Abstract
We did this study to find out the clinical manifestations and prognosis of left atrial thrombosis in different types of atrial fibrillation and the relationship with systemic thromboembolism, hoping to find a better therapy strategy. A single-center retrospective study enrolled patients with definite diagnosis of atrial fibrillation complicated with left atrial thrombosis. Data of general clinical information, anticoagulation medications, thromboembolism events, and thrombosis prognosis were recorded and analyzed. A total of 103 patients were enrolled. Compared with non-valvular atrial fibrillation (NVAF), thrombosis outside the left atrial appendage (LAA) was much more common in valvular atrial fibrillation (VAF) with p=0.003. Total prevalence of systemic thromboembolism was 33.0%. Thrombi disappeared in 78 cases (75.7%) under anticoagulation treatment within 2 years. There was no significant difference between warfarin, dabigatran, and rivaroxaban on thromboembolism events and thrombosis prognosis in NVAF, with p=0.740 and 0.493, respectively. Atrial fibrillation patients with LA thrombosis have a high risk of systemic thromboembolism events. Compared with NVAF, patients with VAF had higher incidence of thrombosis outside the LAA. Standard stroke-preventing doses of anticoagulants might not be sufficient to deplete all LA thrombi. There was no statistically difference between warfarin, dabigatran, and rivaroxaban for depleting LA thrombi in NVAF patients.
Keywords: Atrial fibrillation, Left atrial thrombosis, Systemic thromboembolism, Anticoagulation
Background
Atrial fibrillation is a prevalent arrhythmia worldwide, particularly among the elderly population. The incidence and prevalence of atrial fibrillation are expected to rise with the aging society. Atrial thrombosis and heart dysfunction are major complications strongly associated with atrial fibrillation, which can lead to increased mortality and disability. Thromboembolic events, particularly ischemic stroke, have been shown to be more frequent in patients with atrial fibrillation. Previous studies have demonstrated that thrombi derived from the left atrium are responsible for thromboembolic events. Thrombus formation is mainly due to left atrial dysfunction and blood flow stasis. The left atrial appendage is the most common site for thrombus formation, owing to its unique anatomic structure and susceptibility to turbulence and stasis. Thrombosis outside the left atrial appendage is rare, especially in non-valvular atrial fibrillation [1]. However, there have been few reports on the clinical manifestations and prognosis of left atrial thrombosis, and the exact factors that contribute to its development, prognosis, and relationship with thromboembolic events remain unknown. Furthermore, it is unclear whether the anticoagulants commonly used to prevent stroke can effectively eliminate all thrombi formed inside the left atrium. To address these gaps in knowledge, we conducted a study to investigate the clinical manifestations and prognosis of left atrial thrombosis in different types of atrial fibrillation and its relationship with systemic thromboembolism. Our goal is to identify a more effective therapeutic strategy and improve the current status and prognosis of patients with left atrial thrombosis.
Methods
We conducted a single-center retrospective study at Fuwai Yunnan Cardiovascular Hospital, China. Patients who were admitted between June 2018 and December 2021 and met all four inclusion criteria were included in the study, while those who met any of the exclusion criteria were excluded. The inclusion criteria were as follows: (1) age over 18 years old; (2) definite diagnosis of atrial fibrillation complicated with left atrial (LA) thrombosis; (3) at least one re-evaluation of the LA thrombi by imaging examinations within 2 years since the initial time when thrombosis was diagnosed; and (4) regular anticoagulation medications had been used before or since the LA thrombosis was initially detected. The exclusion criteria were as follows: (1) age under 18 years old and (2) complications with severe liver or renal dysfunction, solid or hematological tumor, or thrombophilia with definite causes.
The diagnosis of atrial arrhythmia was made by two experienced cardiologists based on medical manifestations, history, conventional 12-lead electrocardiogram (ECG), and dynamic ECG. Upon admission to the hospital, general clinical information, including gender, age, height, weight, body mass index (BMI), diagnosis, disease duration, medical history, blood test, and trans-thoracic echocardiography (TTE), was recorded. Valvular atrial fibrillation (VAF) was defined as atrial fibrillation complicated by moderate or severe mitral stenosis, or mechanical mitral/aortic valve replacement. Non-valvular atrial fibrillation (NVAF) was defined as atrial fibrillation without these conditions. Persistent atrial fibrillation was defined as lasting more than a week, while paroxysmal atrial fibrillation was defined as terminating spontaneously or by treatment within a week.
