Association of hemostatic markers with atrial fibrillation: a meta-analysis and meta-regression

Na Wu, Shifei Tong, Ying Xiang, Long Wu, Bin Xu, Yao Zhang, Xiangyu Ma, Yafei Li, Zhiyuan Song, Li Zhong, Na Wu, Shifei Tong, Ying Xiang, Long Wu, Bin Xu, Yao Zhang, Xiangyu Ma, Yafei Li, Zhiyuan Song, Li Zhong

Abstract

Background: There is growing evidence that indicates the presence of a prothrombotic state in atrial fibrillation (AF). However, the role of hemostatic markers in AF remains inconclusive.

Methods: We conducted a meta-analysis of observational studies to evaluate the association between hemostatic markers and AF. A meta-regression was performed to explore potential sources of heterogeneity.

Results: A total of 59 studies met our inclusion criteria for the meta-analysis. For platelet activation, increased circulating platelet factor-4, β-thromboglobulin (BTG) and P-selectin were significantly higher in AF cases compared with controls (standardized mean difference [SMD][95% confidence interval (CI)]: 1.72[0.96-2.49], 1.61[1.03-2.19] and 0.50[0.23-0.77], respectively). For coagulation activation, increased levels of plasma D-dimer, fibrinogen, thrombin-antithrombin, prothrombin fragment 1+2, and antithrombin-III were significantly associated with AF (SMD[95% CI]: 1.82[1.38-2.26], 0.72[0.55-0.89], 0.42[0.13-0.72], 1.00 [0.00-1.99] and 1.38[0.16-2.60], respectively). For fibrinolytic function, tissue-type plasminogen activator and plasminogen activator inhibitor-1 were significantly increased in AF cases compared with controls (SMD[95% CI]: 0.86[0.04-1.67] and 0.87[0.28-1.47], respectively) but the associations became nonsignificant after performing subgroup analysis by anticoagulants treatment status. For endothelial function, increased von Willebrand factor was significantly associated with AF (SMD, 0.79; 95% CI, 0.60-0.99); however, no association was observed for soluble thrombomodulin (SMD, 0.60; 95% CI, -0.13-1.33).

Conclusions: Increased circulating hemostatic factors (PF-4, BTG, P-selectin, D-dimer, fibrinogen, TAT, F1+2, AT- III, and vWf) are significantly associated with AF. Future research is necessary to elucidate the precise mechanism of the prothrombotic state and how hemostatic markers promote thromboembolism in AF.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Flow diagram of the literature…
Fig 1. Flow diagram of the literature search and study selection.
Fig 2. Association between platelet activation markers…
Fig 2. Association between platelet activation markers and AF.
A. platelet count and AF; B. Mean platelet volume and AF; C. Platelet factor-4 and AF; D. β-thromboglobulin and AF; E. P-selectin and AF. Forest plots of SMD and overall SMD with 95% CI between AF cases and controls. Black diamonds indicate the SMD, with the size of the square inversely proportional to its variance, and horizontal lines represent the 95% CI. The pooled results are indicated by the black hollow diamond. AF, atrial fibrillation; MPV, mean platelet volume; PF-4, platelet factor-4; BTG, β-thromboglobulin; PAF, paroxysmal AF; PeAF, persistent AF; PtAF, permanent AF; CAF, chronic AF; SMD, standardized mean difference.
Fig 3. Association between coagulation activation markers…
Fig 3. Association between coagulation activation markers and AF.
A. D-dimer and AF; B. fibrinogen and AF; C. Thrombin-antithrombin and AF; D. Prothrombin fragment 1+2 and AF; E. Antithrombin- III and AF. Forest plots of SMD and overall SMD with 95% CI between AF cases and controls. Black diamonds indicate the SMD, with the size of the square inversely proportional to its variance, and horizontal lines represent the 95% CI. The pooled results are indicated by the black hollow diamond. AF, atrial fibrillation; TAT, thrombin-antithrombin; F1+2, prothrombin fragment 1+2; AT- III, antithrombin- III; PAF, paroxysmal AF; PeAF, persistent AF; PtAF, permanent AF; CAF, chronic AF; aAF, acute AF; SMD, standardized mean difference.
Fig 4. Association between fibrinolytic function makers…
Fig 4. Association between fibrinolytic function makers and AF.
A. Tissue-type plasminogen activator and AF; B. Plasminogen activator inhibitor-1 and AF. Forest plots of SMD and overall SMD with 95% CI between AF cases and controls. Black diamonds indicate the SMD, with the size of the square inversely proportional to its variance, and horizontal lines represent the 95% CI. The pooled results are indicated by the black hollow diamond. AF, atrial fibrillation; tPA, tissue-type plasminogen activator; PAI-1, plasminogen activator inhibitor-1; SMD, standardized mean difference.
Fig 5. Association between endothelial function markers…
Fig 5. Association between endothelial function markers and AF.
A. Von Willebrand factor and AF; B. Soluble thrombomodulin and AF. Forest plots of SMD and overall SMD with 95% CI between AF cases and controls. Black diamonds indicate the SMD, with the size of the square inversely proportional to its variance, and horizontal lines represent the 95% CI. The pooled results are indicated by the black hollow diamond. AF, atrial fibrillation; vWf, von Willebrand factor; sTM, soluble thrombomodulin; PAF, paroxysmal AF; PeAF, persistent AF; PtAF, permanent AF; CAF, chronic AF; aAF, acute AF; SMD, standardized mean difference.

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