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. 2017 Mar 31;23:97–140. doi: 10.12659/MSMBR.902558

Predictive Role of Coagulation, Fibrinolytic, and Endothelial Markers in Patients with Atrial Fibrillation, Stroke, and Thromboembolism: A Meta-Analysis, Meta-Regression, and Systematic Review

Alexander Weymann 1,A,B,C,D,E,F,G,*, Anton Sabashnikov 2,3,A,B,C,D,E,F,G,*, Sadeq Ali-Hasan-Al-Saegh 4,A,B,C,D,E,F,G,*, Aron-Frederik Popov 2,A,B,C,D,E,F,G,*, Seyed Jalil Mirhosseini 4,A,B,C,D,E,F,G,, William L Baker 5,A,B,C,D,E,F,G, Mohammadreza Lotfaliani 4,A,B,C,D,E,F,G, Tong Liu 6,A,B,C,D,E,F,G, Hamidreza Dehghan 7,A,B,C,D,E,F,G, Senol Yavuz 8,A,B,C,D,E,F,G, Michel Pompeu Barros de Oliveira Sá 9,10,11,A,B,C,D,E,F,G, Jae-Sik Jang 12,A,B,C,D,E,F,G, Mohamed Zeriouh 2,3,A,B,C,D,E,F,G, Lei Meng 6,A,B,C,D,E,F,G, Fabrizio D’Ascenzo 13,A,B,C,D,E,F,G, Abhishek J Deshmukh 14,A,B,C,D,E,F,G, Giuseppe Biondi-Zoccai 15,16,A,B,C,D,E,F,G, Pascal M Dohmen 1,A,B,C,D,E,F,G, Hugh Calkins 17,A,B,C,D,E,F,G; Integrated Meta-Analysis of Cardiac Surgery and Cardiology-Group [IMCSC-Group]
PMCID: PMC5452871  PMID: 28360407

Abstract

Background

The pathophysiological mechanism associated with the higher prothrombotic tendency in atrial fibrillation (AF) is complex and multifactorial. However, the role of prothrombotic markers in AF remains inconclusive.

Material/Methods

We conducted a meta-analysis of observational studies evaluating the association of coagulation activation, fibrinolytic, and endothelial function with occurrence of AF and clinical adverse events. A comprehensive subgroup analysis and meta-regression was performed to explore potential sources of heterogeneity.

Results

A literature search of major databases retrieved 1703 studies. After screening, a total of 71 studies were identified. Pooled analysis showed the association of coagulation markers (D-dimer (weighted mean difference (WMD)=197.67 and p<0.001), fibrinogen (WMD=0.43 and p<0.001), prothrombin fragment 1–2 (WMD=0.53 and p<0.001), antithrombin III (WMD=23.90 and p=0.004), thrombin-antithrombin (WMD=5.47 and p=0.004)); fibrinolytic markers (tissue-type plasminogen activator (t-PA) (WMD=2.13 and p<0.001), plasminogen activator inhibitor (WMD=11.44 and p<0.001), fibrinopeptide-A (WMD=4.13 and p=0.01)); and endothelial markers (von Willebrand factor (WMD=27.01 and p<0.001) and soluble thrombomodulin (WMD=3.92 and p<0.001)) with AF.

Conclusions

The levels of coagulation, fibrinolytic, and endothelial markers have been reported to be significantly higher in AF patients than in SR patients.

MeSH Keywords: Atrial Fibrillation, Blood Coagulation Disorders, Fibrinolysis

Background

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the general population and is associated with a high risk of developing morbidities such as hemodynamic instability, thromboembolism, stroke, hospital re-admissions, and increasing health care costs [1]. AF alone is associated with a 1.5% to 1.9% increase in risk of mortality in both sexes across a wide range of ages [2]. Moreover, the situation is likely to worsen since the number of people with AF is expected to double by 2050 [2], AF is linked to a 5-fold increased risk of cerebrovascular events, and approximately 20% of strokes are related to AF [3].

Recently, researchers have suggested several important mechanisms for the occurrence of AF, including oxidative stress reactions and systemic inflammation [4]. The pathophysiological mechanism associated with the higher prothrombotic tendency in AF is highly complex and multifactorial [5]. Virchow’s triad regarding prothrombotic state, including changed blood flow (arterial stasis), abnormalities in vessel wall, and coagulant alternations in the hemostatic balance, may play an important role in the occurrence of supraventricular arrhythmia [6].

Various studies have reported the association of hemostatic markers with the occurrence of AF. However, so far, the data from these studies are largely inconclusive. The present systematic review with meta-analysis sought to determine the strength of evidence for evaluating the role of coagulation activation, fibrinolytic, and endothelial function in the occurrence of AF and related consequent outcomes such as thromboembolism and stroke.

Material and Methods

Literature search

A systematic and comprehensive literature search was conducted in electronic databases (Medline/PubMed, Embase, Web of Science, and Google Scholar) from their inception through 5 August 2016 to identify relevant studies on the association of coagulation, fibrinolytic, and endothelial functional assessment with the occurrence of AF and related consequent clinical adverse events, including thromboembolism and stroke. Predefined search terms were: coagulation [“fibrinogen”, “D-dimer”, “prothrombin fragment 1–2”, “antithrombin III”, “thrombin-antithrombin”], fibrinolytic [“tissue-type plasminogen activator”, “plasminogen activator inhibitor”, “alfa-2 antiplasmin”, “fibrinopeptide-A”, “urokinase-type plasminogen activator”, “plasmin-antiplasmin”], endothelial function [“von Willebrand factor”, “soluble thrombomodulin”], and “atrial fibrillation”. No limitations were imposed on language, time of publication, or sample size of studies. All retrieved references of the included studies and recent published review articles and meta-analyses were also reviewed to determine additional studies not indexed in major databases.