We recorded events of systemic thromboembolism, including ischemic stroke and peripheral limb arteries occlusion, at the same time as the re-evaluation of LA thrombosis. Anticoagulant strategies were determined by experienced cardiologists based on individual patient situations and the 2016 ESC Guidelines for the management of atrial fibrillation [2]. The dose of anticoagulants was in accordance with the standard for preventing ischemic stroke.
Atrial thrombosis was initially diagnosed and re-evaluated using enhanced computed tomography (CT) or trans-esophageal echocardiography (TEE). We used the Somatom Definition Flash (Siemens Healthcare) for CT scans, employing a prospective ECG-gated scanning method. Patients were scanned from the aortic arch to the diaphragm level in a supine position, with non-ionic contrast agent injected into the elbow vein. A filling defect in the atrium detected by enhanced CT indicated atrial thrombosis. TEE was performed by experienced ultrasound doctors using GE or Philips ultrasonic probes. The following manifestations indicated atrial thrombosis: (1) an abnormal solid echo shadow with clear boundary and uniform internal echo; and (2) it usually occurs when the blood flow is slow or stagnant, without pedicle, and the range of motion varies greatly. Figure 1 shows left atrial appendage thrombosis detected by CT and TEE from two cases enrolled in this study.
Fig. 1.
Thrombosis detected by TTE, TEE, or enhanced CT. White arrows indicated LA thrombosis. Case A: Thrombosis outside the LAA was detected by TTE. Case B: Thrombosis inside the LAA was detected by enhanced CT. Case C: Thrombosis inside the LAA was detected by TEE. TTE, trans-thoracic echocardiography; TEE, trans-esophageal echocardiography; CT, computed tomography; LA, left atrium; LAA, left atrial appendage
All of the methods described above were performed in accordance with relevant guidelines and regulations. We used SPSS v20.0 for statistical analysis. The Shapiro-Wilk test was used to perform a normality test of continuous variables. Normal distribution continuous variables were described using mean ± standard deviation, while non-normal distribution continuous variables were described using the median and interquartile range. Categorical variables were described by count and percentage. The independent sample t-test was used to compare the means of two categorical variables, while the Mann-Whitney test was used to compare non-normal distribution continuous variables between two groups. Binary logistic regression analysis was used to determine the factors influencing systemic thromboembolism events and thrombosis prognosis. Cross-tab analysis was performed using the chi-square test. All analyses were considered statistically significant at p < 0.05.
Results
A total of 103 patients admitted to Fuwai Yunnan Cardiovascular Hospital between June 2018 and December 2021 were enrolled in this study. General clinical information is displayed in Table 1. A comparison between male and female patients was performed, and the p-value represented the significance of differences. It is important to note that all patients enrolled in this study were free from COVID-19 infection.
Table 1.
