(Circulation. 1996;94:331-339.)
© 1996 American Heart Association, Inc.
Articles |
Determinants of Increased Regional Left Atrial Coagulation Activity in Patients With Mitral Stenosis
the Cardiology Unit (R.E.P., R.W.H., J.G., J.J.S.), Hematology Unit (T.E.G., G.H.), and Institute of Reproduction and Development (J.J.S.), Monash Medical Centre, Melbourne, Australia.
Correspondence to Dr J.J. Smolich, Cardiology Unit, Monash Medical Centre, 246 Clayton Rd, Clayton, Victoria, 3168, Australia. E-mail joe.smolich@med.monash.edu.au.
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Abstract |
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Background Recent evidence suggests that regional left atrial coagulation activity may be increased in mitral stenosis and perhaps contribute to the pathophysiology of left atrial thrombus. However, the relation of left atrial coagulation activity to factors that predispose to left atrial thrombus formation is unknown, and the relation between left atrial and systemic coagulation activities is unresolved.
Methods and Results Left atrial and peripheral venous levels of the coagulation marker prothrombin fragment 1+2 (F1+2) were measured in 32 patients with mitral stenosis with normal clotting times and no left atrial thrombus who were undergoing percutaneous balloon mitral valvuloplasty. Baseline peripheral venous F1+2 levels, measured at the beginning of the valvuloplasty procedure, did not differ from those of 30 age-matched control patients. Prevalvuloplasty left atrial F1+2 levels, obtained immediately after transseptal puncture, were similar to femoral venous levels in patients without left atrial spontaneous echo contrast (LASEC) (0.81±0.32 versus 0.81±0.27 nmol/L, n=7) but greater than femoral venous levels in patients with LASEC and either sinus rhythm (1.57±0.86 versus 0.99±0.38 nmol/L, n=16, P<.001) or atrial fibrillation (1.52±0.69 versus 0.85±0.33 nmol/L, n=9, P<.003). Furthermore, LASEC emerged as the only significant predictor of increased regional left atrial coagulation activity (P=.005) on stepwise multivariate logistic regression analysis.
Conclusions Increased regional left atrial coagulation activity in mitral stenosis occurs in the presence of LASEC, is evident in either sinus rhythm or atrial fibrillation, and is associated with normal systemic coagulation activity.
Key Words: atrium • coagulation • echocardiography • mitral valve
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Introduction |
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Left atrial thrombus, with its attendant risk of systemic embolization, is a serious and relatively common complication of mitral stenosis.1 2 3 4 5 6 7 8 9 Although the pathogenesis of left atrial thrombus is incompletely understood, epidemiological studies have identified atrial fibrillation and the echocardiographic phenomenon of left atrial spontaneous echo contrast (LASEC) as major factors that predispose to its development.2 4 5 8 10 11 12 13 Thus, the risk of thromboembolism is twofold to sevenfold greater in patients with mitral stenosis and atrial fibrillation than in those with sinus rhythm,2 4 5 8 and it is also increased in the presence of LASEC, independent of the existence of atrial fibrillation.10 11 12 13 Other factors that have been reported to predispose to thromboembolism in mitral stenosis include patient age of >40 years,2 3 4 7 increasing severity of the valvular stenosis,7 left atrial dilatation,7 increasing hematocrit,12 and reduced cardiac output.3 9
The presence of left atrial thrombus in mitral stenosis is accompanied by increased systemic levels of peptide byproducts of the coagulation cascade, including prothrombin fragment 1+2 (F1+2), fibrinopeptide A, and thrombin/antithrombin III.14 15 In other conditions prone to thrombosis, increases in such markers of coagulation activity may also occur in the absence of thrombus, implying that an imbalance in hemostatic regulation favoring procoagulant mechanisms may precede and perhaps predispose to thrombus formation.16 17 Thus, information about coagulation activity in patients with mitral stenosis could provide a method of identifying patients at risk of developing left atrial thrombus. However, the question of whether systemic coagulation activity is altered in mitral stenosis in the absence of left atrial thrombus is unresolved in the literature, with reports of both normal14 and increased15 18 19 peripheral venous levels of fibrinopeptide A and thrombin/antithrombin III.
