Correlation between quantitative left atrial spontaneous echocardiographic contrast and intact fibrinogen levels in mitral stenosis

Abstract

To the Editor:The aim of a recently published study by Wang et al (J Am Soc Echocardiogr 2001;14:285-91) was to evaluate the relation between left atrial spontaneous echo contrast (LASEC) and coagulation activity. The conclusions of this study were that LASEC severity was positively correlated with levels of intact fibrinogen, but that there was no relationship between LASEC severity and left atrial markers of thrombin generation and activity. Although the importance of defining the relationship between LASEC and coagulation activity is not in question, we have significant concerns about 3 areas in the study.First, the relation between coagulation activity and LASEC in mitral stenosis has been addressed in a number of previously published studies that were not cited by Wang et al. In 1996, we measured left atrial and peripheral venous levels of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation, in 32 patients with mitral stenosis.1Peverill RE Harper RW Gelman J Gan TE Harris G Smolich JJ Determinants of increased regional left atrial coagulation activity in patients with mitral stenosis.Circulation. 1996; 94: 331-339Crossref PubMed Scopus (65) Google Scholar The left atrial level of F1+2 exceeded the peripheral venous level, suggesting that there was an increase in thrombin generation in the left atrium. However, although this increase was evident in patients with LASEC and either sinus rhythm or atrial fibrillation, it was not evident in patients without LASEC. Furthermore, the only independent predictor of the presence of increased left atrial thrombin generation was the presence of LASEC.1Peverill RE Harper RW Gelman J Gan TE Harris G Smolich JJ Determinants of increased regional left atrial coagulation activity in patients with mitral stenosis.Circulation. 1996; 94: 331-339Crossref PubMed Scopus (65) Google Scholar Subsequently, Zaki et al2Zaki A Salama M El Masry M Abou-Freikha M Abou-Ammo D Sweelum M et al.Immediate effect of balloon valvuloplasty on hemostatic changes in mitral stenosis.Am J Cardiol. 2000; 85: 370-375Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar measured right and left atrial levels of thrombin antithrombin complex (TAT), also a marker of thrombin generation, and reported not only that the left atrial level exceeded the right atrial level, but that the only significant predictor of an increased left atrial TAT level was LASEC. Two other studies in mitral stenosis have also reported that LASEC is a predictor of increases in systemic levels of markers of thrombin generation.3Buyukasik Y Ileri M Ozcebe OI Haznedaroglu IC Yetkin E Kirazli S et al.Increased systemic coagulation activity in patients with rheumatic mitral stenosis: assessment of the clinical and echocardiographic determinants.Blood Coagul Fibrinolysis. 1999; 10: 417-421Crossref PubMed Scopus (4) Google Scholar, 4Ileri M Buyukasik Y Ileri NS Haznedaroglu lC Goksel S Kirazli S et al.Activation of blood coagulation in patients with mitral stenosis and sinus rhythm.Am J Cardiol. 1998; 81: 795-797Abstract Full Text Full Text PDF PubMed Scopus (31) Google ScholarSecond, there are numerous inconsistencies in the coagulation marker data of Wang et al that have not been discussed. Thus, D-dimer levels were significantly elevated in some patients but undetectable in others. There was also a lack of any relation between right atrial and left atrial levels of D-dimer within patients, even though previous studies have found D-dimer levels to be similar in the left atrium, right atrium, and peripheral vein in mitral stenosis.1Peverill RE Harper RW Gelman J Gan TE Harris G Smolich JJ Determinants of increased regional left atrial coagulation activity in patients with mitral stenosis.Circulation. 1996; 94: 331-339Crossref PubMed Scopus (65) Google Scholar, 5Yamamoto K Ikeda U Seino Y Mito H Fujikawa H Sekiguchi H et al.Coagulation activity is increased in the left atrium of patients with mitral stenosis.J Am Coll Cardiol. 1995; 25: 107-112Abstract Full Text PDF PubMed Scopus (94) Google Scholar In addition, although right atrial levels of TAT were undetectable in more than half the patients, previous studies have shown that systemic levels of TAT are elevated in mitral stenosis.2Zaki A Salama M El Masry M Abou-Freikha M Abou-Ammo D Sweelum M et al.Immediate effect of balloon valvuloplasty on hemostatic changes in mitral stenosis.Am J Cardiol. 