General clinical information
| Variables | Total (n=103) | Male (n=45) | Female (n=58) | p-value | |||
|---|---|---|---|---|---|---|---|
| Age (years) | 58.9±11.9 | 57.0±12.4 | 60.3±11.4 | 0.163 | |||
| BMI (kg/m2) | 23.36±3.25 | 24.01±3.44 | 22.87±3.03 | 0.077 | |||
| TTE parameters: | |||||||
| Antero-posterior diameter of LA (mm) | 51.2±9.9 | 53.7±10.5 | 49.2±9.1 | 0.022* | |||
| Left ventricular end diastolic diameter (mm) | 49.4±9.0 | 54.3±8.7 | 45.7±7.3 | <0.001* | |||
| Left ventricular ejection fraction (%) | 53.5±12.5 | 49.4±14.3 | 56.8±9.8 | 0.004* | |||
| Classification of atrial fibrillation depending on disease duration (n, %) | 0.349 | ||||||
| Persistent atrial fibrillation | 58 | 56.3% | 23 | 51.1% | 35 | 60.3% | |
| Paroxysmal atrial fibrillation | 45 | 43.7% | 22 | 48.9% | 23 | 39.7% | |
| Classification of atrial fibrillation depending on cardiac valvular condition (n, %) | 0.392 | ||||||
| Non-valvular atrial fibrillation | 50 | 48.5% | 24 | 53.3% | 26 | 44.8% | |
| Valvular atrial fibrillation | 53 | 51.5% | 21 | 46.7% | 32 | 55.2% | |
| History of hypertension (n, %) | 46 | 44.7% | 21 | 46.7% | 25 | 43.1% | 0.784 |
| History of coronary heart disease (n, %) | 13 | 12.6% | 9 | 20.0% | 4 | 6.9% | 0.047* |
| Anticoagulation medications (n, %) | |||||||
| Warfarin | 59 | 57.3% | 24 | 53.3% | 35 | 60.3% | 0.168 |
| Rivaroxaban | 30 | 29.1% | 17 | 37.8% | 13 | 22.4% | |
| Dabigatran | 14 | 13.6% | 4 | 8.9% | 10 | 17.2% | |
| NT-proBNP (pg/mL) | 1536.0 (856.2, 2848.0) | 1590.5 (948.1, 3887.2) | 1536.0 (791.4, 2338.2) | 0.277 | |||
| Serum creatinine level (μmol/L) | 84.70±18.67 | 94.91±15.07 | 76.77±17.39 | p<0.001* | |||
*Represents statistically difference between male and female
Of the 103 patients enrolled in the study, 72 cases (69.9%) had thrombosis only inside the left atrial appendage (LAA), 15 cases (14.6%) had thrombosis only outside the LAA, and 16 cases (15.5%) had thrombosis both inside and outside the LAA. In total, 88 cases (85.4%) had thrombosis inside the LAA, and 31 cases (30.1%) had thrombosis outside the LAA. The classification of atrial fibrillation depending on cardiac valvular condition had a significant impact on the thrombosis location. Thrombosis outside the LAA was much more common in VAF compared to NVAF. Thrombosis outside the LAA was found in 43.4% of VAF cases and only 16.0% of NVAF cases. Pearson analysis showed a significant difference with p=0.003, as displayed in Fig. 2.
Fig. 2.
Thirty (56.6%) VAF patients and 42 (84.0%) NVAF patients had thrombosis only inside LAA. Nine (17.0%) VAF patients and six (12.0%) NVAF patients had thrombosis only outside LAA. Fourteen (26.4%) VAF patients and two (4.0%) NVAF patients had thrombosis both inside and outside LAA. LAA, left atrial appendage; VAF, valvular atrial fibrillation; NVAF, non-valvular atrial fibrillation
Based on the re-evaluation results, all enrolled patients could be divided into two groups. Group A was composed of patients with LA thrombi that disappeared, with 78 cases (75.7%), while group B was composed of patients with LA thrombi that did not disappear, with 25 cases (24.3%). Events of systemic thromboembolism were found in 34 (33.0%) cases. The chi-square test showed that there was no significant difference in the occurrence of thromboembolism events between the two groups, with p=0.715, as displayed in Table 2.
Table 2.
Relationship between thromboembolism events and LA thrombosis prognosis
| Thromboembolism events positive, n=34 | Thromboembolism events negative, n=69 | |
|---|---|---|
| Group A (LA thrombi disappeared), n=78 | N=25 (32.1% of group A) | N=53 (67.9% of group A) |
| Group B (LA thrombi not disappeared), n=25 | N=9 (36.0% of group B) | N=16 (64.0% of group B) |
We conducted binary logistic regression analysis using the forward method to identify independent predictors of thromboembolism events and LA thrombosis prognosis. The factors included in the analysis were age, gender, BMI, two types of classification of atrial fibrillation, history of hypertension, history of coronary heart disease, anticoagulation medications, anteroposterior diameter of LA, left ventricular end diastolic diameter, left ventricular ejection fraction, NT-proBNP, and serum creatinine level. Age was the only independent predictor of thromboembolism events (p=0.016, Exp (B)=0.953, 95% CI: 0.917–0.919). The classification of atrial fibrillation depending on disease duration was the only independent predictor of LA thrombosis prognosis (p=0.046, Exp (B)=2.846, 95% CI: 1.019–7.953). LA thrombi disappeared in 38 (84.4%) patients with paroxysmal atrial fibrillation, while in 40 (69.0%) patients with persistent atrial fibrillation. Persistent atrial fibrillation made it harder to deplete LA thrombi compared to paroxysmal cases.