Study selection

Studies were included in the analysis when they met the following criteria: 1) human subjects; 2) case-control or cohort studies; 3) the study investigated the comparison between AF-cases and non-AF-population regarding biomarkers of endothelial, coagulation, and fibrinolytic function; 4) the study compared cohorts of patients with and without stroke, as well as with and without thromboembolic events in patients with AF in terms of biomarkers. Abstracts without peer-review, abstracts from congress presentations, and gray literature were not included.

Data extraction and outcome measures

Three investigators (S.A.-H-S, A.W., and A.S.) extracted the data independently, and discrepancies were resolved via a consensus standardized abstraction checklist used for recording data in each enrolled study. Disagreements were resolved through discussion with senior authors (A.F.-P, G.B.Z, and H.C.). Author’s name, year of publication, country, design of study, procedure, sample size, mean age, sex, coexistent cardiovascular disease and risk factors, anticoagulants, type of AF, and details of hemostatic markers were extracted. For exploration of heterogeneity among trials, subgroup analyses of disparities in the patients’ characteristics were performed for (1) year of publication (before 2000 vs. after 2000); (2) geographic area (Asia, Europe, Africa, North-America, South-America, and Oceania); (3) design of the study (case-control vs. cohort); (4) number of patients (≤300 vs. >300); (5) mean age (≤60 years vs. >60 years); (6) percentage of males (≤70% vs. >70%); (7) diabetes (≤30% vs. >30%); (8) hypertension (≤70% vs. >70%); (9) myocardial infarction (≤20% vs. >20%); (10) AF-classification (acute and sub-acute vs. chronic); (11) type of AF (paroxysmal, persistent, permanent); and (12) anticoagulation (code-1: no patient received anticoagulants in both groups, code-2: all participants were anticoagulated in both groups, code-3: range of percentages between both groups more than 50%, code-4: range of percentages between both groups less than 50%, code-5: anticoagulation information was not available in both groups, and code-6: anticoagulation information was not available in 1 group only).

Homogenization of extracted data

The suitable form of data for analyzing was mean ± standard deviation (SD). For studies that reported interquartile ranges instead of the range, we estimated means according to [minimum+maximum+2(median)]/4 and SD according to (maximum-minimum)/4 for groups with sample sizes up to about 70 and (maximum-minimum)/6 for sample sizes more than 70 [7].

Quality assessment and statistical analysis

Two investigators (L.M. and M.G.) independently assessed the quality of studies by using the Newcastle-Ottawa scale [8]. The total scores ranged from 0 (worst quality) to 9 (best quality) for case-control or cohort studies. Data were analyzed by STATA software version 11.0 utilizing METAN and METABIAS modules. The pooled effect size measured was weighted mean difference (WMD) with 95% CI for non-categorical data. Heterogeneity p value <0.1 for Q test or I2 >50% indicated significant heterogeneity among the studies. Heterogeneity among trials was accounted for by applying a random effect model when indicated. Sample weighting assigned studies with larger sample sizes and more weight, and reduced the effect of sampling error because sampling error generally decreases as the sample size increases. The presence of publication bias was evaluated using the Begg tests. Results were considered statistically significant at a P value <0.05.

Results

Literature search strategy and included studies

The literature search retrieved 1703 studies from screened databases, of which 1527 (89.6%) were excluded after detailed evaluation in the initial review due to either redundant information (n=1095), insufficient reporting of endpoints of interest (n=398), or reporting of non-matched data according to mean ± SD or median [minimum-maximum] (n=34); 176 potentially relevant full-text articles were reviewed, and a total of 71 studies were finally included in the meta-analysis (Supplementary Table 1).

Association of coagulation markers with AF

D-dimer

A total of 7954 cases were included from 41 studies. Patient populations in the included studies ranged from 22 to 3120 patients. Of 7954 cases, 2269 were allocated to AF group and 5685 to the SR group. Mean D-dimer levels were 520.05 μg/mL in AF group and 249.28 μg/mL in SR group (details in Tables 1 and 2). Pooled assessment effect analysis revealed that the mean D-dimer level was significantly higher in patients with AF than in patients with SR with WMD of 197.67 (95% CI: 172.96–222.38; p<0.001, Figure 1) using a random effect model. Significant heterogeneity was observed among the studies (I2=99.8%; heterogeneity p<0.001).

Table 1.

Characteristics of included studies for meta-analysis of association of biomarkers and AF.