2000; 85: 370-375Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 3Buyukasik Y Ileri M Ozcebe OI Haznedaroglu IC Yetkin E Kirazli S et al.Increased systemic coagulation activity in patients with rheumatic mitral stenosis: assessment of the clinical and echocardiographic determinants.Blood Coagul Fibrinolysis. 1999; 10: 417-421Crossref PubMed Scopus (4) Google Scholar, 4Ileri M Buyukasik Y Ileri NS Haznedaroglu lC Goksel S Kirazli S et al.Activation of blood coagulation in patients with mitral stenosis and sinus rhythm.Am J Cardiol. 1998; 81: 795-797Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Finally, the finding that TAT levels were higher in the left than right atrium but that F1+2 levels were similar in the 2 atria is not in accord with the notion that both markers are measures of thrombin generation, or the observation that left atrial levels of both markers were elevated in a previous study in mitral stenosis.6Yamamoto K Ikeda U Minezaki KK Fukazawa H Mizuno O Kim S et al.Effect of mitral valvuloplasty in mitral stenosis on coagulation activity.Am J Cardiol. 1997; 79: 1131-1135Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar An explanation of all these inconsistencies is not readily apparent, but their presence clearly raises concerns about the quality of the coagulation data presented in the study of Wang et al.Lastly, only 11 subjects were included in the study of Wang et al and only 2 of these did not have LASEC. Because of the small patient numbers, the lack of relation between LASEC and coagulation activity in this study could thus easily have been a false-negative result. To the Editor:The aim of a recently published study by Wang et al (J Am Soc Echocardiogr 2001;14:285-91) was to evaluate the relation between left atrial spontaneous echo contrast (LASEC) and coagulation activity. The conclusions of this study were that LASEC severity was positively correlated with levels of intact fibrinogen, but that there was no relationship between LASEC severity and left atrial markers of thrombin generation and activity. Although the importance of defining the relationship between LASEC and coagulation activity is not in question, we have significant concerns about 3 areas in the study.First, the relation between coagulation activity and LASEC in mitral stenosis has been addressed in a number of previously published studies that were not cited by Wang et al. In 1996, we measured left atrial and peripheral venous levels of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation, in 32 patients with mitral stenosis.1Peverill RE Harper RW Gelman J Gan TE Harris G Smolich JJ Determinants of increased regional left atrial coagulation activity in patients with mitral stenosis.Circulation. 1996; 94: 331-339Crossref PubMed Scopus (65) Google Scholar The left atrial level of F1+2 exceeded the peripheral venous level, suggesting that there was an increase in thrombin generation in the left atrium. However, although this increase was evident in patients with LASEC and either sinus rhythm or atrial fibrillation, it was not evident in patients without LASEC. Furthermore, the only independent predictor of the presence of increased left atrial thrombin generation was the presence of LASEC.1Peverill RE Harper RW Gelman J Gan TE Harris G Smolich JJ Determinants of increased regional left atrial coagulation activity in patients with mitral stenosis.Circulation. 1996; 94: 331-339Crossref PubMed Scopus (65) Google Scholar Subsequently, Zaki et al2Zaki A Salama M El Masry M Abou-Freikha M Abou-Ammo D Sweelum M et al.Immediate effect of balloon valvuloplasty on hemostatic changes in mitral stenosis.Am J Cardiol. 2000; 85: 370-375Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar measured right and left atrial levels of thrombin antithrombin complex (TAT), also a marker of thrombin generation, and reported not only that the left atrial level exceeded the right atrial level, but that the only significant predictor of an increased left atrial TAT level was LASEC. Two other studies in mitral stenosis have also reported that LASEC is a predictor of increases in systemic levels of markers of thrombin generation.3Buyukasik Y Ileri M Ozcebe OI Haznedaroglu IC Yetkin E Kirazli S et al.Increased systemic coagulation activity in patients with rheumatic mitral stenosis: assessment of the clinical and echocardiographic determinants.Blood Coagul Fibrinolysis. 1999; 10: 417-421Crossref PubMed Scopus (4) Google Scholar, 4Ileri M Buyukasik Y Ileri NS Haznedaroglu lC Goksel S Kirazli S et al.Activation of blood coagulation in patients with mitral stenosis and sinus rhythm.Am J Cardiol. 