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Communications to the Editor |

Further Insights Into the Prothrombotic State in Mitral Stenosis and Atrial FlutterFurther Insights Into the Prothrombotic State in Mitral Stenosis and Atrial FlutterFurther Insights Into the Prothrombotic State in Mitral Stenosis and Atrial Flutter FREE TO VIEW

Dwayne S. G. Conway, MRCP; Gregory Y. H. Lip, MD
Author and Funding Information

Affiliations: City Hospital, Birmingham, UK,  Chang Gung Memorial Hospital, Taiwan, ROC,  Toyama Medical and Pharmaceutical University Toyama, Japan

Correspondence to: Gregory Y. H. Lip, MD, Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, B18 7QH, UK; e-mail: g.y.h.lip@bham.ac.uk



Chest. 2004;125(6):2361-2363. doi:10.1378/chest.125.6.2361
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To the Editor:

We read with great interest the two articles in the November issue of CHEST examining the prothrombotic state in mitral stenosis1and atrial flutter.2 Chen and colleagues1 described increased expression of membrane-bound P-selectin (mP-sel) on platelets from peripheral blood compared to healthy control subjects and “lone” atrial fibrillation (AF). The authors also found increased mP-sel on platelets from the left atrium compared to peripheral and right atrial levels among cases of mitral stenosis, with left atrial (but not peripheral) mP-sel expression related to severity of mitral stenosis. This study provides evidence of left atrial platelet activation among patients with mitral stenosis; however, peripheral blood samples were obtained from the femoral vein of patients with mitral stenosis and from the antecubital fossa of control subjects, introducing another potential regional difference that has not been accounted for. Furthermore, contrary to the authors’ beliefs that differences in platelet activation between blood from the left and right atria and peripheral blood in mitral stenosis have never been investigated,1 we have previously published data from a much larger cohort of mitral stenosis cases (n = 25) suggesting no differences in plasma levels of platelet indexes soluble P-selectin (sP-sel) or β-thromboglobulin (BTG) in blood samples from these anatomic sites.3Other studies45 of this type exist, and controversy remains regarding the existence of local left atrial platelet activation in mitral stenosis,1,35 especially since the possibility has not been excluded that transseptal puncture itself may activate platelets.

Chen and colleagues1 also used a small sample size (n = 16) that may be prone to statistical error and confounding. The majority (13 of 16 patients) of the cases were in AF, while the lone AF control group was extremely small (n = 8). Furthermore, cases were not well matched for mean age or gender with control subjects or lone AF cases, and no data were presented regarding smoking status, history of ischemic heart disease or peripheral arterial disease, all of which may influence the indexes measured. Indeed, in a large cross-sectional study of patients with nonvalvular AF,6 we found gender, current smoking, and peripheral arterial disease (in addition to prior stroke and diabetes) to be independent predictors of plasma sP-sel levels, and the potential influence of these factors on mP-sel should not have been overlooked by the authors. The comparison between lone AF and healthy control subjects is also not sufficiently powered for the authors to state that no difference in mP-sel expression exists between these groups. However, in view of the influence of other vascular conditions on sP-sel levels in AF,6the absence of a relationship between plasma sP-sel levels and AF in a large community study,7and the lack of a relationship between plasma sP-sel levels and stroke in AF,8 we do share the belief of Chen et al1 that platelet activation may not be a major factor in AF.

Regarding potential mechanisms for left atrial platelet activation in mitral stenosis, we do not share the belief of Chen at al1 that shear stress is a likely factor, as these stresses should be greatest at stenotic (valvar) locations rather than prestenotic (left atrial) sites.9We would propose endocardial changes in mitral stenosis1011 combined with regional blood stasis as an alternative explanation. All cases had evidence of left atrial spontaneous echocontrast suggesting stasis and, although left atrial mP-sel expression was related to mitral valve pressure half-time, there was no relationship to left atrial pressure or transmitral gradient at catheterization, perhaps suggesting a relationship between mP-sel and flow, rather than pressure, per se. Of interest, platelet mP-sel expression may influence the initiation of thrombosis via tissue factor12 from inflammatory cells, but we recently found no evidence of increased left atrial plasma levels of interleukin-6 or tissue factor among 14 patients with AF and mitral stenosis (mean ± SD age, 62 ± 10 years; 3 male patients [21%]) [Table 1] .

