Abstract
Background
Formation of dense fibrin clots has been reported in both atrial fibrillation (AF)
and ischemic stroke. We have previously demonstrated that such clot properties can
predict thromboembolism and major bleeding in AF patients treated with vitamin K antagonists
(VKAs). In this longitudinal cohort study, we evaluated whether impaired fibrinolysis
is associated with clinical outcomes in AF.
Methods
In 236 patients with AF receiving VKAs, we measured ex vivo plasma clot lysis time
(CLT), a measure of global fibrinolysis along, with von Willebrand factor antigen
(vWF), plasminogen activator inhibitor 1 antigen (PAI-1), and other fibrinolysis modulators.
The primary outcome were ischemic cerebrovascular events. Secondary end points were
death and major bleeding.
Results
During a median follow-up time of 4.3 (interquartile range 3.7-4.8) years, annual
rates of death, ischemic cerebrovascular events, and major bleeding were 1.48%, 2.96%,
and 3.45%, respectively. Patients with CLT in the fourth quartile (> 115 min) had
8-fold higher stroke or transient ischemic attack (TIA) rates compared with the other
patients (8.67% vs 1.1%; P < 0.0001). CLT correlated with PAI-1 and vWF (r = 0.59; P < 0.0001 for both). In the multivariate Cox regression analysis adjusted for potential
confounders, the independent predictors of stroke or TIA were CLT > 115 minutes (hazard
ratio [HR] 7.67, 95% confidence interval [CI] 2.78-21.17; P < 0.0001), PAI-1 (HR 1.16, 95% 1.05-1.28; P = 0.003), and CHA2DS2-VASc score ≥3 (HR 5.18, 95% 1.76-15.29; P = 0.003). CLT was not associated with death or major and minor bleeding events.
Conclusions
Impaired fibrinolysis may predict thromboembolic events in AF patients receiving VKA.
Résumé
Contexte
La formation de caillots de fibrine denses a été rapportée chez des patients ayant
subi une fibrillation auriculaire (FA) ou un accident vasculaire cérébral (AVC) ischémique.
Nous avons déjà démontré que la présence de tels caillots permet de prédire une thromboembolie
et des hémorragies majeures chez les patients présentant une FA traités par des antagonistes
de la vitamine K (AVK). Dans le cadre d’une étude de cohorte longitudinale, nous avons
tenté de déterminer si cette anomalie de la fibrinolyse est associée à des résultats
cliniques chez les patients présentant une FA.
Méthodologie
L’étude portait sur 236 patients présentant une FA et recevant un AVK, chez qui nous
avons mesuré le temps de lyse des caillots (TLC) plasmatiques ex vivo (une mesure de la fibrinolyse globale) ainsi que les antigènes du facteur de von
Willebrand (FvW), les antigènes de l’inhibiteur de l’activateur du plasminogène 1
(PAI-1) et d’autres modulateurs de la fibrinolyse. Le critère d’évaluation principal
était les événements vasculaires cérébraux ischémiques. Les critères d’évaluation
secondaires étaient le décès et l’hémorragie majeure.
Résultats
Au cours de la période de suivi médiane de 4,3 ans (intervalle interquartile de 3,7
à 4,8 ans), les taux annuels de décès, d’événements vasculaires cérébraux ischémiques
et d’hémorragie majeure s’établissaient à 1,48 %, 2,96 % et 3,45 %, respectivement.
Les patients dont le TLC se trouvait dans le quatrième quartile (> 115 minutes) présentaient
des taux d’AVC ou d’accidents ischémiques transitoires (AIT) 8 fois plus élevés que
les autres patients (8,67 % vs 1,1 %; p < 0,0001). Le TLC était corrélé avec les taux de PAI-1 et de FvW (r = 0,59; p < 0,0001 dans les deux cas). L’analyse multivariée par régression de Cox, corrigée
pour tenir compte des facteurs de confusion possibles, montre que les facteurs de
prédiction indépendants d’AVC ou d’AIT étaient un TLC > 115 minutes (rapport des risques
instantanés [RRI] de 7,67; intervalle de confiance [IC] à 95 % : de 2,78 à 21,17;
p < 0,0001), le taux de PAI-1 (RRI de 1,16; IC à 95 % : de 1,05 à 1,28; p = 0,003), et un score CHA2DS2-VASc ≥ 3 (RRI de 5,18, IC à 95 % : de 1,76 à 15,29; p = 0,003). Le TLC n’était pas associé au décès ni aux hémorragies mineures ou majeures.