1998; 81: 795-797Abstract Full Text Full Text PDF PubMed Scopus (31) Google ScholarSecond, there are numerous inconsistencies in the coagulation marker data of Wang et al that have not been discussed. Thus, D-dimer levels were significantly elevated in some patients but undetectable in others. There was also a lack of any relation between right atrial and left atrial levels of D-dimer within patients, even though previous studies have found D-dimer levels to be similar in the left atrium, right atrium, and peripheral vein in mitral stenosis.1Peverill RE Harper RW Gelman J Gan TE Harris G Smolich JJ Determinants of increased regional left atrial coagulation activity in patients with mitral stenosis.Circulation. 1996; 94: 331-339Crossref PubMed Scopus (65) Google Scholar, 5Yamamoto K Ikeda U Seino Y Mito H Fujikawa H Sekiguchi H et al.Coagulation activity is increased in the left atrium of patients with mitral stenosis.J Am Coll Cardiol. 1995; 25: 107-112Abstract Full Text PDF PubMed Scopus (94) Google Scholar In addition, although right atrial levels of TAT were undetectable in more than half the patients, previous studies have shown that systemic levels of TAT are elevated in mitral stenosis.2Zaki A Salama M El Masry M Abou-Freikha M Abou-Ammo D Sweelum M et al.Immediate effect of balloon valvuloplasty on hemostatic changes in mitral stenosis.Am J Cardiol. 2000; 85: 370-375Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 3Buyukasik Y Ileri M Ozcebe OI Haznedaroglu IC Yetkin E Kirazli S et al.Increased systemic coagulation activity in patients with rheumatic mitral stenosis: assessment of the clinical and echocardiographic determinants.Blood Coagul Fibrinolysis. 1999; 10: 417-421Crossref PubMed Scopus (4) Google Scholar, 4Ileri M Buyukasik Y Ileri NS Haznedaroglu lC Goksel S Kirazli S et al.Activation of blood coagulation in patients with mitral stenosis and sinus rhythm.Am J Cardiol. 1998; 81: 795-797Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Finally, the finding that TAT levels were higher in the left than right atrium but that F1+2 levels were similar in the 2 atria is not in accord with the notion that both markers are measures of thrombin generation, or the observation that left atrial levels of both markers were elevated in a previous study in mitral stenosis.6Yamamoto K Ikeda U Minezaki KK Fukazawa H Mizuno O Kim S et al.Effect of mitral valvuloplasty in mitral stenosis on coagulation activity.Am J Cardiol. 1997; 79: 1131-1135Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar An explanation of all these inconsistencies is not readily apparent, but their presence clearly raises concerns about the quality of the coagulation data presented in the study of Wang et al.Lastly, only 11 subjects were included in the study of Wang et al and only 2 of these did not have LASEC. Because of the small patient numbers, the lack of relation between LASEC and coagulation activity in this study could thus easily have been a false-negative result. The aim of a recently published study by Wang et al (J Am Soc Echocardiogr 2001;14:285-91) was to evaluate the relation between left atrial spontaneous echo contrast (LASEC) and coagulation activity. The conclusions of this study were that LASEC severity was positively correlated with levels of intact fibrinogen, but that there was no relationship between LASEC severity and left atrial markers of thrombin generation and activity. Although the importance of defining the relationship between LASEC and coagulation activity is not in question, we have significant concerns about 3 areas in the study. First, the relation between coagulation activity and LASEC in mitral stenosis has been addressed in a number of previously published studies that were not cited by Wang et al. In 1996, we measured left atrial and peripheral venous levels of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation, in 32 patients with mitral stenosis.1Peverill RE Harper RW Gelman J Gan TE Harris G Smolich JJ Determinants of increased regional left atrial coagulation activity in patients with mitral stenosis.Circulation. 1996; 94: 331-339Crossref PubMed Scopus (65) Google Scholar The left atrial level of F1+2 exceeded the peripheral venous level, suggesting that there was an increase in thrombin generation in the left atrium. However, although this increase was evident in patients with LASEC and either sinus rhythm or atrial fibrillation, it was not evident in patients without LASEC. Furthermore, the only independent predictor of the presence of increased left atrial thrombin generation was the presence of LASEC.1Peverill RE Harper RW Gelman J Gan TE Harris G Smolich JJ Determinants of increased regional left atrial coagulation activity in patients with mitral stenosis.Circulation. 