Discussion
Our study is the first to show the influence of epicardial LAAO in nonvalvular AF patients on fibrin clot characteristics and thrombin generation assessed 1 month after the procedure. Our novel finding is that the LAAO improves fibrin clot permeability and susceptibility to fibrinolysis. Interestingly, shortened CLT correlated with decreased PAI-1 antigen levels and increased plasminogen activity. Moreover, a tendency to reduced thrombin generation measured 1 month after the LAAO procedure was observed (Figure 2).
Atrial fibrillation increase risk of stroke up to 20%15. In nonvalvular AF patients, 90% of thrombus is located in LAA what was confirmed by autopsy, transesophageal echocardiography or direct inspection study16. In contrast to the anatomy of different hear chambers, LAA present long, tubular structure as well as narrow junction with the atrium17. Increased thromboembolism risk in AF is associated with a combination of pathophysiological mechanism, a Virchow’s triad1. The first factor is left atria dysfunction with stasis observed in spontaneous echocardiography contrast18. The second factor, an abnormal change in the vessel are present by vascular endothelial cell damage reflected by elevated soluble thrombomodulin (TM)19,20. TM, an integral membrane protein expressed on the surface of endothelial cells, binds thrombin with high affinity inhibits fibrinolysis by cleaving thrombin-activatable fibrinolysis inhibitor (TAFI) into its active form20,21. Additionally, unfavourably altered fibrin clot properties have been also described 22. The third factor, hypercoagulable or prothrombotic state is reflected by increased levels of prothrombin fragments 1 + 2 (F1 + 2), elevated thrombin generation markers, including increased levels of prothrombin fragments, plasm fibrinogen and hypofibrinolysis due to increased levels of plasminogen activator inhibitor type 1 (PAI-1) and plasmin-𝛼2-antiplasmin (PAP)20,23. Of note, in our previous study, we have shown, that in patients with AF, the LAA chamber has reduced fibrin clot permeability and prolonged lysis time suggestive increased prothrombotic state (data being published). Additionally, it has been shown that clot lysis time predicts stroke during anticoagulant therapy in patients with atrial fibrillation and that patients with chronic AF and previous stroke are characterized by prolonged CLT and higher TAFI antigen than those free of stroke20. Therefore, the mechanisms underlying a thrombus formation in LAA in patients with AF are complex.
However, the CHA2DS2-VASc score, clinically applicable stroke risk-stratification model in AF patients, do not incorporate biomarkers4,15. Interestingly, CLT, PAI-1, and TAFI activity were positively associated with CHA2DS2-VASc scores, reflecting stroke risk in AF 20.
In last decades LAA became a therapeutic target for stroke prevention in patients who are at high stroke risk and have contraindications for long-term OAC (European Society of Cardiology guidelines Class IIb, Level of Evidence B)24. Multiple observational studies indicate the feasibility and safety of surgical or percutaneous LAA occlusion/exclusion procedure3-6, even in high risk patients with increased thromboembolism risk comorbidities25-27. Epicardial LAAO complete ligate LAA orifice what cause necrosis and fibrosis permanently eliminating LAA 28.
Our study supports the concept of an LAA elimination from the circulatory system based on biomarkers approach in thromboembolic risk assessment in patients with AF. LAAO procedure improves fibrin clot permeability and susceptibility to fibrinolysis. Importantly, this effect lasts for a long time as evidenced by shortened CLT correlated with decreased PAI-1 antigen levels, increased plasminogen activity and a tendency to reduced thrombin generation measured 1 month after the LAAO procedure. Importantly, this effect was achieved in patients not receiving oral anticoagulation.
Therefore, our study confirms two important practical aspects. First, that LAA plays a key role in thrombogenesis and that LAA may be the main source of all thrombus in AF patients. Secondly, that LAAO procedure decreased the thromboembolic risk not only by elimination the local source of thrombus but also by improves fibrin clot permeability and susceptibility to fibrinolysis in peripheral blood. To our knowledge, the present prospective cohort study is unique in this regard.
Our study that is based on biomarkers concepts of thromboembolic risk in AF, may explain the effectiveness and successful results in the reduction of stroke or other thromboembolic episodes in observational studies that assess percutaneous LAA occlusion/exclusion procedure29,30.
For cardiac surgery, obtained results are especially important, because they support the idea to perform concomitant surgical LAA occlusion in patients with AF/flutter who are undergoing routine cardiac surgery7. However, it should be noted, that in our study all LAAO was performed using Lariat or AtriClip (epicardial devices) as an elective procedure. There were also no leaks or thrombus in 1 months follow-up TTE examination. Is should be noted, that we didn’t investigate the effect of amputation of the LAA and closure technique that is allowed in LAAO III trial7.
Study limitations
The number of patients enrolled in the study was limited. We would like to highlight, however, that the number of patients enrolled in our study is comparable with the average number of patients undergoing this kind of blood sampling as published so far. Based on our findings larger studies are warranted to corroborate our observations
Conclusions
Our findings demonstrate that LAA plays a key role in thrombogenesis and is the main source of thrombus in AF. Our study suggests that LAA elimination from the circulatory system not only eliminate the local source of thrombus but also improve fibrin clot permeability and susceptibility to fibrinolysis in peripheral blood. Result of our study based on biomarkers concept of thromboembolic risk in AF support the results of observational of surgical or percutaneous LAA occlusion/exclusion procedure. Further studies are needed to validate our observations.