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(Chest. 2003;124:1670-1674.)
© 2003 American College of Chest Physicians

Left Atrial Appendage Function and Abnormal Hypercoagulability in Patients With Atrial Flutter*

Kenji Sakurai, MD; Tadakazu Hirai, MD; Keiko Nakagawa, MD; Tomoki Kameyama, MD; Takashi Nozawa, MD; Hidetsugu Asanoi, MD and Hiroshi Inoue, MD

* From The Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan.

Correspondence to: Tadakazu Hirai, MD, The Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan; e-mail; thirai{at}ms.toyama-mpu.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: The prevalence of thromboembolism might be higher than previously recognized in patients with atrial flutter (AFL) based on findings of transesophageal echocardiography (TEE). To evaluate the potential prothrombotic state in patients with AFL, TEE findings and hemostatic markers were compared among patient groups with AFL, normal sinus rhythm (NSR) and chronic nonvalvular atrial fibrillation (AF).

Design and settings: Cross-sectional study at a university hospital.

Methods: In 28 patients (mean age, 63 years) with AFL, 58 patients (mean age, 66 years) with AF, and 27 patients (mean age, 61 years) with NSR who underwent TEE, plasma levels of markers for platelet activity (platelet factor 4 and ß-thromboglobulin [ß-TG]), thrombotic status (thrombin-antithrombin III complex and prothrombin fragments 1 and 2) and fibrinolytic status (d-dimer and plasmin-{alpha}2-plasmin inhibitor complex) were determined.

Results: Left atrial appendage (LAA) blood flow velocity in patients with AFL was higher (p < 0.05) than that in patients with AF, but was lower (p < 0.05) than that in patients with NSR (AF, 25 ± 2; AFL, 44 ± 4; NSR, 60 ± 4 cm/s). Dense left atrial spontaneous echo contrast (SEC) was found in 4 patients (14%) with AFL and 16 patients (28%) with AF. There was no significant difference in plasma levels of hemostatic markers between the AFL group and the NSR group. AFL patients with impaired LAA function (LAA flow < 30cm/s, dense SEC, or both), however, showed higher level of d-dimer and ß-TG than those without impaired LAA function (d-dimer, 1.9 ± 0.6 µg/mL vs 0.4 ± 0.1 µg/mL; ß-TG, 73 ± 17 ng/mL vs 33 ± 5 ng/mL, p < 0.05).

Conclusions: Patients with AFL as a whole are not in the prothrombotic state as compared with those with AF. However, patients with AFL and impaired LAA function are at potentially high risk for thromboembolism and might require anticoagulation.

Key Words: atrial flutter • hemostatic markers • thromboembolism • transesophageal echocardiography


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Atrial fibrillation (AF) is a common arrhythmia and is associated with an increased risk of thromboembolism. As compared with patients with AF, those with atrial flutter (AFL) have been traditionally considered at low risk for thromboembolism due to more organized mechanical atrial contraction in this specific arrhythmia.1 However, studies of the risk of thromboembolic complications in patients with AFL have been sparse and often conflicting; some reports suggested a generally low risk for thromboembolism,1 2 and others indicated relatively high prevalence of left atrial thrombi.3 4 5

An elevated level of biochemical markers of coagulation and fibrinolytic activity is well demonstrated in patients with AF.6 7 These markers reflect states of hypercoagulability and thrombogenesis in the left atrium (LA) and left atrial appendage (LAA). However, few studies have determined hemostatic markers in patients with AFL so far. We therefore studied