First Author Year Country Design N-AF N-SR Age-AF Age-SR Male-AF Male-SR AC-AF AC-SR Type of AF NOS
Negreva [9] 2016 Bulgaria Cohort 51 52 59.84 59.5 50.9 50 0 0 Paroxysmal 6
Amdur [10] 2016 USA Cohort 642 3120 60.8 57 53.8 55.3 48.6 42 ND 9
Yusuf (disease control) [11] 2015 India Case-Control 35 30 31.86 31.14 45.7 40 0 0 ND 8
Yusuf (healthy control) [11] 2015 India Case-control 35 30 28.97 31.14 37.1 40 0 0 ND 8
Drabik (persistent) [12] 2015 Poland Case-control 47 50 60.8 59.4 65.9 64 38.3 26 Persistent 8
Drabik (PAF) [12] 2015 Poland Case-control 41 50 60.6 59.4 46.3 64 51.2 26 Paroxysmal 8
Borgi [13] 2015 Tunis Case-control 50 19 61.8 ND 42 ND ND ND Combined 7
Oneal (with comorbidities) [14] 2015 USA Cohort 79 568 71 68 44 64 47 42 ND 9
Oneal (with comorbidities) [14] 2015 USA Cohort 63 820 65 64 22 43 58 38 ND 9
Erdogan [15] 2014 Turkey Case-control 34 33 70.5 68.6 47.05 51.5 66.6 0 Permanent 9
Chen (without comorbidities) [16] 2014 China Cohort 62 100 55.1 52.29 58.06 64 19 12 Combined 8
Chen (with comorbidities) [16] 2014 China Cohort 107 100 59.4 52.29 64.4 64 26 12 Combined 8
Schnabel [17] 2014 Germany Cohort 161 4837 64.9 55.2 59 50 ND ND ND 9
Wei-Hong Ma [18] 2014 China Cohort 55 50 59 57 74.5 70 100 100 ND 8
Xu (without comorbidities) [19] 2014 China Cohort 57 58 65.9 67.8 50.9 50 50.9 15.5 ND 7
Xu (with comorbidities) [19] 2014 China Cohort 57 58 68.95 67 52.6 50 49.1 15.5 ND 7
Distelmaier [20] 2014 USA Case-control 66 132 73.5 73.5 61 61 ND ND ND 7
Scridon (PAF) [21] 2013 France Case-control 52 17 56 55 81 76 100 0 Paroxysmal 7
Scridon (persistent) [21] 2013 France Case-control 36 17 55 55 81 76 100 0 Persistent 7
Berge [22] 2013 Norway Cohort 63 126 75 75 71.4 70.6 8 33 Combined 9
Acevedo [23] 2012 Chile Case-control 130 20 67 ND ND ND 0 0 Combined 8
Zorlu [24] 2012 Turkey Cohort 31 119 72 67 64 60 0 0 ND 8
Alonso (White) [25] 2012 USA Cohort 976 10131 57.3 54.1 58.4 46.1 0 0 ND 9
Alonso (African-American) [25] 2012 USA Cohort 233 3518 56.2 53.4 44.6 37.8 0 0 ND 9
Adamsson Eryd [26] 2011 Sweden Cohort 667 5364 47.8 46.7 100 100 ND ND ND 9
Fu [27] 2011 China Case-control 90 79 54.1 54.8 70 57 22 0 Combined 8
Hou (disease control) [28] 2010 China Case-control 26 26 65.2 64.5 57.6 57.6 7.6 11.5 ND 8
Hou (healthy control) [28] 2010 China Case-control 26 26 65.2 65.4 57.6 57.6 7.6 0 ND 8
Schnabel [29] 2010 USA Cohort 209 2911 66.3 57.8 60 45 ND ND ND 9
Letsas (PAF) [30] 2010 Greece Case-control 45 48 67.5 61.3 62 56 ND ND Paroxysmal 9
Letsas (permanent) [30] 2010 Greece Case-control 41 48 71.9 61.3 63 56 ND ND Permanent 9
Gartner [31] 2008 Austria Case-control 222 28 64.5 54.4 63 68 55 40 ND 6
Targonski (PAF and PeAF) [32] 2008 Poland Case-control 26 30 70.3 56.7 65.4 70 84.6 83.3 Combined (PAF and PeAF) 8
Targonski (Permanent) [32] 2008 Poland Case-control 43 30 69.9 68.7 62.8 70 48.8 83.3 Permanent 8
Marcus [33] 2008 USA Case-control 46 925 74 66 94 81 ND ND ND 9
Blann [34] 2007 UK Case-control 54 28 65 64 64.8 60.7 60 0 ND 6
Topaloglu (disease control) [35] 2007 Turkey Case-control 18 28 37 32 ND ND ND ND ND 6
Topaloglu (healthy control) [35] 2007 Turkey Case-control 18 20 37 35 ND ND ND ND ND 6
Cecchi (with cerebral ischemic) [36] 2006 Italy Case-control 62 130 75 72 61.2 59.2 100 0 ND 6
Cecchi (without cerebral ischemic) [36] 2006 Italy Case-control 94 130 74 72 59.5 59.2 100 0 ND 6
Turgut (disease control) [37] 2006 Turkey Case-control 26 29 67.42 64.8 30.8 58.6 38.5 20.7 ND 8
Turgut (healthy control) [37] 2006 Turkey Case-control 26 20 67.42 65.7 30.8 57.1 38.5 0 ND 8
Heeringa [38] 2006 UK Cohort 162 324 78 77 51 51 ND ND ND 8
Roldan [39] 2005 Spain Case-control 191 74 72 ND 51.3 ND 100 62.2 ND 7
Marin (acute AF) [40] 2004 Spain Case-control 24 24 64 63 50 50 16.6 0 ND 8
Marin (chronic AF) [40] 2004 Spain Case-control 24 24 64 63 45.8 50 41.6 0 ND 8
Inoue (with comorbidities) [41] 2004 Japan Case-control 159 92 ND ND ND ND ND ND ND 7
Inoue (Lone AF) [41] 2004 Japan Case-control 87 19 ND ND ND ND ND ND ND 7
Conway [42] 2004 UK Case-control 106 41 69 67 63 61 86 0 Permanent 6
Hatzinikolaou-Kotsakou (PAF) [43] 2004 Greece Case-control 18 17 59 59 72.2 82.3 ND ND Paroxysmal 8
Hatzinikolaou-Kotsakou (persistent) [43] 2004 Greece Case-control 17 17 61 59 64.7 82.3 ND ND Persistent 8
Hatzinikolaou-Kotsakou (permanent) [43] 2004 Greece Case-control 20 17 64 59 70 82.3 ND ND Permanent 8
Conway [44] 2004 UK Case-control 37 37 67 68 72.9 67.5 ND ND Persistent 6
Kamath (PAF and PeAF) [45] 2003 UK Case-control 31 31 61 66 61.3 41.9 0 0 Combined (PAF and PeAF) 6
Kamath (permanent AF) [45] 2003 UK Case-control 93 31 66 66 63.4 41.9 0 0 Permanent 6
Marin [46] 2003 Spain Case-control 48 32 71 70 63 47 38 9 ND 7
Conway [47] 2003 UK Cohort 162 324 78 77 51.2 50.9 0 0 ND 8
Kamath (PAF) [48] 2002 UK Case-control 29 29 61 65 55.17 41.3 37.9 0 Paroxysmal 7
Kamath (permanent AF) [48] 2002 UK Case-control 87 29 65 65 63.2 41.3 37.9 0 Permanent 7
Kamath [49] 2002 UK Case-control 93 50 70 70 62.4 64 0 0 ND 6
Wang [50] 2002 Taiwan Cohort 53 3159 66.1 53.9 56.6 46.7 ND ND ND 9
Li-saw-Hee (PAF) [51] 2001 UK Case-control 23 20 65 63 69.6 85 69.6 0 Paroxysmal 8
Li-saw-Hee (PeAF) [51] 2001 UK Case-control 23 20 65 63 69.5 85 100 0 Persistent 8
Li-saw-Hee (permanent) [51] 2001 UK Case-control 23 20 67 63 69.5 85 100 0 Permanent 8
Feng [52] 2001 USA Case-control 47 167 62 62.3 74.5 72.5 76.6 ND ND 8
Topcuoglu [53] 2000 Turkey Case-control 15 21 61.9 62.8 66.6 57.14 0 0 ND 6
Mondillo [54] 2000 Italy Case-control 45 35 67.6 66.3 80 85.7 55 0 Permanent 7
Giansante [55] 2000 Italy Case-control 35 70 64 63 54.2 57.14 0 0 Paroxysmal 7
Li-saw-Hee [56] 2000 UK Case-control 52 60 68 66 80 75 0 0 ND 6
Marin (disease control) [57] 1999 Spain Case-control 18 24 56 51 22.2 12.5 0 0 ND 6
Marin (healthy control) [57] 1999 Spain Case-control 18 20 56 ND 22.2 ND 0 0 ND 6
Li-saw-Hee [58] 1999 UK Case-control 25 25 60 58 20 20 ND ND ND 6
Roldan [59] 1998 Spain Case-control 36 20 62 62 62 ND 0 0 ND 7
Tsai [50] 1998 Taiwan Case-control 73 38 65 63 75.3 73.6 11 0 ND 6
Minamino [61] 1997 Japan Case-control 45 45 63 63 73.3 73.3 ND ND ND 6
Kahn [62] 1997 Canada Case-control 50 31 ND 65 ND 38.7 0 0 ND 7
Sohara [63] 1997 Japan Case-control 21 9 59.1 59.1 71.4 ND 0 0 Paroxysmal 6
Lip (PAF) [64] 1996 UK Case-control 30 158 60.8 58.9 60 55.6 0 0 Paroxysmal 8
Lip (chronic) [64] 1996 UK Case-control 56 158 64.7 58.9 57.14 55.6 0 0 ND 8
Lip [65] 1996 UK Case-control 51 26 70.4 ND ND ND 0 0 ND 6
Mitusch [66] 1996 Germany Case-control 69 28 72 70 42 60.7 0 0 ND 7
Nagao [67] 1995 Japan Case-control 17 19 81.5 78.4 47.05 42.1 0 0 ND 8
Lip [68] 1995 UK Case-control 87 158 63 59.3 50.6 56 ND ND ND 7
Sohara [69] 1994 Japan Case-control 13 9 60 ND 76.9 ND 0 0 Paroxysmal 6
Kumagai [70] 1990 Japan Case-control 73 21 64 61 53.4 42.9 0 0 ND 7
Gustafsson (with stroke) [71] 1990 Sweden case-control 20 40 77 77 ND ND 0 0 ND 8
Gustafsson (without stroke) [71] 1990 Sweden case-control 20 40 77 77 ND ND 0 0 ND 8
Table 2.