Conclusions
Une fibrinolyse altérée pourrait être un facteur de prédiction d’événements thromboemboliques
chez les patients présentant une FA traités par un AVK.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Canadian Journal of CardiologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.Eur Heart J. 2016; 7: 2893-2962
- Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis.Chest. 2004; 126: 1938-1945
- 2018 focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation.Can J Cardiol. 2018; 34: 1371-1392
- Biomarkers in atrial fibrillation: a clinical review.Eur Heart J. 2013; 34: 1475-1480
- Prothrombotic state in atrial fibrillation patients with one additional risk factor of the CHA2DS2-VASc score (beyond sex).Can J Cardiol. 2019; 35: 634-643
- Prethrombotic state in young very low-risk patients with atrial fibrillation.J Am Coll Cardiol. 2017; 69: 1990-1992
- Mechanisms of thrombogenesis in atrial fibrillation: Virchow’s triad revisited.Lancet. 2009; 373: 155-166
- Inflammation in atrial fibrillation.J Am Coll Cardiol. 2012; 60: 2263-2270
- Association of cardiac troponin I with prothrombotic alterations in atrial fibrillation.Kardiol Pol. 2018; 76: 1106-1109
- Denser plasma clot formation and impaired fibrinolysis in paroxysmal and persistent atrial fibrillation while on sinus rhythm: association with thrombin generation, endothelial injury and platelet activation.Thromb Res. 2015; 136: 408-414
- d-Dimer can predict survival in patients with chronic atrial fibrillation.Blood Coagul Fibrinolysis. 2004; 15: 413-417
- Fibrin(ogen) and thrombotic disease.J Thromb Haemost. 2013; 11: 294-305
- Fibrin clot structure and function: A role in the pathophysiology of arterial and venous thromboembolic diseases.Arterioscler Thromb Vasc Biol. 2011; 31: e88-e99
- Fibrin clot permeability as a predictor of stroke and bleeding in anticoagulated patients with atrial fibrillation.Stroke. 2017; 48: 2716-2722
- An international study on the standardization of fibrin clot permeability measurement: methodological considerations and implications for healthy control values.J Thromb Haemost. 2012; 10: 2179-2181
- Vitamin K antagonists favourably modulate fibrin clot properties in patients with atrial fibrillation as early as after 3 days of treatment: Relation to coagulation factors and thrombin generation.Thromb Res. 2015; 136: 832-838
- Fibrin clot properties independently predict adverse clinical outcome following acute coronary syndrome: a PLATO substudy.Eur Heart J. 2018; 39: 1078-1085
- Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.BMJ. 2011; 342: d124
- A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.Chest. 2010; 138: 1093-1100
- Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin.Chest. 2013; 144: 1555-1563
- A history of early stent thrombosis is associated with prolonged clot lysis time.Thromb Haemost. 2012; 107: 513-520
- Experience from a multicentre stroke register: a preliminary report.Bull World Health Organ. 1976; 54: 541-553
- Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in nonsurgical patients.J Thromb Haemost. 2005; 3: 692-694
- How to assess fibrinogen levels and fibrin clot properties in clinical practice?.Semin Thromb Hemost. 2016; 1: 381-388
- Elevated NT-proBNP is associated with unfavorably altered plasma fibrin clot properties in atrial fibrillation.Int J Cardiol. 2017; 243: 244-250
- Thromboembolic events are associated with prolonged clot lysis time in patients with permanent atrial fibrillation.Pol Arch Intern Med. 2011; 121: 400-407
- Role of von Willebrand factor in vascular disease.Hamostaseologie. 2009; 29: 32-38
- Additive role of plasma von Willebrand factor levels to clinical factors for risk stratification of patients with atrial fibrillation.Stroke. 2006; 37: 2294-2300
- Association of inflammatory and hemostatic markers with stroke and thromboembolic events in atrial fibrillation: a systematic review and meta-analysis.Can J Cardiol. 2015; 31: 278-286
- Lysability of fibrin clots is a potential new determinant of stroke risk in atrial fibrillation.Thromb Res. 2014; 134: 717-722
- Fibrin clot properties and their modulation in thrombotic disorders.Thromb Haemost. 2014; 112: 32-42
- Safety and efficacy of well managed warfarin. A report from the Swedish quality register Auricula.Thromb Haemost. 2015; 113: 1370-1377
- Evaluation of the recommended prevention of thrombosis in hospitalised patients with atrial fibrillation and high thromboembolism risk.Kardiol Pol. 2018; 76: 625-632
- Comparison of clinical characteristics of real-life atrial fibrillation patients treated with vitamin K antagonists, dabigatran, and rivaroxaban: results from the CRAFT study.Kardiol Pol. 2018; 76: 889-898
Article info
Publication history
Published online: August 08, 2019
Accepted:
August 4,
2019
Received:
April 21,
2019
Footnotes
See page 125 for disclosure information.
Identification
Copyright
© 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