In the VAF subgroup, 53 patients accepted warfarin, while in the NVAF subgroup, 6 patients accepted warfarin, 14 accepted dabigatran, and 30 accepted rivaroxaban. Subgroup analysis of the 50 NVAF cases showed that different anticoagulation medications did not affect thromboembolism events and LA thrombosis prognosis, with p=0.740 and 0.493, respectively, as displayed in Fig. 3. The prevalence of systemic thromboembolism events was 42.0%. Regular anticoagulation therapy could make LA thrombosis disappear in only 37 (74.0%) NVAF patients. There was no significant difference in the impact on thrombosis events and LA thrombosis prognosis between vitamin K antagonist (VKA) and non-vitamin K antagonist oral anticoagulants (NOAC).
Fig. 3.
Subgroup analysis of 50 NVAF patients. Six cases accepted warfarin; 33.3% had thromboembolism events and 33.3% had LA thrombosis persisted. Thirty cases accepted rivaroxaban; 40.0% had thromboembolism events and 20.0% had LA thrombosis persisted. Fourteen cases accepted dabigatran; 50.0% had thromboembolism events and 35.7% had LA thrombosis persisted. NVAF, non-valvular atrial fibrillation; LA, left atrium
Discussion
As we know, thromboembolism events can only occur when thrombosis falls off from the LA. In this study, the prevalence of thromboembolism events in patients with atrial fibrillation and LA thrombosis was 33.0%. It is much more higher than that in common atrial fibrillation population. The only independent predictor was age, suggesting that as age increases, LA thrombosis is more likely to fall off and result in systemic thromboembolism. This provides us with a preliminary answer regarding the risk of thrombosis falling off and its influencing factors.
One of our previous studies reported a prevalence of LA thrombosis of 25.8% in patients with an anteroposterior diameter of LA ≥ 50 mm, which was also found to be a strong independent predictor [3]. In this study, the average anteroposterior diameter of LA was 51.2±9.9 mm. Based on these findings, we can roughly estimate that the prevalence of thromboembolism events in atrial fibrillation patients with severe LA remodeling is 25.8% × 33.0% = 8.5%. This is a really high prevalence that requires serious medical attention.
Previous studies have reported that the LAA accounts for more than 90% of thrombus formation in patients with atrial fibrillation, which is associated with its anatomic, mechanical, and electrophysiologic properties [4]. Thrombosis outside the LAA is much rarer and has received little attention. Mainstream points explain the relationship between LA function and thrombosis, suggesting that as the function of LA/LAA worsens, the easier it is for thrombus to form. This study showed that although most thrombus was formed inside the LAA, there was still 30.1% thrombosis outside the LAA. Compared with NVAF, thrombosis outside the LAA was much more common in VAF. These results indicate that patients with VAF are more likely to develop whole LA dysfunction rather than only LAA dysfunction. This might be attributed to mitral valve stenosis, which could have a more negative impact on whole LA function than other possible factors. However, this hypothesis needs more data and evidence to demonstrate.
