Assessment of endogenous fibrinolysis in clinical using novel tests - Ready for clinical roll-out?

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.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 systemis 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 howwe might integrate the assessment of endogenous fibrinolysis into clinical practice in the future.Peer reviewedFinal Published versio

Diurnal Variation in thrombolytic status in patients presenting with STEMI

Abstract Funding Acknowledgements Type of funding sources: None. Background Prior studies mainly in healthy volunteers and patients with stable coronary artery disease (CAD) indicate circadian variation in spontaneous fibrinolytic activity. This is predominantly attributable to changes plasminogen activator inhibitor-1 (PAI-1) levels peaking between midnight and 06:00 hr, with a nadir at 18:00 hr. Whether circadian variation in spontaneous fibrinolysis exists amongst patients with ST-elevation myocardial infarction (STEMI) is unknown. Purpose It was our aim to assess circadian variation in fibrinolytic status in the acute setting in patients presenting with STEMI. Methods A prospective, observational study was conducted in patients presenting with STEMI for primary percutaneous coronary intervention (PPCI). Blood was tested on arrival pre-PPCI, after aspirin and P2Y12 inhibitor administration, but before any anticoagulant or antithrombotic agent administration in the cardiac cath lab. Venous blood was assessed to determine endogenous fibrinolysis using the Global Thrombosis Test, which utilises non-anticoagulated blood to assess the formation of an occlusive thrombus under high shear and the time taken for spontaneous restart of flow as a measure of endogenous fibrinolysis (lysis time, LT). Results A total of 527 patients were included, aged 64±13 years and 78% were male. 304 (58%) patients presented within working hours (08:00-17:00) with peak presentation between 11:00-12:00 and trough between 03:00 to 05:00 hrs. Lysis time was not related to time of presentation. Time of presentation was divided into 4 groups (A 00:00-05:59, B 06:00-11:59, C 12:00-17:59, D 18:00-23:59 hrs). There was no significant difference in LT between patients presenting at the 4 timepoints (median 1362s [interquartile range IQR 1077-1808] vs 1503s [1182-2056] vs 1440s [1164-1998] vs. 1420s [1125-1820], respectively, p=0.340). When comparing Group A to C, the LT was not significantly different (1362s [1077-1808] vs. 1440 [1164-1998], p=0.413). The presentation time of patients with impaired endogenous fibrinolysis (LT&amp;gt;3000 sec) did not differ significantly from patients with normal endogenous fibrinolysis. The hourly variation was similar in diabetics and non-diabetics, but the variation in lysis time appeared blunted in patients taking long term aspirin prior to presentation compared to non-aspirin takers. Conclusion In contrast to the known circadian variation in fibrinolysis in normal volunteers, and stable CAD, in our large cohort of STEMI patients, there appears to be no relationship between time of presentation/onset of STEMI and the effectiveness spontaneous fibrinolysis. This is reflected in our observation, supported by most contemporary studies, that peak time of STEMI presentation is during the late morning, and this does not relate to known circadian variation in fibrinolysis markers in CAD. </jats:sec

Impaired endogenous fibrinolysis in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention is a predictor of recurrent cardiovascular events: the RISK PPCI study

Aims: The endogenous fibrinolytic system serves to prevent lasting thrombotic occlusion and infarction following initiation of coronary thrombosis. We aimed to determine whether impaired endogenous fibrinolysis can identify patients with ST-segment elevation myocardial infarction (STEMI) who remain at high cardiovascular risk despite dual antiplatelet therapy (DAPT). Methods and results: A prospective, observational study was conducted in 496 patients presenting with STEMI for primary percutaneous coronary intervention (PPCI). Blood was tested on arrival pre-PPCI, at discharge and at 30 days to assess thrombotic status using the automated point-of-care global thrombosis test and patients followed for 1 year for major adverse cardiovascular events (MACEs). Endogenous fibrinolysis was significantly impaired [baseline lysis time (LT) ≥2500 s] in 14% of patients and was highly predictive of recurrent MACE [hazard ratio (HR) 9.1, 95% confidence interval (CI) 5.29-15.75; P 50% (P < 0.001). Patients with spontaneous ST-segment resolution pre-PPCI had more rapid, effective fibrinolysis [LT 1050 (1004-1125) s vs. 1501 (1239-1997) s, P < 0.001] than those without. Lysis time was not altered by standard of care STEMI treatment including DAPT and was unchanged at 30 days. Conclusion: Endogenous fibrinolysis assessment can identify patients with STEMI who remain at very high cardiovascular risk despite PPCI and DAPT. Further studies are needed to assess whether these patients may benefit from additional, personalized antithrombotic/anticoagulant medication to reduce future cardiovascular risk. Clinical trial registration: http://www.clinicaltrials.gov. Unique identifier: NCT02562690