whether there would be potential hypercoagulable or prothrombotic state in patients with AFL by measuring hemostatic biochemical markers, and determined factors predisposing to LA thrombus formation in these patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Patients
The study population consisted of 113 consecutive patients (82 men and 31 women; mean age, 64 ± 1 years [SE]) who underwent transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) and also determination of levels of hemostatic markers at our University Hospital. Patients were classified into three groups according to their cardiac rhythm; normal sinus rhythm (NSR), AFL or AF. Underlying disease of the study patients included the following: hypertension (n = 37), ischemic heart disease (n = 12), hypertrophic cardiomyopathy (n = 6), and dilated cardiomyopathy (n = 3). No apparent underlying diseases were identified in 66 patients. The diagnosis of AFL was made from a 12-lead ECG using the standard criteria,8 and patients with AFL lasting > 2 days (mean duration, 6.0 ± 1.8 months) were enrolled in this study (AFL group). Chronic AF was defined as AF that had been documented by ECG and lasted for >= 6 months (AF group). Patients with rheumatic valvular disease were not included in the present study. Subjects with NSR underwent TEE to investigate potential intracardiac thrombi for ischemic cerebral events or intracardiac shunt for heart murmur. Baseline clinical characteristics including hypertension, diabetes mellitus, hyperlipidemia, and embolic cerebrovascular events were determined from medical record and routine laboratory data. The use of oral antiplatelet or anticoagulant agents at the time of the echocardiographic studies was carefully determined.

Echocardiography
All patients underwent TTE and TEE studies after giving informed consent as in our previous study.9 Briefly, TTE was performed with a 2.5-MHz or 3.75-MHz phased-array transducer connected to an ultrasound system (SSH-140A; Toshiba; Tokyo, Japan). The left atrial dimension (LAD), left ventricular end-diastolic dimension, and left ventricular ejection fraction (LVEF) were determined by M-mode.10 In 28 patients with AFL, mitral flow velocity was assessed using pulsed Doppler echocardiography. TEE was performed with a 5-MHz multiplane transducer. Each patient was studied in the fasted state without any premedications except for topical anesthesia of the hypopharynx with lidocaine spray. Multiple standard tomographic planes were imaged, and peak LAA flow velocity, presence of LA thrombi, and severity of LA spontaneous echo contrast (LASEC) were determined. LASEC was diagnosed in the presence of dynamic smoke-like echoes within the LA or LAA, with a characteristic swirling motion that was distinct from white noise artifact. The severity of LASEC was defined by the criteria of Fatkin et al.11 The presence of LA thrombus and spontaneous echo contrast (SEC) was determined by two independent observers. Any difference in the determination was resolved by a third observer.

To assess potential embolic risk, patients with AFL were further classified into two groups according to LAA flow velocity and LASEC. Those with low LAA flow < 30 cm/s, dense LASEC greater or equal to grade 3, or both were considered to have impaired LAA function and be at high risk for thromboembolism.

Determination of Hemostatic Markers
The following hemostatic markers were determined: platelet factor 4 (PF4) and ß-thromboglobulin (ß-TG) levels as indexes of platelet activation, thrombin-antithrombin III complex (TAT) and prothrombin fragments 1 and 2 (F1 + 2) as markers of thrombin activity, and d-dimer and plasmin-{alpha}2-plasmin inhibitor complex (PIC) as indexes of active fibrinolysis. Blood samples for determination of these hemostatic markers were obtained from all patients with NSR, AF, and AFL on the day of the TEE study using the two-syringe technique. An international normalized ratio of the prothrombin time (PT-INR) was also measured at each blood sample. Preparation of blood samples and determination of hemostatic markers were performed as in our previous studies.9 12

Statistical Analysis
Data are presented as mean value ± SE. {chi}2 test was used to compare the categorical variables. For comparison of the continuous variables among the three groups, one-way analysis of variance was employed and multiple comparisons were made with Scheffe post hoc analysis (SPSS 11.0; SPSS; Chicago, IL). A p value < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient Characteristics
Baseline clinical characteristics in the three patient groups are summarized in Table 1 . No significant difference was found in age, sex, and the use of an oral antiplatelet drug among the groups. An oral anticoagulant was used more frequently in patients with AFL and chronic AF than in those with NSR. Prior embolic events and hypertension were observed more frequently in patients with AF than in those with NSR.


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  		Table 1.. Baseline Clinical Variables*

 
Echocardiographic Variables
TTE and TEE variables are shown in Table 2 . As expected, LAD was larger in patients with AF than in those with NSR and AFL, but LVEF did not differ among the three groups. In patients with AF, LAA flow velocity was significantly reduced and the severity of LASEC was significantly higher as compared with patients with NSR and AFL. LAA flow velocity in patients with AFL was lower than that in patients with NSR. LAA thrombi were observed more frequently in patients with AF than in NSR as expected.