In the same issue of CHEST, Sakurai and colleagues2 provided a valuable insight into the prothrombotic state in atrial flutter. Until now, there has been relatively little information regarding the prothrombotic state in this arrhythmia, compared to the wealth of information available for AF.68 However, we do not agree with the conclusion “patients with atrial flutter as a whole are not in the prothrombotic state as compared with those in AF.” Although significantly higher levels of plasma d-dimer and the platelet indexes BTG and platelet factor 4 (PF4) were found in AF but not atrial flutter, when compared to sinus rhythm control subjects, no significant differences in levels of BTG and PF4 were found between AF and atrial flutter. Indeed, the data presented in the tables suggest intermediate levels of BTG, PF4, and d-dimer in atrial flutter. The authors also found higher levels of BTG and d-dimer among “high-risk” (ie, those with evidence of left atrial stasis on transesophageal echocardiography) atrial flutter cases, and suggested that those with low levels of these markers might therefore safely undergo cardioversion without anticoagulation. However, in the absence of prospective data to support this suggestion, we would advise caution, recommending that the use of anticoagulation in atrial flutter should follow current guidelines for AF using risk stratification,13 and transesophageal echocardiography remains necessary if precardioversion anticoagulation is to be avoided.

Table Graphic Jump Location
Table 1. Regional Levels of Plasma Interleukin-6 and Tissue Factor Among 14 Patients With AF and Mitral Stenosis*
* 

All comparisons are p > 0.05 except where indicated. IQR = interquartile range.

 

p = 0.005, compared to peripheral vein.

Chen, MC, Wu, CJ, Yip, HK, et al (2003) Left atrial platelet activity with rheumatic mitral stenosis: correlation study of severity and platelet P-selectin expression by flow cytometry.Chest124,1663-1669. [CrossRef] [PubMed]
 
Sakurai, K, Hirai, T, Nakagawa, K, et al Left atrial appendage function and abnormal hypercoagulability in patients with atrial flutter.Chest2003;124,1670-1674. [CrossRef] [PubMed]
 
Li-Saw-Hee, FL, Blann, AD, Goldsmith, I, et al Indexes of hypercoagulability measured in peripheral blood reflect levels in intracardiac blood in patients with atrial fibrillation secondary to mitral stenosis.Am J Cardiol1999;83,1206-1209. [CrossRef] [PubMed]
 
Yamamoto, K, Ikeda, U, Seino, Y, et al Coagulation activity is increased in the left atrium of patients with mitral stenosis.J Am Coll Cardiol1995;25,107-112. [CrossRef] [PubMed]
 
Wang, J, Xie, X, He, H, et al Hypercoagulability existing in the local left atrium of patient with mitral stenosis.Chin Med J2003;116,1198-1202. [PubMed]
 
Conway, DSG, Pearce, LA, Chin, BSP, et al Plasma von Willebrand factor and soluble P-selectin as indices of endothelial damage and platelet activation in 1321 patients with non-valvular atrial fibrillation: relationship to stroke risk factors.Circulation2002;106,1962-1967. [CrossRef] [PubMed]
 
Conway, DSG, Heeringa, J, Van der Kuip, D, et al Atrial fibrillation and the prothrombotic state in the elderly: the Rotterdam Study.Stroke2003;34,413-417. [CrossRef] [PubMed]
 
Conway, DSG, Pearce, LA, Chin, BSP, et al Prognostic value of plasma von Willebrand factor and soluble p-selectin as indices of endothelial damage and platelet activation in 994 patients with nonvalvular atrial fibrillation.Circulation2003;107,3133-3140. [CrossRef] [PubMed]
 
Lowe, GD Blood rheology and hyperviscosity syndromes.Ballieres Clin Haematol1987;1,597-861. [CrossRef]
 
Goldsmith, I, Kumar, P, Carter, P, et al Atrial endocardial changes in mitral valve disease: a scanning electron microscopy study.Am Heart J2000;140,777-784. [CrossRef] [PubMed]
 
Fukuchi, M, Watanabe, J, Kumagai, K, et al Increased von Willebrand factor in the endocardium as a local predisposing factor for thrombogenesis in overloaded human atrial appendage.J Am Coll Cardiol2001;37,1436-1442. [CrossRef] [PubMed]
 
Falati, S, Liu, Q, Gross, P, et al Accumulation of tissue factor into developing thrombiin vivois dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin.J Exp Med2003;197,1585-1598. [CrossRef] [PubMed]
 
Lip, GY, Kamath, S Thromboprophylaxis for atrial flutter.Eur Heart J2001;22,984-987. [CrossRef] [PubMed]
 

To the Editor:

Lip and associates address the difficulty to recruit a large number of patients with rheumatic mitral stenosis in order to investigate their platelet activities. They also raise the issue regarding the techniques to evaluate platelet activation. In our study, we investigated the differences in platelet activation between the blood from left and right atria and between peripheral and atrial blood with the use of flow cytometry, and platelet activation was defined by the fraction of peripheral venous platelets expressing P-selectin. As mentioned in our article,1measurement of key biochemical markers, such as P-selectin (or CD 62p antigen), by flow cytometry allows us to see changes in individual platelets. However, measurement of the secretory substances of platelets (ie, platelet factor 4 and β-thromboglobulin), which are plasma markers for evaluating platelet activation, do not reflect changes in individual platelets. In another study,2 we also found that the plasma levels of soluble P-selectin in the left atrium (47.4 ± 30.1 ng/mL) [± SD] did not significantly differ from those in the right atrium (39.3 ± 26.0 ng/mL), femoral vein (49.8 ± 37.7 ng/mL), or femoral artery (44.2 ± 29.3 ng/mL) [p = 0.05]. This might explain the discrepancy between our and their findings.

We share the belief of Lip et al that there are endothelial changes in mitral stenosis. However, we do not share their belief that there is differential activation of the endothelium between the left and right atria. In another study,3 we observed that the plasma endothelin-1 concentration in the femoral vein (2.46 ± 0.90 pg/mL) was significantly higher than that in the right atrium (2.02 ± 0.69 pg/mL), left atrium (2.11 ± 0.99 pg/mL), and femoral artery (2.05 ± 0.75 pg/mL) [p = 0.0001]. In addition, although the area of mitral valve increased significantly (1.06 ± 0.17 cm2 vs 1.48 ± 0.32 cm2, p < 0.0001), and the mean left atrial pressure (23.0 ± 5.1 mm Hg vs 17.6 ± 5.9 mm Hg, p < 0.0001) and mean pulmonary arterial pressure (31.0 ± 7.9 mm Hg vs 25.5 ± 7.0 mm Hg, p < 0.001) fell significantly and immediately after percutaneous transluminal mitral valvuloplasty, there were no significant changes in the plasma endothelin-1 concentrations in the femoral vein, right atrium, left atrium, and femoral artery immediately after valvuloplasty. However, there was no significant change in the mean right atrial pressure immediately after valvuloplasty (8.0 ± 5.9 mm Hg vs 8.4 ± 6.0 mm Hg, p = not significant). We proposed that one of the mechanisms of increased endothelin-1 concentration in the femoral vein was increased peripheral endothelin-1 release due to increased systemic venous pressure and mechanical damage of the endothelium.

We share the belief of Lip et al that regional blood stasis is a mechanism for left atrial platelet activation in mitral stenosis. However, we do believe that shear stresses in turbulent flow as a result of stenotic valves induce platelet activation. In one of our studies,4 we found that the fraction of platelets expressing P-selectin in the venous blood fell significantly after valvuloplasty (before, 4.7 ± 2.4%, vs 1 week after, 2.2 ± 2.1%; 4 weeks after, 2.0 ± 1.7%, p < 0.0001). In addition, correlation analysis demonstrated that there was a significantly direct relationship between the magnitude of increase in mitral valve area and the magnitude of decrease in the fraction of platelets expressing P-selectin in the venous blood 4 weeks after valvuloplasty (p = 0.0013; r = 0.682).

Recently, we have also found that the circulating levels of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), were significantly elevated in patients with rheumatic mitral stenosis.5 In addition, the plasma levels of soluble VCAM-1 and ICAM-1 in the left atrium (1,232.8 ± 612.1 ng/mL and 778.5 ± 311.8 ng/mL, respectively) did not differ from those in the right atrium (1,157.7 ± 477.1 ng/mL and 755.6 ± 334.7 ng/mL, respectively), femoral vein (1,205.4 ± 462.4 ng/mL and 772.6 ± 305.8 ng/mL, respectively) or femoral artery (1,211.5 ± 503.9 ng/mL and 808.3 ± 391.3 ng/mL, respectively) [p = 0.668 for VCAM-1 and p = 0.232 for ICAM-1]. Moreover, we have demonstrated that the elevated plasma soluble VCAM-1 concentration is associated with hemodynamic abnormality rather than with rheumatic activity. As these adhesion molecules are expressed on vascular endothelium and on immune and inflammatory cells, our observation is consistent with the finding of Lip et al regarding the left atrial plasma levels of interleukin-6 in patients with mitral stenosis. In conclusion, different assay methods might produce different results. Larger studies should be conducted to provide a definite conclusion as to which method is optimal.