More recently, the observation that left atrial levels of fibrinopeptide A and thrombin/antithrombin III exceeded those in the right atrium in patients with mitral stenosis has given rise to the suggestion that coagulation activity is regionally increased within the left atrium in this condition.20 However, while providing additional information about the possible pathophysiology of left atrial thrombus, the foregoing study20 also left a number of important questions unanswered. First, because patients were anticoagulated with warfarin, a drug known to suppress coagulation activity,21 22 it is unclear to what extent left atrial coagulation activity is altered in the presence of normal blood clotting times. Second, as only 12 patients were studied, no meaningful conclusions could be drawn about either the prevalence of increased left atrial coagulation activity in mitral stenosis or its relation to factors known to predispose to left atrial thrombus formation.1 2 3 4 5 6 7 8 9 10 11 12 13 Third, as 11 of the 12 patients were in atrial fibrillation, which may itself be associated with coagulation abnormalities,23 it is unknown to what extent increased regional left atrial coagulation activity occurs in patients with mitral stenosis who have sinus rhythm. Finally, because the peripheral venous thrombin/antithrombin III level was similar to that of control patients but the fibrinopeptide A level was higher, it is not clear whether increased regional left atrial coagulation activity in mitral stenosis is accompanied by normal or elevated systemic coagulation activity.
Accordingly, the aim of the present study was to assess regional left atrial and systemic coagulation activities in patients with mitral stenosis, normal blood clotting times, and no left atrial thrombus. Studies were performed while patients were undergoing percutaneous balloon mitral valvuloplasty. Coagulation activity was quantified by measuring left atrial and peripheral venous plasma levels of F1+2, a peptide that is a direct byproduct of the conversion of prothrombin to thrombin, the pivotal event in the initiation of the coagulation cascade.16 17 Left atrial coagulation activity was then analyzed in relation to hemodynamic, echocardiographic, and hematologic findings through univariate and multivariate approaches.
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Methods |
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Between April 1992 and May 1995, a total of 62 patients with symptomatic mitral stenosis (New York Heart Association functional class II or III) underwent percutaneous balloon mitral valvuloplasty at our institution. Ten patients were excluded from this study because of pregnancy (n=3), coexistent left ventricular dysfunction (n=2), or thrombus in the left atrial appendage as detected with transesophageal echocardiography (TEE) (n=5). An additional 20 patients were excluded because of a prolonged activated partial thromboplastin time or international normalized ratio (n=18), failed transseptal puncture (n=1), or a markedly elevated D-dimer level at the time of the valvuloplasty procedure (n=1). The study group thus consisted of 32 patients with mitral stenosis, in whom both peripheral venous and left atrial coagulation activities were assessed. Peripheral venous coagulation activity was also evaluated in 30 control patients. The study was conducted in accordance with guidelines established by the National Health and Medical Research Council of Australia and approved by the Monash Medical Centre Human Research and Ethics Committee. Written informed consent was obtained from all subjects before blood sampling.
Control Patients
The group of control patients included 19 women and 11 men aged 43±9 years (mean±SD; range, 32 to 65 years) who were normal volunteers (n=14) or were undergoing electrophysiological studies for investigation of supraventricular arrhythmias (n=9) or coronary angiography for investigation of suspected coronary artery disease (n=7). The normal volunteers and patients undergoing electrophysiological studies had no history or examination findings suggestive of structural heart disease. Patients undergoing coronary angiography had a normal coronary angiogram and no significant valvular heart disease or left ventricular dysfunction. All control patients were in sinus rhythm, and none had a history of renal or liver disease, malignancy, deep venous thrombosis, or pulmonary embolism.
Patients With Mitral Stenosis
The patients with mitral stenosis included 4 men and 28 women aged 49±12 years (range, 31 to 74 years), which was not significantly different from the control group. No patient had a history of renal or liver disease, malignancy, rheumatoid arthritis, deep venous thrombosis, or pulmonary embolism. Two patients had a history of a single episode of systemic embolism, occurring more than 3 months before mitral valvuloplasty. No source of embolization was identified in these patients during subsequent investigation, which included transesophageal echocardiography (TEE). Two patients were receiving long-term treatment with aspirin, which was discontinued 4 days before the valvuloplasty procedure. Fifteen patients were anticoagulated with warfarin because of a previous embolic episode, the presence of atrial fibrillation, or the existence of other recognized thromboembolic risk factors. In these patients, warfarin was withdrawn on admission to hospital, 4 days before the valvuloplasty procedure, and an intravenous infusion of sodium heparin was begun at a dose that maintained the activated partial thromboplastin time at two to three times the upper limit of the normal range. The sodium heparin infusion was stopped 
4 hours before mitral valvuloplasty, and the activated partial thromboplastin and prothrombin times were confirmed to be within the normal range at the beginning of the valvuloplasty procedure.