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  		Table 2.. Echocardiographic Variables*

 
Hemostatic Markers
Plasma levels of hemostatic markers are summarized in Table 3 . Patients with AF showed significantly higher level of d-dimer, ß-TG, and PF4 than those with NSR. In addition, d-dimer level in patients with AF was significantly elevated compared with that of patients with AFL. Levels of these hemostatic markers, however, did not differ between the NSR and AFL groups, indicating that patients with AFL as a whole were not in the hypercoagulable state.


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  		Table 3.. Plasma Levels of Hemostatic Markers*

 
Subanalysis of Thromboembolic Risk in AFL
Eleven patients with AFL were classified as a high-risk group for thromboembolism; the remaining patients with AFL were classified as a low-risk group (Table 4 ). There was no significant difference regarding the duration of AFL between the high-risk and low-risk groups (7.4 ± 3.1 months vs 5.0 ± 2.1 months, respectively; p = 0.74). LAD and left ventricular end-diastolic dimension and LVEF were not different between the two groups, although LA thrombi were observed only in the high-risk patient group. Organic heart disease was complicated more frequently in the high-risk patient group than in the low-risk patient group. High-risk AFL patients showed higher ß-TG and d-dimer levels than low-risk AFL patients (Table 5 ). Borderline significance was observed in PF4 and F1 + 2 levels. These results indicated that high-risk AFL patients based on TEE findings were in the prothrombotic state as compared with low-risk AFL patients.


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  		Table 4.. Comparison of Echocardiographic Characteristics Between AFL Patients at High and Low Risk for Thromboembolism*

 

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  		Table 5.. Comparison of Hemostatic Markers Between AFL Patients at High and Low Risk for Thromboembolism*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Major findings of the present study were as follows. First, patients with AFL as a whole had well-preserved LAA function when compared to patients with AF. Levels of hemostatic markers did not differ between patients with NSR and AFL. Secondly, AFL patients with impaired LAA function had higher levels of d-dimer and ß-TG than those without impaired LAA function, suggesting that LAA dysfunction could be associated with the prothrombotic state in AFL.

Thromboembolic Risk in AFL
The risk of thromboembolism in patients with AFL seems higher than previously thought. Wood et al13 found that 12 of 86 patients (14%) with AFL had thromboembolic events. Other investigators4 also showed a higher prevalence of cerebrovascular accident (11%) in patients with AFL; a similar prevalence to the present study as shown in Table 1 (11%). This higher prevalence of thromboembolism could be due to patient selection. An earlier study14 using TTE reported that organic heart disease, depressed left ventricular function, history of hypertension, and diabetes mellitus emerged as embolic risk factors in patients with AFL.

Previous studies2 14 15 16 as well as the present study, however, showed a relatively low prevalence (1 to 11%) of LA or LAA thrombi in patients with AFL. Particularly, the European multicenter study16 reported that LAA thrombus was present in only 2 of 134 patients (1.6%) with AFL. The low prevalence of LA or LAA thrombi could be attributed to more organized atrial contraction in patients with AFL. In contrast, Bikkina et al3 reported that 21% (5 of 24 patients) with AFL had LA thrombus. This higher figure could be due to patient selection; 63% (15 of 24 patients) with AFL had prior embolic event in their study.3

LAA Flow Velocity and LASEC in Patients With AFL
Atrial contraction is more organized in patients with AFL as compared with patients with AF. Therefore, patients with AFL as a whole would have well-preserved LAA flow velocity and lower prevalence of dense SEC.1 Actually, previous studies1 2 4 14 16 reported that LAA flow velocity was 42 to 93 cm/s and the prevalence of dense SEC was 6 to 16% in AFL. Similarly, in the present study, LAA flow velocity was 44 cm/s, the grade of LASEC was low (0.8 ± 0.2), and prevalence of dense SEC was 14% (4 of 28 patients) in those with AFL. Irani et al,4 however, found the prevalence of dense SEC in AFL was high (32%; 15 of 47 patients); this could be explained by an abnormal left ventricular function seen in 53% of their study patients.

Hemostatic Markers in AFL
Markers of thrombogenesis and platelet activation were higher in patients with AF than in those with NSR, suggestive of a prothrombotic state associated with AF.6 However, to our knowledge, hemostatic markers have not been determined thoroughly in patients with AFL. We found that plasma levels of hemostatic markers did not differ significantly between the AFL group and the NSR group. This suggests patients with AFL could be at less prothrombotic risk than those with AF.