Information about markers and these levels in each study.

First author Markers Levels
Occurrence of AF
Negreva [9] sTM sTM: AF: 6.5±0.4 vs. SR: 4.48±0.28
Amdur [10] Fibrinogen Fibrinogen: AF: 4.3±1.1 vs. SR: 4.1±1.2
Yusuf (disease control) [11] TAT and PAI TAT: AF: 22.65±2.35 vs. SR: 9.07±1.22
PAI: AF: 47.9±2.5 vs. SR: 13.52±3.57
Yusuf (healthy control) [11] TAT and PAI TAT: AF: 15.37±1.87 vs. SR: 9.07±1.22
PAI: AF: 26.72±3.37 vs. SR: 13.52±3.57
Drabik (persistent) [12] Fibrinogen, tPA, PAI, and vWF Fibrinogen: AF: 3.32±0.27 vs. SR: 3.12±0.32
tPA: AF: 12.8±1.8 vs. SR: 9.4±2.1
PAI: AF: 28.1±1.35 vs. SR: 24.07±3.12
vWF: AF: 171±8 vs. SR: 121.75±5.25
Drabik (PAF) [12] Fibrinogen, tPA, PAI, and vWF Fibrinogen: AF: 3.25±0.25 vs. SR: 3.12±0.32
tPA: AF: 11.9±2.5 vs. SR: 9.4±2.1
PAI: AF: 27.95±1.65 vs. SR: 24.07±3.12
vWF: AF: 172.75±10.75 vs. SR: 121.75±5.25
Borgi [13] D-dimer D-dimer: AF: 590±506 vs. SR: 225.26±112.95
Oneal (with comorbidities) [14] Fibrinogen Fibrinogen: AF: 0.42±0.10 vs. SR: 0.41±0.11
Oneal (with comorbidities) [14] Fibrinogen Fibrinogen: AF: 0.41±0.07 vs. SR: 0.38±0.10
Erdogan [15] D-dimer and Fibrinogen D-dimer: AF: 204.7±159.2 vs. SR: 186.2±105.6
Fibrinogen: AF: 2.74±0.63 vs. SR: 2.27±0.51
Chen (without comorbidities) [16] D-dimer and Fibrinogen D-dimer: AF: 660±60 vs. SR: 270±20
Fibrinogen: AF: 2.63±0.07 vs. SR: 2.57±0.12
Chen (with comorbidities) [16] D-dimer and Fibrinogen D-dimer: AF: 350±20 vs. SR: 270±20
Fibrinogen: AF: 2.62±0.05 vs. SR: 2.57±0.12
Schnabel [17] Fibrinogen Fibrinogen: AF: 4.11±0.35 vs. SR: 3.47±0.23
Wei-Hong Ma [18] vWF vWF: AF: 166±46 vs. SR: 141±24
Xu (without comorbidities) [19] D-dimer and Fibrinogen D-dimer: AF: 379.5±48 vs. SR: 98.5±5
Fibrinogen: AF: 3.64±0.89 vs. SR: 2.62±0.5
Xu (with comorbidities) [19] D-dimer and Fibrinogen D-dimer: AF: 398.25±54.75 vs. SR: 98.5±5
Fibrinogen: AF: 3.68±0.62 vs. SR: 2.62±0.5
Distelmaier [20] Fibrinogen Fibrinogen: AF: 4±0.27 vs. SR: 4.11±0.23
Scridon (PAF) [21] vWF vWF: AF: 107.5±9.4 vs. SR: 86.8±14
Scridon (persistent) [21] vWF vWF: AF: 125.2±10.4 vs. SR: 86.8±14
Berge [22] tPA tPA: AF: 15.2±1.8 vs. SR: 15.2±1
Acevedo [23] TAT and sTM TAT: AF: 0.054±0.23 vs. SR: 0.002±0.003
sTM: AF: 52.2±111 vs. 44±13
Zorlu [24] D-dimer D-dimer: AF: 1351.75±497.75 vs. SR: 644.25±113.8
Alonso (White) [25] Fibrinogen and vWF Fibrinogen: AF: 3.19±0.64 vs. SR: 2.95±0.61
vWF: AF: 124.5±46.4 vs. SR: 111.3±42.6
Alonso (African-American) [25] Fibrinogen and vWF Fibrinogen: AF: 3.32±0.76 vs. SR: 3.18±0.71
vWF: AF: 148.9±67.5 vs. SR: 132.4±55.6
Adamsson Eryd [26] Fibrinogen Fibrinogen: AF: 3.6±0.8 vs. SR: 3.5±0.8
Fu [27] Fibrinogen and vWF Fibrinogen: AF: 3.3±0.9 vs. SR: 3±0.6
vWF: AF: 116.5±37.4 vs. SR: 105.6±29.8
Hou (disease control) [28] D-dimer and vWF D-dimer: AF: 327±96 vs. SR: 231±83
vWF: AF: 132±38 vs. SR: 126±36
Hou (healthy control) [28] D-dimer and vWF D-dimer: AF: 327±96 vs. SR: 208±80
vWF: AF: 132±38 vs. SR: 113±37
Schnabel [29] D-dimer and Fibrinogen D-dimer: AF: 451.5±56 vs. SR: 321±43.6
Fibrinogen: AF: 3.52±0.15 vs. SR: 3.31±0.15
Letsas (PAF) [30] Fibrinogen Fibrinogen: AF: 3.74±1.03 vs. SR: 3.6±0.89
Letsas (permanent) [30] Fibrinogen Fibrinogen: AF: 4.12±0.99 vs. SR: 3.6±0.89
Gartner [31] D-dimer D-dimer: AF: 929.3±105.1 vs. SR: 457.3±108.8
Targonski (PAF and PeAF) [32] Fibrinogen Fibrinogen: AF: 3.39±0.67 vs. SR: 3.6±0.76
