a prospective, observational study of consecutive patients admitted with ACS. Venous blood was taken to assess thrombotic and thrombolytic status using the point-of-care Global Thrombosis Test, assessing time to occlusive thrombus formation under high shear (occlusion time, OT) and time taken for spontaneous lysis of the thrombus (lysis yime, LT). Blood was taken after dual antiplatelet therapy (DAPT) loading, but before administration of fondaparinux or low molecular weight heparin. Patients with renal or hepatic impairment, known bleeding diathesis, thrombocytopenia and those taking anticoagulation were excluded. Results A total of 775 patients were included, of whom 158 (20%) had DM. Patients with DM, compared to those without DM, more frequently had hypertension (70% vs. 39%, p Conclusions Amongst patients with ACS, those with DM exhibit markedly impaired endogenous fibrinolysis compared to those without DM, and this can be detected with a bedside assay using whole blood. This may explain the increased risk of secondary events in patients with ACS and DM. Funding Acknowledgement Type of funding source: None

Introduction Acute coronary syndrome (ACS) is caused by disruption of an atherosclerotic plaque with initiation of thrombosis, and outcome determined by the balance between prothrombotic drivers and the efficacy of endogenous fibrinolysis. Most patients have obstructive coronary artery disease (CAD), with high shear forces and turbulent flow across severe stenoses enhancing platelet activation. Recognition that some ACS patients have myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) has led to a search to identify drivers behind such presentations. Purpose To assess and compare the thrombotic status of patients with MINOCA and those with ACS due to obstructive CAD. Methods In a prospective observational study in patients with ACS, thrombotic and thrombolytic status was assessed from venous blood using the point-of-care Global Thrombosis Test, assessing time to in vitro occlusive thrombus formation under high shear (occlusion time,OT) and time taken for spontaneous lysis of the thrombus (lysis time,LT). Blood was taken after dual antiplatelet therapy loading, but before fondaparinux or heparin administration. Those with renal or hepatic impairment, bleeding diathesis, thrombocytopenia or on anticoagulation were excluded. MINOCA diagnosis was made according to the Fourth Universal Definition of MI, in the absence of obstructive CAD (no lesion ≥50%) and excluding patients with 1) other overt causes for elevated troponin, 2) overlooked obstructive CAD, and 3) nonischaemic causes for myocyte injury, according to the American Heart Association 2019 recommendation. Patients with Type 2, 4 and 5 MI were excluded. Results We assessed 746 patients, of whom 621 (83%) had ST-segment elevation MI (STEMI) and the rest non-STEMI. Of these, 706 (95%) had obstructive CAD and 40 (5%) had MINOCA. Apart from sex (78% obstructive CAD patients were male vs 50% MINOCA patients), cardiovascular risk factors were similar in MINOCA and obstructive CAD patients (smoking 28 vs 31%, p=0.615; hypertension 35 vs 47%, p=0.153; diabetes 20 vs 20%, p=0.948; hyperlipidaemia 30 vs 36%, p=0.475 and family history of premature CAD 35 vs 35%, p=1.000). There was no difference in time to form occlusive thrombus (OT 424 [371–471] vs 395 [287–512] s, p=0.093) or in endogenous fibrinolysis (LT 1450 [1082–2099] vs 1582 [1252–2130] s, p=0.178) between MINOCA and obstructive CAD patients. Even after propensity score matching with a ratio of 3:1 for clinical characteristics, there was no difference between patients with MINOCA and those with obstructive CAD, with respect to thrombus formation (OT 424 [371–471] vs 430 [300–538] s, p=0.602) or endogenous fibrinolysis (LT 1470 [1082- 2099] vs 1494 [1140–2074] s, p=0.625). Conclusion Amongst patients with ACS, those with MINOCA exhibit similar thrombotic profiles to patients with obstructive CAD with ACS. This represents a potential therapeutic target to modulate risk post myocardial infarction in patients with MINOCA and requires further research. Funding Acknowledgement Type of funding source: None