Both VKA and NOAC have been proven to be effective in preventing ischemic stroke in high-risk atrial fibrillation population. Dabigatran and rivaroxaban used in this study are believed to have equal benefits with warfarin in preventing thromboembolism events, according to previous studies [5, 6]. Currently, anticoagulant strategies for depleting formed thrombus in the LA are not clear due to a lack of evidence. To date, the available evidence only comes from case reports and small-sample research studies [7]. VKA is currently the most widely adopted strategy for LA/LAA thrombosis, with a success rate of 50–60% at 12 months [8]. The clinical outcome of using NOAC for LA/LAA thrombosis is not clear. However, its pharmacological effects of limiting fibrin accretion and favoring endogenous fibrinolysis might be helpful to deplete thrombus, according to previous research studies [7]. In this study, as described above, LA thrombus disappeared in 75.7% of cases after anticoagulation medications within 2 years, with 24.3% left to develop chronic LA thrombus. There was no statistically significant difference between warfarin, dabigatran, and rivaroxaban for depleting thrombus in NVAF patients. The only independent factor to predict prognosis of LA thrombosis was the classification of atrial fibrillation depending on disease duration.
According to the results, LA thrombi of persistent atrial fibrillation were more likely to persist and develop to chronic. Clinical strategies that may be useful include treating paroxysmal atrial fibrillation as early as possible to prevent it from developing into persistent atrial fibrillation, and increasing the dose of NOAC or INR when using warfarin above the regular standard. However, it should be noted that increasing the dose or INR could increase the risk of bleeding, so the decision must be made cautiously. These strategies also require more research to prove their long-term benefits. A perfect dose for treating LA thrombosis may be different from the standard stroke-preventing dose, which needs further exploration.
There are several limitations to this study. The evidence level of a single-center retrospective study is lower than that of a prospective study. Events of thromboembolism did not cover all systemic arteries, so some may have been missed, and the prevalence may be underestimated. This study could not provide a perfect strategy to prevent and deal with LA thrombosis, which also requires further exploration.
Conclusions
In summary, atrial fibrillation patients with LA thrombosis had a high risk of systemic thromboembolism events. Patients with VAF are more likely to develop whole LA dysfunction rather than only LAA dysfunction, as evidenced by the higher incidence of thrombosis outside the LAA. Standard stroke-preventing doses of anticoagulants might not be sufficient to deplete all LA thrombi. Furthermore, there was no statistically difference between warfarin, dabigatran, and rivaroxaban for depleting thrombi in NVAF patients.
Code Availability
We state that all data and materials as well as software application or custom code support our published claims and comply with field standards.
Abbreviations
- LA
left atrium/atrial
- LAA
left atrial appendage
- BMI
body mass index
- ECG
electrocardiogram
- TTE
trans-thoracic echocardiography
- CT
computed tomography
- TEE
trans-esophageal echocardiography
- NVAF
non-valvular atrial fibrillation
- VAF
valvular atrial fibrillation
- VKA
vitamin K antagonist
- NOAC
non-vitamin K antagonist oral anticoagulants
- INR
international normalized ratio
Author Contributions
GYL was the head in charge of the whole study, and made quality control of every steps in this work. YQ collected cases and did ECG reading, CT measurement, and data input. LS did data analysis and manuscript writing. WJ provided advice and help for TTE and TEE reading.
Funding
This work was supported by following funding.
Yunnan Provincial Fund for High Level Reserve Talents in Health Science (H-2017068, H-2018037) supported research and clinical work of Shuang Liu and Yulong Guo, respectively.
Fuwai Yunnan Cardiovascular Hospital, Yunnan Provincial Cardiovascular Disease Clinical Medical Center Project (No. FZX2019-06-01) supported Yulong Guo’s cardiovascular researches.
Yunnan Applied Basic Research Projects, Kunming Medical University Union Special Fund (202301AY070001-043, 202301AY070001-159) supported research and clinical work of Yulong Guo and Shuang Liu, respectively.
The Youth Talent of Ten Thousand Scientists Program of Yunnan Province (YNWR-QNBJ-2018-152) supported Shuang Liu’s clinical researches.
Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics Approval and Consent to Participate
This study was approved by the ethics committee of Fuwai Yunnan Cardiovascular Hospital. Consent forms were approved by the ethics committee. We confirm that written informed consent was obtained from all enrolled participants.
Consent for Publication
All authors agreed to publish this work.
Competing Interests
The authors declare no competing interests.
Footnotes
Qian Yang and Shuang Liu are co-first authors of this article.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.