Targonski (Permanent) [32] Fibrinogen Fibrinogen: AF: 3.91±0.77 vs. SR: 3.6±0.76
Marcus [33] D-dimer D-dimer: AF: 392±91 vs. SR: 408±72
Blann [34] vWF vWF: AF: 180±86 vs. SR: 109±62
Topaloglu (disease control) [35] D-dimer, Fibrinogen, AT-III, tPA, PAI and vWF D-dimer: AF: 384±130 vs. SR: 372±160
Fibrinogen: AF: 2.89±0.71 vs. SR: 2.82±0.37
AT-III: AF: 98.6±11.1 vs. SR: 97.9±21.2
tPA: AF: 8.89±3.5 vs. SR: 5.82±1.79
PAI: AF: 1.05±0.97 vs. SR: 1.16±0.7
vWF: AF: 134.9±68 vs. SR: 115.7±53.4
Topaloglu (healthy control) [35] D-dimer, Fibrinogen, AT-III, tPA, PAI and vWF D-dimer: AF: 384±130 vs. SR: 19±8.3
Fibrinogen: AF: 2.89±0.71 vs. SR: 2.3±0.47
AT-III: AF: 98.6±11.1 vs. SR: 82.8±8.6
tPA: AF: 8.89±3.5 vs. SR: 7.3±3.7
PAI: AF: 1.05±0.97 vs. SR: 1.24±0.65
vWF: AF: 134.9±68 vs. SR: 75.1±17
Cecchi (with cerebral ischemic) [36] Fibrinogen Fibrinogen: AF: 3.68±1.04 vs. SR: 3.07±0.3
Cecchi (without cerebral ischemic) [36] Fibrinogen Fibrinogen: AF: 4.36±1.22 vs. SR: 3.07±0.3
Turgut (disease control) [37] Fibrinogen and PF1–2 Fibrinogen: AF: 3.64±0.86 vs. SR: 3.47±1.1
PF1–2: AF: 2.83±0.89 vs. SR: 2.33±0.8
Turgut (healthy control) [37] Fibrinogen and PF1–2 Fibrinogen: AF: 3.64±0.86 vs. SR: 2.51±0.61
PF1–2: AF: 2.83±0.89 vs. SR: 1.94±0.64
Heeringa [38] Fibrinogen and vWF Fibrinogen: AF: 2.32±0.7 vs. SR: 2.32±0.9
vWF: AF: 144±32 vs. SR: 138±40.2
Roldan [39] PF1–2 PF1–2: AF: 1.41±0.15 vs. SR: 1.05±0.09
Marin (acute AF) [40] D-dimer, vWF and sTM D-dimer: AF: 2350±2680 vs. SR: 390±280
vWF: AF: 137±36.9 vs. SR: 86.7±33.2
sTM: AF: 12.1±4.1 vs. 5.9±2.7
Marin (chronic AF) [40] D-dimer, vWF and sTM D-dimer: AF: 1120±650 vs. SR: 390±280
vWF: AF: 133.1±25 vs. SR: 86.7±33.2
sTM: AF: 11.8±4.6 vs. 5.9±2.7
Inoue (with comorbidities) [41] D-dimer and PF1–2 D-dimer: AF: 158.6±9.2 vs. SR: 79.1±10.3
PF1–2: AF: 0.98±0.05 vs. SR: 1.04±0.04
Inoue (Lone AF) [41] D-dimer and PF1–2 D-dimer: AF: 92.1±6.7 vs. SR: 31±7.4
PF1–2: AF: 0.79±0.06 vs. SR: 0.82±0.05
Conway [42] Fibrinogen and vWF Fibrinogen: AF: 2.65±0.17 vs. SR: 2.72±0.28
vWF: AF: 132±26 vs. SR: 125±21
Hatzinikolaou-Kotsakou (PAF) [43] Fibrinogen and vWF Fibrinogen: AF: 3.3±0.9 vs. SR: 2.4±0.8
vWF: AF: 119±0.9 vs. SR: 104±22
Hatzinikolaou-Kotsakou (persistent) [43] Fibrinogen and vWF Fibrinogen: AF: 3.8±0.4 vs. SR: 2.4±0.8
vWF: AF: 129±19 vs. SR: 104±22
Hatzinikolaou-Kotsakou (permanent) [43] Fibrinogen and vWF Fibrinogen: AF: 4.5±0.6 vs. SR: 2.4±0.8
vWF: AF: 158±15 vs. SR: 104±22
Conway [44] Fibrinogen and vWF Fibrinogen: AF: 2.83±0.25 vs. SR: 2.67±0.27
vWF: AF: 130±25 vs. SR: 126±21
Kamath (PAF and PeAF) [45] D-dimer and Fibrinogen D-dimer: AF: 760±195 vs. SR: 637.5±202.5
Fibrinogen: AF: 2.9±0.7 vs. SR: 2.6±0.4
Kamath (permanent AF) [45] D-dimer and Fibrinogen D-dimer: AF: 1497.5±368.3 vs. SR: 637.5±202.5
Fibrinogen: AF: 2.7±0.6 vs. SR: 2.6±0.4
Marin [46] PF1–2 PF1–2: AF: 1.61±0.31 vs. SR: 0.94±0.1
Conway [47] Fibrinogen and vWF Fibrinogen: AF: 0.8±0.29 vs. SR: 0.79±0.3
vWF: AF: 144±32 vs. SR: 138±32
Kamath (PAF) [48] D-dimer and Fibrinogen D-dimer: AF: 675.75±151.75 vs. SR: 659.5±185.5
Fibrinogen: AF: 2.9±0.7 vs. SR: 2.6±0.5
Kamath (permanent AF) [48] D-dimer and Fibrinogen D-dimer: AF: 1552.5±398.3 vs. SR: 659.5±185.5
Fibrinogen: AF: 2.7±0.6 vs. SR: 2.6±0.5
Kamath [49] D-dimer and Fibrinogen D-dimer: AF: 1085±176.6 vs. SR: 724.25±240.75
Fibrinogen: AF: 2.8±0.7 vs. SR: 2.6±0.4