Patients hospitalised with COVID-19 have a high mortality. Identification of patients at increased risk of adverse outcome would be important, to allow closer observation and earlier medical intervention for those at risk, and to objectively guide prognosis for friends and family of affected individuals. We conducted a single-centre retrospective cohort study in all-comers with COVID-19 admitted to a large general hospital in the United Kingdom. Clinical characteristics and features on admission, including observations, haematological and biochemical characteristics, were used to develop a score to predict 30-day mortality, using multivariable logistic regression. We identified 316 patients, of whom 46% died within 30-days. We developed a mortality score incorporating age, sex, platelet count, international normalised ratio, and observations on admission including the Glasgow Coma Scale, respiratory rate and blood pressure. The score was highly predictive of 30-day mortality with an area under the receiver operating curve of 0.7933 (95% CI 0.745–0.841). The optimal cut-point was a score ≥ 4, which had a specificity of 78.36% and a sensitivity of 67.59%. Patients with a score ≥ 4 had an odds ratio of 7.6 for 30-day mortality compared to those with a score

Background Aspirin forms a cornerstone of management in patients with established cardiovascular disease (CVD). Despite proven efficacy, variability of aspirin response has long been recognised, with early studies suggesting rates of high on treatment platelet reactivity (HTPR) as ranging between 5 and 45%. Whether aspirin responsiveness relates to long-term prognosis in patients with CVD is unknown. Methods A prospective, single-centre analysis of 224 troponin positive non-ST elevation myocardial infarction (NSTEMI) patients undergoing coronary angiography. Aspirin-naive patients were loaded with 300 mg aspirin and maintained on 75 mg daily. Blood samples were obtained at the time of angiography and the VerifyNow Aspirin assay utilised to determine aspirin effect. The primary end point was all-cause mortality at 10 years. Results Time from aspirin loading (or admission on aspirin) to angiography was 4.9 ± 2.7 days. Platelet aggregation results, expressed as aspirin reaction units (ARU) were divided into tertiles: T1 (ARU 363–405) (n = 76), T2 (ARU 406–436) (n = 76), T3 (ARU 437–596) (n = 72). Higher ARU values were associated with increased mortality (log rank, p = 0.009), with those in the T3 having a 3-fold higher rate of events than those in the T1 (HR 3.03 [95% CI 1.33–6.99], p = 0.009) over a 10-year follow up. Conclusion Our study demonstrates that aspirin responsiveness is directly related to 10-year survival and may identify patients who may benefit from additional antithrombotic therapy. Further, ARU values less than the previously defined cut off 550 are associated with reduced survival at 10 years.

Acute coronary syndrome and atrial fibrillation are both common and can occur in the same patient. Combination therapy with dual antiplatelet therapy and oral anticoagulation increases risk of bleeding. Where the two conditions coexist, careful consideration is needed to determine the optimal antithrombotic treatment to reduce the risks of future ischaemic events associated with both conditions. Choices can be made in intraprocedural anticoagulation, type and dosing of oral anticoagulant, duration of combination therapy, and selection of P2Y12 inhibitor including genetic testing. This review article provides an overview of the available evidence to support clinicians in finding the delicate balance between antithrombotic efficacy and bleeding risk in patients with acute coronary syndrome and atrial fibrillation.

© 2020 Oxford University Press. This is a pre-copyedited, author-produced PDF of an article accepted for publication in Cardiovascular Research following peer review. The version of record, Diana A Gorog, Gemma Vilahur, Peripartum cardiomyopathy: can the link between prolactin and PAI-1 provide a clue?, Cardiovascular Research, cvaa109, is available online at: https://doi.org/10.1093/cvr/cvaa109.

Identification of vulnerability to severe coronavirus disease 2019 (COVID-19) is extremely important and might allow optimised shielding and easing of lockdown. The disease is attributed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which enters host cells through binding to angiotensin converting enzyme 2 (ACE2) on the cell surface. Clinical syndromes such as hypertension that display reduced ACE2 expression tend to correlate with a more severe disease course, whereas treatments which upregulate ACE2 such as the use of angiotensin converting enzyme inhibitors (ACE-i) appear to have a protective effect against COVID-19. Pre-clinical studies have shown that plasma soluble ACE2 could render SARS-CoV-2 inactive in a dose-dependent manner. The association of clinical syndromes or treatments that impact ACE2 expression and clinical severity of COVID-19 infection combined with the reduction in viral load with human recombinant serum ACE2 shown in pre-clinical studies indicate a key role for ACE2 in determining COVID-19 severity. In conclusion, we propose that measurement of ACE2 level may help identify individuals at risk of severe infection where targeted shielding can be used and could provide a novel therapeutic target.