Although patients with AFL as a whole were not in the prothrombotic state, patients with AFL and impaired LAA function had increased levels of ß-TG and d-dimer in the present study. This indicates that AFL patients with impaired LAA function might have stasis of blood in LAA as in patients with AF and thereby be in the prothrombotic state. Platelet activity was also elevated in patients with AFL and impaired LAA function. While the platelet markers were less likely to be affected, some previous reports6 7 indicated patients with AF had increased platelet activity. Although PT-INR was relatively low, anticoagulation with warfarin might lead to underestimate hypercoagulability in patients with impaired LAA function.

Risk Stratification of Thromboembolism in AFL
We classified the patients with AFL into two group (high risk vs low risk) according to echocardiographic findings as reported in the third Stroke Prevention in Atrial Fibrillation trial.17 The prevalence of embolic events did not differ between the high-risk and the low-risk groups, but LA thrombi was detected more frequently in the high-risk group.

Previous studies2 14 showed that risk factors of thromboembolism in AFL are hypertension, diabetes mellitus, impaired left ventricular function, and prior embolic event. Prevalences of these factors were not different between the two groups with AFL in the present study possibly because of limited number of the patients. Alternatively, risk of thromboembolism may be affected by the duration of AFL, because we studied patients whose duration of AFL was > 2 days and the mean duration of AFL was 6 months. In the present study, however, there was no significant difference in the duration of AFL between the high-risk and low-risk groups, suggesting that duration of AFL may not be critical for LAA dysfunction in the present study.

Controversies persist over which AFL patients would benefit from pretreatment with warfarin. Long-term anticoagulation in patients prior to conversion is costly, time consuming, and had side effects. In the present study, plasma levels of hemostatic markers show substantial heterogeneity among patients with AFL. Specifically, AFL patients in whom thrombi and LA blood stasis were excluded by TEE (ie, low-risk patients) showed normal plasma levels of hemostatic markers. These observations imply that cardioversion could be performed without the need for long-term anticoagulation in this subset of AFL patients, although thromboembolic risk after cardioversion remains to be determined.

Study Limitations
The present study is limited for several reasons. First, antithrombotic therapy might bias our results, because patients who had received antithrombotic therapy were included in this study. There were no significant differences in frequency of aspirin treatment and intensity of anticoagulation (PT-INR) among patients with NSR, AFL, and AF. Additionally, LAA flow velocity and LASEC measured with TEE are known to be unaffected with antithrombotic drugs.18 LAA function in patients with AFL as a whole remained nearly normal, and consequently hemostatic markers were not activated. Secondly, we did not determine hemostatic markers after NSR was restored in the AFL group. Atrial stunning could ensue after restoration of sinus rhythm and be associated with formation of new atrial thrombi.14 Thirdly, the number of patients with AFL who underwent TEE and determination of hemostatic markers was not large enough to draw definite conclusion.

Although limited for these reasons, the present study indicates patients with AFL as a whole have well-preserved LAA function and are not in the prothrombotic state. However, some patient with AFL have impaired LAA function and are in the prothrombotic state. Anticoagulation needs to be administered for prevention of embolic event in these patients with AFL.


   Footnotes
 
Abbreviations: AF = atrial fibrillation; AFL = atrial flutter; ß-TG = ß-thromboglobulin; F1 + 2 = prothrombin fragments 1 and 2; LA = left atrium; LAA = left atrial appendage; LAD = left atrial dimension; LASEC = spontaneous echo contrast in the left atrium; LVEF = left ventricular ejection fraction; NSR = normal sinus rhythm; PF4 = platelet factor 4; PIC = plasmin-{alpha}2-plasmin inhibitor complex; PT-INR = international normalized ratio of prothrombin time; SEC = spontaneous echo contrast; TAT = thrombin-antithrombin III complex; TEE = transesophageal echocardiography; TTE = transthoracic echocardiography

Supported by a Grant from the Ministry of Education, Science and Culture of Japan (Dr. Inoue).

Received for publication December 18, 2002. Accepted for publication July 8, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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