Wang [50] Fibrinogen, tPA and PAI Fibrinogen: AF: 3.15±0.76 vs. SR: 3.03±0.63
tPA: AF: 12.05±1.85 vs. SR: 8.25±0.96
PAI: AF: 23.95±8.1 vs. SR: 19.05±4.1
Li-saw-Hee (PAF) [51] Fibrinogen and vWF Fibrinogen: AF: 3.3±0.7 vs. SR: 2.5±0.6
vWF: AF: 130±34 vs. SR: 101±30
Li-saw-Hee (PeAF) [51] Fibrinogen and vWF Fibrinogen: AF: 2.7±0.8 vs. SR: 2.5±0.6
vWF: AF: 106±26 vs. SR: 101±30
Li-saw-Hee (permanent) [51] Fibrinogen and vWF Fibrinogen: AF: 3.1±0.9 vs. SR: 2.5±0.6
vWF: AF: 143±47 vs. SR: 101±30
Feng [52] Fibrinogen, tPA, PAI and vWF Fibrinogen: AF: 3.33±0.53 vs. SR: 3.28±0.65
tPA: AF: 11.8±4 vs. SR: 10.5±3.9
PAI: AF: 24.2±10.7 vs. SR: 25.7±17.3
vWF: AF: 142±46.2 vs. SR: 137±43.4
Topcuoglu [53] PF1–2, TAT, tPA and PAI PF1–2: AF: 2.29±1.25 vs. SR: 1.37±0.87
TAT: AF: 10.07±6.04 vs. SR: 6.59±5.12
tPA: AF: 23.93±10.17 vs. SR: 21.16±12.72
PAI: AF: 37.05±22.32 vs. SR: 31.36±21.5
Mondillo [54] D-dimer, Fibrinogen, AT-III, tPA, PAI, vWF and sTM D-dimer: AF: 458.5±175 vs. SR: 170.25±23.75
Fibrinogen: AF: 3.81±1.09 vs. SR: 2.68±0.8
AT-III: AF: 99.9±15.8 vs. SR: 103.7±7.1
tPA: AF: 20.37±7.8 vs. SR: 9.8±3.21
PAI: AF: 15.2±6.2 vs. SR: 9.3±4.8
vWF: AF: 164.04±43.8 vs. SR: 93.44±33.04
sTM: AF: 39.14±13.2 vs. SR: 26.86±14.6
Giansante [55] D-dimer and Fibrinopeptide-A D-dimer: AF: 347±54 vs. SR: 323.75±46.75
Fibrinopeptide-A: AF: 12.9±2 vs. SR: 2.85±0.57
Li-saw-Hee [56] Fibrinogen, vWF and sTM Fibrinogen: AF: 2.9±0.9 vs. SR: 2.6±0.8
vWF: AF: 137±27 vs. SR: 103±33
sTM: AF: 52±17 vs. SR: 44±13
Marin (disease control) [57] D-dimer, AT-III, tPA and PAI D-dimer: AF: 533±111.25 vs. SR: 542.02±147.4
AT-III: AF: 58.4±32.75 vs. SR: 14.85±4.8
tPA: AF: 1.94±0.34 vs. SR: 2.34±0.14
PAI: AF: 43.77±8.62 vs. SR: 31.37±9.3
Marin (healthy control) [57] D-dimer, AT-III, tPA and PAI D-dimer: AF: 533±111.25 vs. SR: 15.92±6.07
AT-III: AF: 58.4±32.75 vs. SR: 10.25±1.1
tPA: AF: 1.94±0.34 vs. SR: 3.01±0.8
PAI: AF: 43.77±8.62 vs. SR: 7.35±0.9
Li-saw-Hee [58] D-dimer, Fibrinogen, vWF and sTM D-dimer: AF: 54±26 vs. SR: 32±20
Fibrinogen: AF: 4.2±0.6 vs. SR: 3.1±0.6
vWF: AF: 149±24 vs. SR: 103±30
sTM: AF: 27±10 vs. SR: 40±12
Roldan [59] D-dimer, Fibrinogen, AT-III, tPA, PAI and Plasmin-antiplasmin D-dimer: AF: 549.38±311.16 vs. SR: 12.3±3.7
Fibrinogen: AF: 3.69±0.81 vs. SR: 3.11±0.6
AT-III: AF: 62.47±79.46 vs. SR: 10.35±2.9
tPA: AF: 2.31±0.9 vs. SR: 2.88±1.58
PAI: AF: 42.78±22.85 vs. SR: 8.8±5.04
Plasmin-antiplasmin: AF: 275.31±151.69 vs. SR: 232.5±65.7
Tsai [50] PF1–2 and Fibrinopeptide-A PF1–2: AF: 4.74±0.49 vs. SR: 2.99±0.24
Fibrinopeptide-A: AF: 6±1.3 vs. SR: 1.4±0.3
Minamino [61] D-dimer, Fibrinogen, tPA and PAI D-dimer: AF: 160±55 vs. SR: 90±21
Fibrinogen: AF: 2.55±0.9 vs. SR: 1.93±0.71
tPA: AF: 12.05±5.4 vs. SR: 8.4±1.85
PAI: AF: 62.12±33.07 vs. SR: 52±17.4
Kahn [62] Fibrinogen Fibrinogen: AF: 3.7±0.8 vs. SR: 3.2±1.1
Sohara [63] D-dimer, Fibrinogen and TAT D-dimer: AF: 141.7±208.6 vs. SR: 67.2±31.6
Fibrinogen: AF: 2.62±0.65 vs. SR: 2.25±0.37
TAT: AF: 6.68±5.11 vs. SR: 3.11±1.86
Lip (PAF) [64] D-dimer and Fibrinogen D-dimer: AF: 96.75±21.75 vs. SR: 77.5±8.33
Fibrinogen: AF: 3.15±0.24 vs. SR: 2.6±0.19
Lip (chronic) [64] D-dimer and Fibrinogen D-dimer: AF: 149.5±37.5 vs. SR: 77.5±8.33
Fibrinogen: AF: 3.82±0.28 vs. SR: 2.6±0.19
Lip [65] D-dimer D-dimer: AF: 241.25±56.75 vs. SR: 103±22