References
Chen, MC, Wu, CJ, Yip, HK, et al Left atrial platelet activity with rheumatic mitral stenosis: correlation study of severity and platelet p-selectin expression by flow cytometry.Chest2003;124,1663-1669. [CrossRef] [PubMed]
 
Chen MC, Chang HW, Juang SS, et al. Increased plasma levels of soluble p-selectin in rheumatic mitral stenosis. Chest 2004 (in press).
 
Chen, MC, Wu, CJ, Yip, HK, et al Increased circulating endothelin-1 in rheumatic mitral stenosis: irrelevance to left atrial and pulmonary artery pressures.Chest2004;125,390-396. [CrossRef] [PubMed]
 
Chen, MC, Wu, CJ, Chang, HW, et al Mechanism of reducing platelet activity by percutaneous transluminal mitral valvuloplasty in patients with rheumatic mitral stenosis.Chest2004;125,1629-1634. [CrossRef] [PubMed]
 
Chen, MC, Chang, HW, Juang, SS, et al Percutaneous transluminal mitral valvuloplasty reduces circulating vascular cell adhesion molecule-1 in rheumatic mitral stenosis.Chest2004;125,1213-1217. [CrossRef] [PubMed]
 

To the Editor:

We thank Drs. Conway and Lip for raising comments on our article (November 2003).1Large prospective, randomized trials have demonstrated the efficacy of anticoagulation for the prevention of cardioembolic stroke in atrial fibrillation (AF). However, there are few randomized trials of anticoagulation for stroke prevention in atrial flutter (AFL). Although clinical risk factors such as advanced age, elevated BP, and prior stroke have been used for risk stratification in patients with AF,2 whether AFL carries a similar risk to AF for cardioembolic stroke remains unsolved. Thus, the objective of our study1 was to evaluate whether patients with AFL were in a prothrombotic state using hemostatic markers and transesophageal echocardiography (TEE).

As pointed out by Drs. Conway and Lip, plasma levels of β-thromboglobulin (β-TG), platelet factor 4, and d-dimer in AFL were intermediate between those in sinus rhythm (SR) and AF, suggesting that a certain group of patients with AFL suffered from potential hypercoagulable or prothrombotic state and should receive anticoagulation. Indeed, AFL patients with impaired left atrial appendage (LAA) function had increased levels of β-TG and d-dimer. However, > 50% of patients with AFL showed well-preserved LAA function and no elevated levels of hemostatic markers, suggesting these AFL patients were at low risk of thromboembolism and were safe without long-term anticoagulation. Recently, measuring fibrin d-dimer levels as a noninvasive test has been proposed to exclude left atrial thrombi in AF.3 Measurement of hemostatic markers and TEE findings could be a useful strategy to determine which patients with AFL are at low or high risk of thromboembolism.

The use of anticoagulation in AFL should follow current guidelines for AF using risk stratification, when cardioversion of AFL is planned. We agree with Drs. Conway and Lip. As discussed in our study, atrial stunning could ensue after restoration of SR and be associated with formation of new LAA thrombi. Large randomized controlled trials of anticoagulation therapy on an unselected population of AFL would give us the definitive answer regarding the role of anticoagulation in AFL.

References
Sakurai, K, Hirai, T, Nakagawa, K, et al Left atrial appendage function and abnormal hypercoagulability in patients with atrial flutter.Chest2003;124,1670-1674. [CrossRef] [PubMed]
 
Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials.Arch Intern Med1994;154,1449-1457. [CrossRef] [PubMed]
 
Tayebjee, MH, Lip, GYH Fibrin d-dimer levels in atrial fibrillation as an index of thrombogenesis: a possible test to exclude left atrial thrombus?Am J Cardiol2003;92,47-49. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Regional Levels of Plasma Interleukin-6 and Tissue Factor Among 14 Patients With AF and Mitral Stenosis*
* 

All comparisons are p > 0.05 except where indicated. IQR = interquartile range.

 

p = 0.005, compared to peripheral vein.

