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.