Mitusch [66] D-dimer, Fibrinogen, PF1–2, TAT, tPA and PAI D-dimer: AF: 788±76 vs. SR: 405±46
Fibrinogen: AF: 4.5±0.2 vs. SR: 3.1±0.3
PF1–2: AF: 1.2±0.1 vs. SR: 1±0.1
TAT: AF: 8.5±1.6 vs. SR: 2.5±0.3
tPA: AF: 9.6±0.5 vs. SR: 7.2±0.5
PAI: 57.9±4.3 vs. SR: 47.7±4.9
Nagao [67] D-dimer and TAT D-dimer: AF: 366.3±211.3 vs. SR: 147.2±60.9
TAT: AF: 13.81±14.51 vs. SR: 3.47±2.52
Lip [68] D-dimer, Fibrinogen and vWF D-dimer: AF: 105.25±23.8 vs. SR: 77±8.3
Fibrinogen: AF: 3.71±0.28 vs. SR: 2.6±0.12
vWF: AF: 157.5±14.3 vs. SR: 109.25±11.16
Sohara [69] D-dimer, Fibrinogen and TAT D-dimer: AF: 78.6±48.2 vs. SR: 67.2±31.7
Fibrinogen: AF: 2.4±0.31 vs. SR: 2.25±0.3
TAT: AF: 4.7±3.2 vs. SR: 3.1±1.9
Kumagai [70] D-dimer D-dimer: AF: 150±19 vs. SR: 61±3
Gustafsson (with stroke) [71] D-dimer, Fibrinogen, Fibrinopeptide-A and vWF D-dimer: AF: 279.4±78.12 vs. SR: 169.12±34.3
Fibrinogen: AF: 4.4±0.2 vs. SR: 3.82±0.22
Fibrinopeptide-A: AF: 5.75±1.25 vs. SR: 4.25±0.7
vWF: AF: 17.75±2.25 vs. SR: 14.75±1.27
Gustafsson (without stroke) [71] D-dimer, Fibrinogen, Fibrinopeptide-A and vWF D-dimer: AF: 258.25±67 vs. SR: 169.12±34.3
Fibrinogen: AF: 4.5±0.35 vs. SR: 3.82±0.22
Fibrinopeptide-A: AF: 4.67±0.5 vs. SR: 4.25±0.7
vWF: AF: 17.87±2.62 vs. SR: 14.75±1.27
Occurrence of stroke in AF patients
Skov [72] D-dimer and Fibrinogen D-dimer: Stroke: 240±135 vs. without stroke: 250±63
Fibrinogen: Stroke: 3.63±0.34 vs. without stroke: 3.77±0.36
Zabczyk [73] D-dimer, Fibrinogen, PAI and sTM D-dimer: Stroke: 306±164.4 vs. without stroke: 234±106.5
Fibrinogen: Stroke: 3.24±0.27 vs. without stroke: 3.32±0.22
PAI: Stroke: 28.35±7.33 vs. without stroke: 20.3±6.1
sTM: Stroke: 7.37±0.87 vs. without stroke: 3.27±0.32
Cecchi [36] Fibrinogen Fibrinogen: Stroke: 3.68±1.04 vs. without stroke: 4.36±1.22
Loffredo [74] Fibrinogen Fibrinogen: Stroke: 3.63±1.06 vs. without stroke: 3.14±0.78
Topcuoglu [53] PF1–2, TAT, tPA and PAI PF1–2: Stroke: 2.68±2.84 vs. without stroke: 2.29±1.25
TAT: Stroke: 43.88±44.45 vs. without stroke: 10.07±6.04
tPA: Stroke: 25.42±27.23 vs. without stroke: 23.93±10.17
PAI: Stroke: 53.39±32.91 vs. without stroke: 37.05±22.32
Soncini [75] PF1–2 and TAT PF1–2: Stroke: 2.65±0.53 vs. without stroke: 1.41±0.17
TAT: Stroke: 26.05±9.22 vs. without stroke: 11.18±4.5
Kahn [62] Fibrinogen and AT-III Fibrinogen: Stroke: 3.8±0.9 vs. without stroke: 3.7±0.8
AT-III: Stroke: 1±0.14 vs. without stroke: 1±0.13
Gustafsson [71] D-dimer, Fibrinogen, AT-III, Fibrinopeptide-A and vWF D-dimer: Stroke: 291.5±156.3 vs. without stroke: 275.5±134
Fibrinogen: Stroke: 4.4±0.2 vs. without stroke: 4.5±0.35
AT-III: Stroke: 0.92±0.04 vs. without stroke: 0.91±0.01
Fibrinopeptide-A: Stroke: 5.75±1.25 vs. without stroke: 4.67±0.57
vWF: Stroke: 17.1±2.2 vs. without stroke: 15.6±2.6
Occurrence of Thromboembolism events in AF patients
Zabczyk [73] D-dimer, Fibrinogen and sTM D-dimer: TE: 311±134 vs. without TE: 234±105.5
Fibrinogen: TE: 3.4±0.15 vs. without TE: 3.35±0.25
sTM: TE: 6.05±1.25 vs. without TE: 3.20±0.35
Roldan [76] PF1–2 PF1–2: TE: 1.37±0.4 vs. without TE: 1.31±0.33
Feinberg [77] PF1–2 PF1–2: TE: 0.7±0.5 vs. without TE: 0.6±0.4
Pongratz [78] Fibrinogen and AT-III Fibrinogen: TE: 4.1±1.3 vs. without TE: 3.7±1.5
AT-III: TE: 99±13 vs. without TE: 105±22
Black [79] Fibrinogen Fibrinogen: TE: 6±1.32 vs. without TE: 4.56±1.64
Kumagi [70] D-dimer D-dimer: TE: 196±73 vs. without TE: 140±19
Figure 1.