P-Wave Duration in a 12-lead electrogram used as a predictor of recurrence in atrial fibrillation cryoballoon ablation

Abstract Funding Acknowledgements Type of funding sources: None. Background There is growing evidence that p-wave duration (PWD) is associated with the extent of left atrial scarring and may be a potential predictor of AF recurrence following ablation. Previous studies have used amplified techniques to measure this, however its predictive role using only a 12-lead surface electrogram (ECG) is not known. Patients with paroxysmal atrial fibrillation (AF) are often treated (75% clinical success) with a single cryoballoon catheter ablation procedure. In contrast, in patients with long persistent AF, cryoballoon ablation often yields lower success rates resulting in multiple ablations. Purpose We aimed to investigate whether PWD in a baseline 12-lead ECG is associated with AF recurrence post acutely successful PVI cryoablation. Methods In this retrospective single center study we assessed (n = 104) consecutive patients undergoing cryoablation for AF between 2016 and 2020. 12-lead surface ECGs along with demographic, echocardiographic and procedural data were extracted from patients’ case notes at the time they were in sinus rhythm prior to AF ablation, including following direct current cardioversion (DCCV) in patients with persistent AF. Measurements of the PWD were taken by two independent assessors blinded to the results in lead II or V1 at standard settings of 25mm/sec speed and 1mV per 10mm voltage. The outcome of interest was documented recurrence of AF after acutely successful PVI ablation at a median follow up of 16 months. Predictive ability of PWD for the primary outcome was tested using the ROC curve analysis and c-statistics. Results  AF ablation was successful in 60% of the patients with greater effect in paroxysmal AF (78%, n = 36 paroxysmal AF ; 48% n = 26 long-persistent AF). The pre-procedural PWD was significantly longer among patients with recurrence of AF compared to the ones that remained in sinus rhythm (145 ± 14 ms vs 92 ± 26 ms, p &amp;lt; 0.00001 ; paroxysmal AF p &amp;lt; 0.00001 ; long-persistent AF p &amp;lt; 0.0001). There was no difference in the baseline characteristics between the two groups. A PWD ≥ 130ms was strongly predictive of AF recurrence (c-statistic 0.94, 95% CI 0.90 – 0.98 ; p &amp;lt;0.0001) with a positive predictive value of 88.5% and a negative predictive value of 87.5%. Patients with a PWD ≥130ms had a 2.4-fold risk of AF recurrence compared to those with PWD &amp;lt; 130 at baseline (HR 2.38 , 95% CI 1.605 – 3.160 ; p &amp;lt; 0.0001) (figure 1). There was no significant intra-operator variability in the measurements of the PWD (Bias 1.39 ± 13.9, 95% CI -0.42 – 4.79 ; p = NS). Conclusion In patients undergoing pulmonary vein isolation cryoablation, a baseline 12-lead ECG appears to be useful in predicting AF recurrence. Patients with PWD ≥130ms have a 2.4-fold risk of AF recurrence compared with patients with lower PWD. If confirmed in larger data sets, this simple technique may be a useful additional tool for clinical decision-making in the selection of patients for AF ablation. Abstract Figure 1 </jats:sec

P4744Patients with atrial fibrillation exhibit a systemic prothrombotic state attributable to impaired endogenous fibrinolysis