Echocardiography
In patients with mitral stenosis, transthoracic echocardiography was performed on the day before the valvuloplasty procedure with a 2.5-MHz transducer and a Hewlett Packard phased-array Sonos 1000 system to assess left atrial diameter, mitral valve area, and the transmitral pressure gradient. The left atrial anteroposterior diameter was determined with standard M-mode criteria,24 and mitral valve area was calculated according to the pressure half-time method.25
TEE was performed before the valvuloplasty procedure in all patients to exclude the presence of left atrial thrombus and to assess the presence and degree of LASEC. Patients were sedated with midazolam (2 to 5 mg IV) and fentanyl (25 to 50 µg IV), and a Hewlett Packard biplane (n=14), an Omniplane (n=16), or an Acuson 128 biplane transducer (n=2) was passed into the esophagus after application of lidocaine spray to the back of the pharynx. Adequate views of the left atrial cavity and appendage were obtained in all patients. Left atrial thrombus was excluded by the absence of a clearly defined intracavity mass that was acoustically distinct from the underlying endocardium.26 LASEC was diagnosed on the basis of dynamic smokelike echoes within the left atrial cavity or appendage (Fig 1
), with a characteristic swirling motion distinct from white noise artefact.27 LASEC was graded as mild if discrete or only seen at high gain or marked if visible throughout the entire left atrium at normal gain control of the equipment.27 Two experienced echocardiographers evaluated the presence and degree of LASEC independently and without reference to blood test results. Interobserver differences regarding the presence or absence of LASEC occurred in four patients and were resolved by consensus.
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The TEE/valvuloplasty interval was >24 hours (n=10), 1 day to 2 months (n=12), or 2 to 6 months (n=10). This extended TEE/valvuloplasty interval had two potential drawbacks for our study. Most importantly, patients could have developed a left atrial thrombus in the interval between the TEE and valvuloplasty procedures. Therefore, to ensure that no patient in the study group had a left atrial thrombus at the time of assessment of coagulation activity, peripheral venous and left atrial levels of D-dimer, a peptide released during fibrinolysis,28 were measured in all patients during the valvuloplasty procedure. Patients were excluded from the study if the plasma D-dimer level exceeded 200 ng/mL, a value that is highly suggestive of left atrial thrombus in patients with mitral stenosis.14 Another potential drawback of an extended TEE/valvuloplasty interval was that the severity of LASEC could have changed between the TEE and valvuloplasty procedures. To examine this possibility, two experienced echocardiographers independently and in a blinded fashion compared the grading of LASEC in 18 of the original 62 patients with mitral stenosis who had either mild (n=5) or marked (n=13) LASEC during an initial TEE study and who underwent repeat TEE at intervals ranging from 39 to 685 days (median, 86 days). No change was seen in the grading of LASEC in any patient, indicating that LASEC was a stable phenomenon within the TEE/valvuloplasty interval encompassed by our study.
Valvuloplasty Procedure
Patients were sedated with 10 mg of oral diazepam 1 hour before transfer to the catheterization laboratory, supplemented as required with bolus doses of diazepam (2.5 mg IV) during the valvuloplasty procedure. In the catheterization laboratory, introducer sheaths were inserted into the left subclavian and left femoral veins and left femoral artery. A 7.5F heparin-coated Swan-Ganz thermodilution catheter (Baxter Healthcare Corp) was inserted via a subclavian approach to measure right heart pressures and cardiac output. A 6F polymer pigtail catheter (C.R. Bard Inc) was inserted into the left ventricle for pressure measurement and ventriculography. The left ventricular/pulmonary wedge pressure gradient was measured and the mitral valve area was calculated according to the formula of Gorlin and Gorlin.29 Left ventriculography was performed in a right anterior oblique projection with the use of nonionic contrast (Iopamiro 370, Schering AG), and the severity of any observed mitral regurgitation was graded on a scale of 1 to 4 according to standard criteria.30 After atrial transseptal puncture with a Brockenborough needle, an 8F transseptal catheter was advanced into the left atrium, and the mitral valve was subsequently dilated with an Inoue balloon catheter (Toray Medical Industries).31 No thromboembolic event occurred in any patient during or after the mitral valvuloplasty procedure.
