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

Wu N, Tong S, Xiang Y, Wu L, Xu B, Zhang Y, Ma X, Li Y, Song Z, Zhong L - PLoS ONE (2015)

Bottom Line: 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).Increased circulating hemostatic factors (PF-4, BTG, P-selectin, D-dimer, fibrinogen, TAT, F1+2, AT- III, and vWf) are significantly associated with AF.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, College of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China; Evidence-based Medicine and Clinical Epidemiology Center, Third Military Medical University, Chongqing, People's Republic of China.

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.

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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.
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pone.0124716.g003: 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.

Mentions: Coagulation activation markers, including plasma D-dimer, fibrinogen, thrombin-antithrombin (TAT), prothrombin fragment 1+2 (F1+2), and antithrombin- III (AT- III), were significantly higher in patients with AF than controls, with a pooled SMD of 1.82 (95% CI, 1.38–2.26; P<0.001), 0.72 (95% CI, 0.55–0.89; P<0.001), 0.42 (95% CI, 0.13–0.72; P = 0.005), 1.00 (95% CI, 0.00–1.99; P = 0.049), and 1.38 (95% CI, 0.16–2.60; P = 0.027), respectively (Fig 3A–3E). There was significant heterogeneity between the studies investigating D-dimer, fibrinogen, F1+2, and AT- III (Table 1). According to the univariate meta-regression results, the type of AF was associated with heterogeneity for D-dimer. The publication year and gender were associated with heterogeneity for fibrinogen (S3 Table), and multivariate meta-analysis showed similar result with univariate model, indicating publication year and gender were significantly associated with heterogeneity for fibrinogen. The proportion of between-study variance explained by these two covariates was 41.26% (S4 Table). A subgroup analysis demonstrated that the association between D-dimer and AF was significant in paroxysmal, persistent and permanent AF (S3 Fig). After grouping by publication year, the associations between fibrinogen and AF were significant for studies published after 2000 and those published before 2000 (S4 Fig). Results of subgroup analyses by anticoagulants treatment status for D-dimer, fibrinogen, TAT, F1+2 and AT- III were consistent with the overall effects (data not shown). A meta-regression analysis was not performed for TAT, F1+2, and AT- III because of a limited number of studies.


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

Wu N, Tong S, Xiang Y, Wu L, Xu B, Zhang Y, Ma X, Li Y, Song Z, Zhong L - PLoS ONE (2015)

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.
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pone.0124716.g003: 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.
Mentions: Coagulation activation markers, including plasma D-dimer, fibrinogen, thrombin-antithrombin (TAT), prothrombin fragment 1+2 (F1+2), and antithrombin- III (AT- III), were significantly higher in patients with AF than controls, with a pooled SMD of 1.82 (95% CI, 1.38–2.26; P<0.001), 0.72 (95% CI, 0.55–0.89; P<0.001), 0.42 (95% CI, 0.13–0.72; P = 0.005), 1.00 (95% CI, 0.00–1.99; P = 0.049), and 1.38 (95% CI, 0.16–2.60; P = 0.027), respectively (Fig 3A–3E). There was significant heterogeneity between the studies investigating D-dimer, fibrinogen, F1+2, and AT- III (Table 1). According to the univariate meta-regression results, the type of AF was associated with heterogeneity for D-dimer. The publication year and gender were associated with heterogeneity for fibrinogen (S3 Table), and multivariate meta-analysis showed similar result with univariate model, indicating publication year and gender were significantly associated with heterogeneity for fibrinogen. The proportion of between-study variance explained by these two covariates was 41.26% (S4 Table). A subgroup analysis demonstrated that the association between D-dimer and AF was significant in paroxysmal, persistent and permanent AF (S3 Fig). After grouping by publication year, the associations between fibrinogen and AF were significant for studies published after 2000 and those published before 2000 (S4 Fig). Results of subgroup analyses by anticoagulants treatment status for D-dimer, fibrinogen, TAT, F1+2 and AT- III were consistent with the overall effects (data not shown). A meta-regression analysis was not performed for TAT, F1+2, and AT- III because of a limited number of studies.

Bottom Line: 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).Increased circulating hemostatic factors (PF-4, BTG, P-selectin, D-dimer, fibrinogen, TAT, F1+2, AT- III, and vWf) are significantly associated with AF.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, College of Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China; Evidence-based Medicine and Clinical Epidemiology Center, Third Military Medical University, Chongqing, People's Republic of China.

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.

Show MeSH
Related in: MedlinePlus