1996; 94: 331-339Crossref PubMed Scopus (65) Google Scholar Subsequently, Zaki et al2Zaki A Salama M El Masry M Abou-Freikha M Abou-Ammo D Sweelum M et al.Immediate effect of balloon valvuloplasty on hemostatic changes in mitral stenosis.Am J Cardiol. 2000; 85: 370-375Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar measured right and left atrial levels of thrombin antithrombin complex (TAT), also a marker of thrombin generation, and reported not only that the left atrial level exceeded the right atrial level, but that the only significant predictor of an increased left atrial TAT level was LASEC. Two other studies in mitral stenosis have also reported that LASEC is a predictor of increases in systemic levels of markers of thrombin generation.3Buyukasik Y Ileri M Ozcebe OI Haznedaroglu IC Yetkin E Kirazli S et al.Increased systemic coagulation activity in patients with rheumatic mitral stenosis: assessment of the clinical and echocardiographic determinants.Blood Coagul Fibrinolysis. 1999; 10: 417-421Crossref PubMed Scopus (4) Google Scholar, 4Ileri M Buyukasik Y Ileri NS Haznedaroglu lC Goksel S Kirazli S et al.Activation of blood coagulation in patients with mitral stenosis and sinus rhythm.Am J Cardiol. 1998; 81: 795-797Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Second, there are numerous inconsistencies in the coagulation marker data of Wang et al that have not been discussed. Thus, D-dimer levels were significantly elevated in some patients but undetectable in others. There was also a lack of any relation between right atrial and left atrial levels of D-dimer within patients, even though previous studies have found D-dimer levels to be similar in the left atrium, right atrium, and peripheral vein in mitral stenosis.1Peverill RE Harper RW Gelman J Gan TE Harris G Smolich JJ Determinants of increased regional left atrial coagulation activity in patients with mitral stenosis.Circulation. 1996; 94: 331-339Crossref PubMed Scopus (65) Google Scholar, 5Yamamoto K Ikeda U Seino Y Mito H Fujikawa H Sekiguchi H et al.Coagulation activity is increased in the left atrium of patients with mitral stenosis.J Am Coll Cardiol. 1995; 25: 107-112Abstract Full Text PDF PubMed Scopus (94) Google Scholar In addition, although right atrial levels of TAT were undetectable in more than half the patients, previous studies have shown that systemic levels of TAT are elevated in mitral stenosis.2Zaki A Salama M El Masry M Abou-Freikha M Abou-Ammo D Sweelum M et al.Immediate effect of balloon valvuloplasty on hemostatic changes in mitral stenosis.Am J Cardiol. 2000; 85: 370-375Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 3Buyukasik Y Ileri M Ozcebe OI Haznedaroglu IC Yetkin E Kirazli S et al.Increased systemic coagulation activity in patients with rheumatic mitral stenosis: assessment of the clinical and echocardiographic determinants.Blood Coagul Fibrinolysis. 1999; 10: 417-421Crossref PubMed Scopus (4) Google Scholar, 4Ileri M Buyukasik Y Ileri NS Haznedaroglu lC Goksel S Kirazli S et al.Activation of blood coagulation in patients with mitral stenosis and sinus rhythm.Am J Cardiol. 1998; 81: 795-797Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Finally, the finding that TAT levels were higher in the left than right atrium but that F1+2 levels were similar in the 2 atria is not in accord with the notion that both markers are measures of thrombin generation, or the observation that left atrial levels of both markers were elevated in a previous study in mitral stenosis.6Yamamoto K Ikeda U Minezaki KK Fukazawa H Mizuno O Kim S et al.Effect of mitral valvuloplasty in mitral stenosis on coagulation activity.Am J Cardiol. 1997; 79: 1131-1135Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar An explanation of all these inconsistencies is not readily apparent, but their presence clearly raises concerns about the quality of the coagulation data presented in the study of Wang et al. Lastly, only 11 subjects were included in the study of Wang et al and only 2 of these did not have LASEC. Because of the small patient numbers, the lack of relation between LASEC and coagulation activity in this study could thus easily have been a false-negative result.