Blood Sampling
Four milliliters of blood were collected in a sterile syringe and immediately transferred to an evacuated 5 mL polyethylene terephthalate tube containing 3.13% sodium citrate (Vacuette, Greiner).
Blood samples from patients with mitral stenosis were collected through introducer sheaths or central catheters at two time points during the valvuloplasty procedure, after at least twice the dead space volume was withdrawn. Baseline peripheral venous blood samples were collected for F1+2 assay in 27 patients from the femoral venous introducer sheath soon after its insertion and before heparin administration. Baseline blood samples were also taken from the pulmonary artery via the distal lumen of the Swan-Ganz catheter in a subgroup of 13 patients to compare peripheral and central venous F1+2 levels. After baseline sample collection, a bolus dose of 2500 U heparin was administered intravenously. Immediately after transseptal puncture, prevalvuloplasty samples were withdrawn from all 32 patients through the transseptal catheter positioned in the body of the left atrium and through the femoral venous sheath for measurement of F1+2 and D-dimer levels.
In control patients, peripheral venous samples were collected through needle puncture (n=17) or via introducer sheath (n=13) for assay of F1+2 levels, after the initial 3 mL of blood was discarded. In the patients undergoing coronary angiography, blood samples were collected before heparin administration. To validate comparison of needle puncture and introducer sheath F1+2 levels, femoral venous samples were collected in rapid sequence via needle puncture and introducer sheath; no difference was revealed between these two methods in control patients (1.19±0.46 versus 1.08±0.48 nmol/L, n=13) or patients with mitral stenosis (0.75±0.43 versus 0.77±0.37 nmol/L, n=23).
Assay Procedure
Blood samples were centrifuged within 2 hours of collection at 2500g and 15°C for 10 minutes to obtain platelet-poor plasma, which was then separated and stored at -20°C before assay of F1+2 and D-dimer levels. All plasma samples were assigned a numeric code and assayed without knowledge of the site of origin or time of collection of the sample or of the patient echocardiographic data. Plasma samples from each patient were measured within the same F1+2 or D-dimer assay run. The plasma F1+2 concentration was measured with the use of a highly specific enzyme immunoassay (Enzygnost F1+2, Behringwerke AG) that detects a 14–amino acid sequence located within the carboxy-terminal portion of the F1+2 moiety.21 The plasma D-dimer concentration was measured with an enzyme immunoassay (Dimertest EIA, Agen Biomedical Ltd).28
Data Analysis
Results are expressed as mean±SD and were analyzed with standard statistical tests32 and a commercial statistical package (SigmaStat, Jandel Scientific). Data obtained from different sites at the same time point in patients with mitral stenosis were compared with the use of a two-tailed paired t test if normally distributed or the Wilcoxon signed rank test if not normally distributed. Data from similar sites in different patient groups were compared with the use of unpaired t tests if normally distributed or the Mann-Whitney test if not normally distributed. The determinants of left atrial coagulation activity were evaluated with the use of univariate and stepwise multivariate logistic regression analysis.33 The independent variables evaluated were age, atrial fibrillation, LASEC, hematocrit, cardiac index, left atrial diameter, and mitral valve area, and hypotheses were tested with the log-likelihood ratio statistic, which has a 
2 distribution. A value of P
.05 was considered significant in all statistical analyses.
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Peripheral Venous F1+2 Levels
The baseline peripheral venous F1+2 level in patients with mitral stenosis (1.00±0.81 nmol/L, n=27) was not significantly different from that in control patients (1.13±0.42 nmol/L, n=30) or the corresponding prevalvuloplasty peripheral venous F1+2 level (0.95±0.33 nmol/L). Furthermore, the baseline F1+2 level was similar in paired peripheral venous and pulmonary arterial samples (0.89±0.39 versus 0.95±0.48 nmol/L, n=13).
Left Atrial F1+2 Levels
Analysis of prevalvuloplasty data in the 32 patients with mitral stenosis revealed that the F1+2 level in the left atrium was higher than that in the peripheral vein (P<.0001; Fig 2). However, as visual inspection of individual data points indicated that the left atrial F1+2 level did not exceed the peripheral venous level in all patients, subgroup analysis was used to evaluate possible factors influencing the level of left atrial coagulation activity.