References

Chen, MC, Wu, CJ, Yip, HK, et al (2003) Left atrial platelet activity with rheumatic mitral stenosis: correlation study of severity and platelet P-selectin expression by flow cytometry.Chest124,1663-1669. [CrossRef] [PubMed]
 
Sakurai, K, Hirai, T, Nakagawa, K, et al Left atrial appendage function and abnormal hypercoagulability in patients with atrial flutter.Chest2003;124,1670-1674. [CrossRef] [PubMed]
 
Li-Saw-Hee, FL, Blann, AD, Goldsmith, I, et al Indexes of hypercoagulability measured in peripheral blood reflect levels in intracardiac blood in patients with atrial fibrillation secondary to mitral stenosis.Am J Cardiol1999;83,1206-1209. [CrossRef] [PubMed]
 
Yamamoto, K, Ikeda, U, Seino, Y, et al Coagulation activity is increased in the left atrium of patients with mitral stenosis.J Am Coll Cardiol1995;25,107-112. [CrossRef] [PubMed]
 
Wang, J, Xie, X, He, H, et al Hypercoagulability existing in the local left atrium of patient with mitral stenosis.Chin Med J2003;116,1198-1202. [PubMed]
 
Conway, DSG, Pearce, LA, Chin, BSP, et al Plasma von Willebrand factor and soluble P-selectin as indices of endothelial damage and platelet activation in 1321 patients with non-valvular atrial fibrillation: relationship to stroke risk factors.Circulation2002;106,1962-1967. [CrossRef] [PubMed]
 
Conway, DSG, Heeringa, J, Van der Kuip, D, et al Atrial fibrillation and the prothrombotic state in the elderly: the Rotterdam Study.Stroke2003;34,413-417. [CrossRef] [PubMed]
 
Conway, DSG, Pearce, LA, Chin, BSP, et al Prognostic value of plasma von Willebrand factor and soluble p-selectin as indices of endothelial damage and platelet activation in 994 patients with nonvalvular atrial fibrillation.Circulation2003;107,3133-3140. [CrossRef] [PubMed]
 
Lowe, GD Blood rheology and hyperviscosity syndromes.Ballieres Clin Haematol1987;1,597-861. [CrossRef]
 
Goldsmith, I, Kumar, P, Carter, P, et al Atrial endocardial changes in mitral valve disease: a scanning electron microscopy study.Am Heart J2000;140,777-784. [CrossRef] [PubMed]
 
Fukuchi, M, Watanabe, J, Kumagai, K, et al Increased von Willebrand factor in the endocardium as a local predisposing factor for thrombogenesis in overloaded human atrial appendage.J Am Coll Cardiol2001;37,1436-1442. [CrossRef] [PubMed]
 
Falati, S, Liu, Q, Gross, P, et al Accumulation of tissue factor into developing thrombiin vivois dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin.J Exp Med2003;197,1585-1598. [CrossRef] [PubMed]
 
Lip, GY, Kamath, S Thromboprophylaxis for atrial flutter.Eur Heart J2001;22,984-987. [CrossRef] [PubMed]
 
Chen, MC, Wu, CJ, Yip, HK, et al Left atrial platelet activity with rheumatic mitral stenosis: correlation study of severity and platelet p-selectin expression by flow cytometry.Chest2003;124,1663-1669. [CrossRef] [PubMed]
 
Chen MC, Chang HW, Juang SS, et al. Increased plasma levels of soluble p-selectin in rheumatic mitral stenosis. Chest 2004 (in press).
 
Chen, MC, Wu, CJ, Yip, HK, et al Increased circulating endothelin-1 in rheumatic mitral stenosis: irrelevance to left atrial and pulmonary artery pressures.Chest2004;125,390-396. [CrossRef] [PubMed]
 
Chen, MC, Wu, CJ, Chang, HW, et al Mechanism of reducing platelet activity by percutaneous transluminal mitral valvuloplasty in patients with rheumatic mitral stenosis.Chest2004;125,1629-1634. [CrossRef] [PubMed]
 
Chen, MC, Chang, HW, Juang, SS, et al Percutaneous transluminal mitral valvuloplasty reduces circulating vascular cell adhesion molecule-1 in rheumatic mitral stenosis.Chest2004;125,1213-1217. [CrossRef] [PubMed]
 
Sakurai, K, Hirai, T, Nakagawa, K, et al Left atrial appendage function and abnormal hypercoagulability in patients with atrial flutter.Chest2003;124,1670-1674. [CrossRef] [PubMed]
 
Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials.Arch Intern Med1994;154,1449-1457. [CrossRef] [PubMed]
 
Tayebjee, MH, Lip, GYH Fibrin d-dimer levels in atrial fibrillation as an index of thrombogenesis: a possible test to exclude left atrial thrombus?Am J Cardiol2003;92,47-49. [PubMed]
 
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