Abstract Background The association of atrial fibrillation (AF) with thromboembolic stroke due to stasis in the left atrium and left atrial appendage is well described. Whether AF is associated with a systemic prothrombotic state, detectable in peripheral blood, unclear. Previous studies have been inconsistent, with some very small previous studies (&lt;30 patients each) variably indicating that patients with AF may have raised platelet reactivity and levels of antithrombin III, d-dimer, PAI-1 and t-PA-PAI complexes. These cumbersome laboratory tests of coagulation and fibrinolysis are not readily available in the clinical setting. Purpose It was our aim to compare, in peripheral venous blood, thrombotic and endogenous fibrinolytic profile of healthy volunteers and patients with newly diagnosed nonvalvular atrial fibrillation (NVAF), using a point-of-care technique. Methods In a prospective observational study, venous blood samples were taken from 98 healthy volunteers and 100 patients with newly diagnosed NVAF in the out-patient setting. Patients with newly diagnosed NVAF had venous blood tested before any treatment was initiated with aspirin or oral anticoagulation. Thrombotic status was assessed using the Global Thrombosis Test (GTT), a point-of-care test using native non-coagulated blood, assessed within 15 sec of blood withdrawal. The time to form an occlusive venous thrombus in native (non-citrated) blood, a measure of platelet reactivity (occlusion time, OT) and the time taken to spontaneous endogenous fibrinolysis to restore flow (lysis time, LT) were assessed. Results Basic blood tests (full blood count, renal and liver function, inflammatory markers) were normal in all subjects. The groups were matched for sex and race. Mean age of the healthy cohort was 34±8 years and patients 65±10 years. Endogenous fibrinolysis was markedly impaired in patients with NVAF compared to healthy individuals as shown by markedly prolonged LT (median 2015s [interquartile range IQR 1555–2507] vs. 1124s [IQR 919–1554], p&lt;0.ehz745.11201). There was no difference in platelet reactivity between patients and normal volunteers (369s [IQR 308–445]vs 368s [IQR 309–441], p=0.704). Sensitivity analysis was performed on a subgroup matched for age, sex and race. LT remained significantly longer in patients with NVAF compared to controls (1569s [IQR 1499–2244] vs. 1219s [IQR 943–1560], p=0.03), with no difference in platelet reactivity (p=NS). Conclusion In the largest study to date and using a clinically-friendly automated point-of-care technique, we show that patients with NVAF exhibit a systemic prothrombotic state, attributable to significantly impaired endogenous fibrinolysis compared with healthy volunteers. Further studies are needed to see if this could become a screening test for the prothrombotic state in patients with NVAF. Acknowledgement/Funding None </jats:sec

Relationship between coronary stenosis severity and high shear thrombosis assessment in vitro

Abstract Funding Acknowledgements Type of funding sources: None. Among stable outpatients presenting with suspected coronary artery disease, the presence and extent of coronary artery calcification (CAC) and the severity of disease on CT coronary angiography (CTCA) has been shown to be predictive of future major adverse cardiovascular events (MACE) including myocardial infarction (MI). In stable patients, high on-treatment platelet reactivity has also been shown to relate to an increased risk of MACE including MI. The relationship between thrombotic markers in peripheral blood and the extent of CAC and coronary disease severity, is unknown. It was the aim of this pilot study to assess the relationship between thrombotic status and the extent of CAC and severity of coronary stenosis on CT. Subjects with suspected coronary disease undergoing CTCA and CAC were invited to participate in this observational study. Venous blood was obtained to assess platelet reactivity to high shear (occlusion time, OT) and endogenous fibrinolysis (lysis time, LT) using the Global Thrombosis Test, and related to CAC and to maximum stenosis in any main coronary artery on CTCA. Eighty patients were recruited, specifically 20 patients from each CAC quartile (adjusted for age, gender and ethnicity), 58% were male, aged 61±10 y. Groups were matched for age, sex, diabetes, and hs-CRP. The median Agatson CAC score was 27 [interquartile range (IQR) 0.5-125.5] and in each quartile (Q) as follows: Q1 0[0-0]; Q2 17[6-51.5]; Q3 70.25[26-111.5] and Q4 192.6[70.5-413.5]. Patients were divided into 4 groups according to maximal severity of coronary stenosis on CTCA (0%, 1-49%, 50-69%, &amp;gt;70%). With increasing stenosis severity, we found patients exhibited less efficient endogenous fibrinolysis (longer LT) (LT 1728s[1512-2102] vs. 2028s[1687-2288] vs. 1728s[1634-1927] vs. 2524s[2425-2623] respectively, p=0.040) whilst platelet reactivity appeared unrelated to severity of coronary stenosis (438s[341-479] vs. 415s[357-484] vs. 444s[384-504] vs. 391s[357-425], p=0.907). Platelet reactivity (OT 430s[339-477] vs. 458s[391-499] vs. 409s[351-488] vs. 413s[354-496], p=0.76) and spontaneous fibrinolysis (LT 1754s[1548-2162] vs. 1809s[1635-2291] vs. 2111s[1838-2312] vs. 1846s[1666-2090], p=0.253) were similar between the quartiles. Furthermore, there was no difference in platelet reactivity (430s[339-477] vs. 413s[354-496], p=0.830) or spontaneous fibrinolysis (1754s[1548-2162] vs. 1846s[1666-2090], p=0.561) when comparing patients within the lowest and the highest quartiles of CAC. The severity of maximal coronary stenosis, but not the extent of CAC, is related to the effectiveness of spontaneous fibrinolysis at high shear in vitro, with patients with more severe stenoses exhibiting less efficient fibrinolysis. Further studies are required to investigate whether the extent of in vivo coronary shear (related to plaque morphology) can be reflected by the assessment of thrombosis and fibrinolysis in response to high shear in vitro. </jats:sec