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Relation to Cardiac Rhythm and LASEC
To examine the relation among left atrial coagulation activity, cardiac rhythm, and LASEC, patients with mitral stenosis were divided into three subgroups: those with sinus rhythm without LASEC (n=7), those with sinus rhythm and LASEC (n=16), and those with atrial fibrillation and LASEC (n=9). There were no patients with atrial fibrillation who did not have LASEC. Patient characteristics were similar in sinus rhythm regardless of the absence or presence of LASEC. In particular, peripheral venous and left atrial D-dimer levels were neither elevated nor significantly different in any subgroup, and the time interval between collection of baseline and prevalvuloplasty blood samples was similar. However, patients with atrial fibrillation with LASEC were older (P<.05) and had a lower left atrial pressure (P<.05) and cardiac index (P<.05) than did patients with sinus rhythm (Table 1).
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The peripheral venous F1+2 level was not significantly different in patients with sinus rhythm without LASEC, sinus rhythm with LASEC, and atrial fibrillation with LASEC. Moreover, in patients with sinus rhythm and no LASEC, the left atrial and peripheral venous F1+2 levels were identical (Fig 3A). In contrast, the left atrial F1+2 level was greater than the peripheral venous level in patients with sinus rhythm and LASEC (1.57±0.86 versus 0.99±0.38 nmol/L, P<.0001; Fig 3B) and atrial fibrillation with LASEC (1.52±0.69 versus 0.85±0.33 nmol/L, P<.003; Fig 3C). Two additional observations suggested that an increased left atrial F1+2 level was related to the presence of LASEC rather than to the nature of the cardiac rhythm. First, no difference was evident in the left atrial F1+2 level between sinus rhythm with LASEC and atrial fibrillation with LASEC (P=.88). Second, although the left atrial F1+2 level did not differ significantly in patients with sinus rhythm or atrial fibrillation (P=.51), the pooled left atrial F1+2 level in patients with LASEC (1.55±0.78 nmol/L) exceeded that in patients without LASEC (0.81±0.32 nmol/L, P<.03).
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Effect of LASEC Grade
LASEC was mild in 11 and marked in 14 patients. Atrial fibrillation was more common in the presence of marked LASEC (91% versus 38%, P<.03), but echocardiographic and hemodynamic characteristics were otherwise similar in the two subgroups. The left atrial F1+2 level exceeded the peripheral venous level in both patients with mild (P<.0005; Fig 4A) and patients with marked (P<.008; Fig 4B) LASEC. However, although the mean values were similar, the left atrial F1+2 level was more variable in patients with marked LASEC (P<.002, Levene's test for homogeneity of variance).
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Effect of Prior Warfarinization
In the presence of LASEC, the left atrial F1+2 level was greater than the peripheral venous level regardless of whether patients had been (1.55±0.93 versus 0.84±0.31 nmol/L, n=15, P<.0002) or had not been (1.51±0.49 versus 1.07±0.39 nmol/L, n=10, P<.008) anticoagulated with warfarin before the valvuloplasty procedure. Moreover, neither peripheral venous nor left atrial F1+2 levels differed significantly between patients with and without prior warfarin treatment.
Effect of TEE/Valvuloplasty Interval
In the 25 patients with LASEC, left atrial F1+2 levels exceeded peripheral venous levels in patients with a TEE/valvuloplasty interval of 24 hours (1.58±0.46 versus 0.98±0.37 nmol/L, n=10, P<.002), 1 day to 2 months (1.33±0.67 versus 0.74±0.24 nmol/L, n=8, P<.02), and 2 months to 6 months (1.70±1.2 versus 1.07±0.39 nmol/L, n=7, P<.05).
Determinants of Increased Left Atrial Coagulation Activity
The 32 patients with mitral stenosis were divided into those with normal and those with increased regional left atrial coagulation activity with the use of a regression equation that represented the normal variability associated with measurement of paired peripheral venous F1+2 levels in our laboratory (Fig 5A). Thus, normal left atrial coagulation activity was defined as a left atrial F1+2 level less than and increased left atrial coagulation activity was defined as a left atrial F1+2 level more than the upper 95% prediction interval of this regression equation. Based on this definition, increased regional left atrial coagulation activity was present in 15 patients (Fig 5B), which constituted 60% of patients with mitral stenosis and LASEC. Apart from a higher incidence of LASEC in the presence of increased left atrial coagulation activity (P<.02), hemodynamic, echocardiographic, and hematologic characteristics and, in particular, the peripheral venous F1+2 levels were similar in patients with normal or increased left atrial coagulation activity (Table 2).
