Tissue factor expression in atrial endothelia associated with nonvalvular atrial fibrillation: possible involvement in intracardiac thrombogenesis

doi:10.1016/S0049-3848(03)00405-5

Thrombosis Research

Volume 111, Issue 3, 2003, Pages 137-142

https://doi.org/10.1016/S0049-3848(03)00405-5 Get rights and content

Abstract

Introduction: Tissue factor plays a key role in the extrinsic coagulation pathway and is induced by inflammatory cytokines. Atrial myocarditis has been detected recently in some patients with lone atrial fibrillation. Virchow's triad of low blood flow, hypercoagulability, and endothelial dysfunction, enhances thrombus formation. The present study was designed to elucidate the role of endothelial dysfunction in thrombogenesis associated with nonvalvular atrial fibrillation. Material and methods: We investigated tissue factor expression in the endothelia of left atrial appendages obtained from seven patients with nonvalvular atrial fibrillation and cardiogenic thromboembolism. Tissues were divided into 7–13 sections and compared with control specimens from four patients who died of noncardiac events. Expression of tissue factor, von Willebrand factor and tissue factor pathway inhibitor was evaluated by immunohistochemistry. Results: Histopathologically, inflammatory cells infiltrated the endocardium and all seven patients showed features of persistent myocarditis. Activated T cells [15.3±9.4 cells/high power field (HPF, mean±S.D.) vs. control 2.2±4.4/HPF (P=0.0294)] and a few macrophages [5.1±8.4 cells/HPF vs. control 2.4±3.5 cells/HPF (P=NS)] infiltrated the endocardium. Tissue factor was overexpressed in the endothelia particularly in tissues containing inflammatory cells and denuded matrix of the endocardium, compared with the control group. Von Willebrand factor, but not tissue factor pathway inhibitor, was also overexpressed in these tissues. Conclusion: Tissue factor expression induced by local inflammation is involved in the pathogenesis of thrombosis in patients with nonvalvular atrial fibrillation.

Introduction

Atrial fibrillation is a well known risk factor of cardiogenic thromboembolism. The incidence of left atrial thrombosis in patients with nonvalvular atrial fibrillation is approximately 10% [1], [2]. The incidence of strokes in patients with nonvalvular atrial fibrillation reported in several control studies varied from 5.5% in the Copenhagen AFASAK study [3], 6.3% in SPAF study [4], 3.0% in the Boston BAATAF study [5], 5.2% in the Canadian CAFA study [6], and 4.3% in the SPINAF study [7].

Thrombus formation in cardiac chambers during atrial arrhythmia may result from Virchow's triad of endothelial injury, stagnant blood flow, and a hypercoagulable state. While diminished flow through the atrial appendage [8], [9], [10] and activation of coagulation [11], [12], [13], [14], [15], [16] have been demonstrated previously in patients with atrial fibrillation, there are no studies that identified a definite disorder or dysfunction of the endothelium in these patients, although a healthy endothelium is known to exhibit a potent anticoagulant function [17].

The present study was designed to investigate the role of endothelial dysfunction in atrial fibrillation-associated thrombus formation. For this purpose, we assessed the histological integrity of the left atrial appendage, especially the endocardium. In addition, using a semiquantitative assay, we examined the expression levels of various procoagulant factors, such as tissue factor, von Willebrand factor, and tissue factor pathway inhibitor (TFPI), an anticoagulant factor, in the endothelium of atrial appendages of patients who experienced cardiogenic thromboembolism during nonvalvular atrial fibrillation.

Section snippets

Materials

Atrial samples were obtained from seven patients with cardiogenic thromboembolism. Five patients with a recent history of embolism had undergone surgical thrombectomy with left atrial appendectomy because of large, floating thrombi. The other two atrial samples were obtained from autopsy specimens. The four patients who served as controls died of noncardiac events did not have atrial fibrillation, and had no evidence of cardiogenic thromboembolism. The study protocol was approved by the Human

Patients population

Table 1 summarizes the clinical data of patients and control subjects. Case 1 was not treated with warfarin because embolism caused acute brain herniation. Another patient was treated with warfarin for at least 1 month.

Overexpression of tissue factors in the endothelia

The expression levels of tissue factor in the endothelia, inflammatory cells and denuded matrix of the endocardium were higher in patients with cardiogenic thromboembolism compared with the control tissues (Fig. 1). Von Willebrand factor was also overexpressed in the endothelia

Discussion

Our study demonstrated a high expression of tissue factor, a strong initiator of the coagulation cascade, in the endothelia of patients with atrial fibrillation in association with atrial myocarditis. Furthermore, semiquantitative analysis also demonstrated overexpression of von Willebrand factor in endothelial injury.

Previous studies indicated that the normal endothelium exhibits potent anti-coagulant properties because it expresses thrombomodulin, tissue plasminogen activator, and TFPI,

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Citation Excerpt :
In the present study, using either clone, we observed significant differences in TF-bearing EV levels, comparing AF patients with controls. Nakamura et al. demonstrated inflammatory cell infiltration and expression of TF in the endothelium of the LAA in patients with nonvalvular AF and a recent thromboembolic event [10]. Furthermore, vWF was overexpressed in the LAA endothelium in AF patients [10].
The risk of thrombus formation in the left atrial appendage (LAA) in patients with atrial fibrillation (AF) may result from blood stasis, local endocardial changes, and/or changed blood composition. Extracellular vesicles (EVs), especially subtypes exposing tissue factor (TF), have procoagulant capacity. We hypothesized that blood concentrations of TF-bearing EVs and other procoagulant biomarkers are elevated in AF patients, particularly in the LAA lumen.
From 13 AF patients and 12 controls a venous blood sample was drawn prior to cardiac surgery. Intraoperatively, venous blood and blood directly from the LAA was drawn. Plasma levels of EVs, including TF- and cell type specific antigen-bearing EVs, were measured using a protein microarray platform. Plasma levels of TF, von Willebrand factor (vWF), cell free deoxyribonucleic acid (cf-DNA), procoagulant phospholipids (PPLs), and total submicron particles were also evaluated.
Significantly higher EV levels, including a several-fold higher median level of TF-bearing EVs were measured in AF patients compared with controls. Median concentrations of TF and vWF were approximately 40% and 30% higher, respectively, in the AF group than in the control group, while no significant differences in levels of cf-DNA, PPLs, or total submicron particles were observed. No significant differences in levels of any of the measured analytes were observed between intraoperative venous and LAA samples.
Increased plasma concentrations of TF in AF patients are accompanied and probably at least partly explained by increased levels of TF-bearing EVs, which may be mechanistically involved in increased thrombogenicity in AF patients.
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Regular articleTissue factor expression in atrial endothelia associated with nonvalvular atrial fibrillation: possible involvement in intracardiac thrombogenesis

Abstract

Introduction

Section snippets

Materials

Patients population

Overexpression of tissue factors in the endothelia

Discussion

Am. Heart J.

Am. Heart J.

Lancet

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

Am. Heart J.

Int. J. Cardiol.

Biomed. Pharmacother.

Atherosclerosis

Thromb. Res.

Thromb. Res.

Am. J. Cardiol.

J. Pediatr.

Chest

Int. J. Biochem. Cell Biol.

Regular article
Tissue factor expression in atrial endothelia associated with nonvalvular atrial fibrillation: possible involvement in intracardiac thrombogenesis