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Based on univariate logistic regression, atrial fibrillation (2=4.98, P=.03) and LASEC (2=10.58, P=.002) emerged as significant predictors of increased regional left atrial coagulation activity, whereas age, hematocrit, cardiac index, left atrial diameter, and mitral valve area did not (P=.14 to .76). However, based on multivariate logistic regression, the effect of atrial fibrillation conditional on the other variables was no longer significant, but the effect of LASEC conditional on other variables remained significant (Table 3), indicating that LASEC was the only independent predictor of increased regional left atrial coagulation activity in our study group.
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Discussion |
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The present study, in which we examined left atrial coagulation activity in patients with mitral stenosis by measuring plasma levels of F1+2 in left atrial and peripheral venous blood samples, produced four main findings. First, regional left atrial coagulation activity is increased in the presence of LASEC. Second, increased regional left atrial coagulation activity is evident in both sinus rhythm and atrial fibrillation. Third, of the hemodynamic, echocardiographic, and hematologic factors implicated in the formation of left atrial thrombus, only LASEC emerges as an independent predictor of increased regional left atrial coagulation activity on multivariate logistic regression analysis. Finally, increased regional left atrial coagulation activity is not reflected in peripheral venous blood samples.
In our experimental design, we sought to minimize the influence of factors that might confound the assessment of coagulation activity in patients with mitral stenosis. Thus, patients with left atrial thrombus, which is associated with increased circulating levels of peptide byproducts of the coagulation cascade,14 15 were excluded with a combined echocardiographic and hematologic approach. In the first instance, left atrial thrombus was identified during prevalvuloplasty investigations with TEE, a technique that has a high specificity and sensitivity for detection of left atrial thrombus.34 35 36 Subsequently, left atrial and peripheral venous D-dimer levels were measured during the valvuloplasty procedure, and only patients with a D-dimer level within normal limits were included in the study. In addition, warfarin, which is known to depress circulating levels of coagulation markers21 22 37 and to therefore interfere with the assessment of coagulation activity, was withdrawn 4 days before valvuloplasty, and only patients with a normal international normalized ratio at the time of valvuloplasty were included in the study group. Finally, coagulation activity was assessed with F1+2, a peptide that is less prone to artefactual elevations during blood sampling than are other commonly used coagulation markers, such as fibrinopeptide A38 39 or the thrombin/antithrombin III complex.40
The increased left atrial F1+2 level observed within the mitral stenosis group as a whole (Fig 2
) was not related to the valvuloplasty procedure or the effects of preceding anticoagulation. Thus, activation of coagulation arising from the presence of indwelling catheters38 was unlikely, not only because F1+2 levels are not elevated by long-term catheter placement40 but also because no difference in peripheral venous F1+2 levels was found in our study between the baseline samples obtained immediately after insertion of the femoral venous sheath and prevalvuloplasty samples taken after transseptal puncture 50 to 60 minutes later. The lack of effect of prior anticoagulation on peripheral venous and left atrial F1+2 levels also discounted either any rebound increase or persistent suppression of coagulation activity after cessation of anticoagulation.41 42 Our data were therefore in accordance with the findings of Yamamoto et al,20 who observed that left atrial fibrinopeptide A and thrombin/antithrombin III levels were greater than in the right atrium in patients with mitral stenosis and are therefore consistent with the notion that this condition is associated with an increase in regional left atrial coagulation activity. However, additional subgroup analysis of our data revealed three previously unrecognized features of increased regional left atrial coagulation activity in mitral stenosis: it occurred in patients with LASEC (Fig 3B and 3C) but not in those without LASEC (Fig 3A), it was evident with sinus rhythm or atrial fibrillation (Fig 3B and 3C), and it accompanied both mild and marked LASEC (Fig 4A and 4B).
The finding that LASEC was the only independent predictor of increased left atrial coagulation activity on multivariate logistic regression analysis (Table 3) was not surprising, given that LASEC is an independent risk factor for the development of left atrial thrombus and systemic embolism.10 11 12 13 27 43 44 45 46 However, the underlying basis of this association between LASEC and increased left atrial coagulation activity remains to be determined. As stasis is a well-recognized precipitant of thrombus formation47 and LASEC is a marker of left atrial stasis,48 49 one possibility is that left atrial stasis predisposes to both LASEC and increased regional coagulation activity. However, as in vitro studies suggest that LASEC arises from aggregation of red blood cells in the presence of fibrinogen,48 50 it is possible that the presence of LASEC directly facilitates activation of the coagulation cascade by an as-yet-undefined mechanism.
An important observation that emerged from our study was that increased regional left atrial coagulation activity was not a uniform finding in mitral stenosis but occurred in 
60% of patients with LASEC. This difference in the prevalence of LASEC and increased regional coagulation activity could have been related to three factors. First, the development of LASEC may precede the emergence of increased left atrial coagulation activity. Second, some patients with LASEC may never develop increased regional coagulation activity, a notion consistent with the clinical observation that only a portion of patients with mitral stenosis and LASEC develop thromboembolic complications.1 3 5 7 Last, as LASEC is most prominent in the left atrial appendage,51 increased coagulation activity may be localized to or most pronounced within this region of the left atrium and therefore variably reflected in blood samples obtained from the body of the left atrium.
Although left atrial F1+2 levels were elevated in patients with mitral stenosis and LASEC in our study, our experimental design did not permit identification of the precise site of increased coagulation activation. However, the similarity of baseline peripheral venous and pulmonary arterial F1+2 levels suggests that any increased F1+2 generation occurred within the pulmonary circulation, the left atrium, or a combination of both sites. The predisposition of left atrial stasis to left atrial thrombus formation9 49 is consistent with increased generation of F1+2 within the left atrial cavity itself. Moreover, the association of LASEC with decreased left atrial appendage flow velocities51 and the predilection for thrombus formation within the atrial appendage52 53 point to the latter site being a likely focus of increased F1+2 generation in the left atrium. However, a pulmonary contribution cannot be ruled out, particularly if stasis is indeed a precipitant of increased F1+2 formation, because left atrial stasis may be accompanied by pulmonary venous stasis.10
The occurrence of increased regional left atrial coagulation activity in patients with mitral stenosis and sinus rhythm is consistent with reports that such patients are at increased risk of thromboembolism compared with the normal population.2 6 On the other hand, our observation that the left atrial F1+2 level was similarly elevated in patients with sinus rhythm or atrial fibrillation is at first surprising, given that previous epidemiological studies have suggested that atrial fibrillation confers a greater risk of thromboembolism than sinus rhythm in mitral stenosis.2 4 5 8 However, our study differed from these epidemiological studies,2 4 5 8 not only because our patients constituted a select subgroup with symptomatic, moderate to severe mitral stenosis but also because our study included LASEC as a variable within the logistic regression analysis. Thus, although both atrial fibrillation and LASEC were significantly associated with increased left atrial coagulation activity on univariate logistic regression in our study, LASEC was the only independent predictor of increased left atrial coagulation activity on multivariate logistic regression. This presumably reflects the presence of a collinearity between atrial fibrillation and LASEC, a conclusion indirectly supported by more recent epidemiological data that suggest that LASEC, but not atrial fibrillation, is an independent risk factor for thromboembolism.10 12 13
Peripheral venous F1+2 levels were not elevated in our study, even in the presence of increased left atrial coagulation activity, suggesting that systemic coagulation activity, and, more specifically, thrombin generation, is normal in mitral stenosis uncomplicated by left atrial thrombus. This conclusion contrasts with a number of earlier studies of systemic coagulation activity in mitral stenosis that reported elevated levels of fibrinopeptide A15 19 and thrombin/antithrombin III18 19 in peripheral venous blood. However, left atrial thrombus in these studies was excluded with the use of transthoracic echocardiography, a technique that offers only a limited view of the left atrium and left atrial appendage34 54 and thus identifies only a small proportion of left atrial thrombi detectable with TEE11 34 35 36 54 or directly at surgery.54 It is therefore possible that the elevation of peripheral venous coagulation markers in previous studies15 18 19 was in part related to the presence of unrecognized left atrial thrombus, a notion consistent with the presence of raised D-dimer levels in two of these studies.15 18 Our results also contrast with the more recent report by Yamamoto et al20 that the peripheral venous fibrinopeptide A level in patients with mitral stenosis in whom left atrial thrombus was excluded with TEE was higher than in control patients, even though the thrombin/antithrombin III levels were similar. This apparently conflicting assessment of systemic coagulation activity in mitral stenosis has at least two possible explanations. First, the peptides F1+2, fibrinopeptide A, and thrombin/antithrombin III are formed at different stages of the coagulation cascade16 17 and therefore provide differing information about coagulation activity.22 55 56 57 Second, the left atrial fibrinopeptide A level in patients with mitral stenosis is 18-fold greater than the corresponding peripheral venous level in control patients,20 an increment that far exceeds the sevenfold difference in thrombin/antithrombin III levels20 and the twofold difference in F1+2 levels (present study). The elevated peripheral venous fibrinopeptide A level observed in mitral stenosis in the absence of left atrial thrombus20 may therefore in part reflect incomplete systemic clearance of regional fibrinopeptide A overproduction rather than an increase in systemic coagulation activity per se.
Study Limitations
The main limitation of our study was that TEE was performed at variable intervals before the valvuloplasty procedure. However, three observations suggest that this was unlikely to have substantially affected the major conclusions of our study. First, development of left atrial thrombus in the TEE/valvuloplasty interval was excluded by measurement of D-dimer levels at the time of valvuloplasty. Second, a repeat TEE study performed in a subgroup of patients with mitral stenosis at intervals ranging from 1 month to 2 years indicated that LASEC was a stable phenomenon in the TEE/valvuloplasty interval spanned by our study. Indirect support for the latter conclusion is also provided by the clinical observation of Leung et al46 that the presence of LASEC on TEE examination predicted subsequent embolic events during a mean follow-up period of 18 months. Third, and most important, left atrial F1+2 levels were greater than peripheral venous levels in patients with LASEC regardless of the duration of the TEE/valvuloplasty interval.
A second limitation of our study relates to the finding that suppression of plasma F1+2 levels occurs within 24 hours of starting full-dose intravenous heparin therapy.56 58 Administration of heparin after collection of baseline blood samples in our study could therefore have potentially reduced F1+2 levels in blood samples obtained after transseptal puncture. However, this was unlikely to have been a significant factor in our study, not only because the administered heparin dose was low (2500 U) and given 1 hour before collection of blood samples but also because of the similarity between the F1+2 level in peripheral venous blood samples taken at baseline and those taken after transseptal puncture.
Clinical Implications
Our study has two main clinical implications. First, our results suggest that 60% of patients with moderate to severe mitral stenosis and LASEC have increased regional left atrial coagulation activity. Given that LASEC is an independent predictor of both increased left atrial coagulation activity (Table 3) and thromboembolism,10 12 13 it is likely that this subgroup of patients with mitral stenosis represent those at highest risk of developing left atrial thrombus. Indeed, LASEC and increased left atrial coagulation activity were both present in the two patients of our study group with a past history of systemic embolism. Second, our findings indicate that measurement of F1+2 levels in peripheral venous blood alone is unlikely to aid in the identification of patients with increased regional left atrial coagulation activity.
Conclusions
We evaluated regional left atrial coagulation activity in patients with mitral stenosis, normal blood clotting times, and no left atrial thrombus by measuring plasma F1+2 levels in left atrial and peripheral venous blood samples. Our results suggest that increased regional left atrial coagulation activity occurs in the presence of LASEC and in association with either sinus rhythm or atrial fibrillation. Moreover, LASEC is the only independent predictor of increased regional left atrial coagulation activity evident on multivariate logistic regression analysis of hemodynamic, echocardiographic, and hematologic variables. Finally, increased regional left atrial coagulation activity is not reflected in peripheral venous blood samples. The recognition of the association between LASEC and increased regional left atrial coagulation activity further contributes to understanding of the pathophysiology of left atrial thrombus in mitral stenosis.
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Acknowledgments |
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R.E. Peverill was supported by a Postgraduate Medical Research Scholarship from the National Heart Foundation of Australia. We thank Joan Mitvalsky for performing the transthoracic echocardiographic studies and Agen Biomedical Ltd for supplying the D-dimer assay kits.
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Footnotes |
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Presented in part at the 41st Annual Scientific Meeting of the Cardiac Society of Australia and New Zealand, August 1993, Christchurch, New Zealand, and at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994.
Received October 18, 1995; revision received January 30, 1996; accepted February 1, 1996.
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