Figure 1

Forest plot of weighted mean difference (WMD) for association between level of D-dimer and occurrence of AF.

Fibrinogen

A total of 43174 cases were included from 58 studies. Patient populations of the included studies ranged from 22 to 11 107 patients. Of 43 174 cases, 5583 were allocated to AF group and 37 591 to the SR group. Mean level of fibrinogen was 3.24 g/L in the AF group and 2.78 g/L in the SR group (details in Tables 1 and 2). Pooled analysis showed that fibrinogen level was significantly higher in patients with AF compared to those with SR with WMD of 0.43 (95% CI: 0.36–0.51; p<0.001, Figure 2) using a random effect model. There was significant heterogeneity among the studies (I2=98.4%; heterogeneity p<0.001).

Figure 2.

Figure 2

Forest plot of weighted mean difference (WMD) for association between level of fibrinogen and occurrence of AF.

Prothrombin fragment 1–2 (PF 1–2)

A total of 1047 cases were included from 9 studies, of which 694 cases were allocated to the AF group and 353 to the SR group. The mean level of PF 1–2 was 1.88 nmol/mL in the AF group and 1.35 nmol/mL in the SR group (details in Tables 1 and 2). Pooled analysis revealed that PF 1–2 was significantly higher in the AF group than SR with WMD of 0.53 nmol/mL (95% CI: 0.33–0.73; p<0.001, Figure 3) using a random effect model. There was significant heterogeneity among the studies (I2=99.5%; heterogeneity p<0.001)

Figure 3.

Figure 3

Forest plot of weighted mean difference (WMD) for association between level of PF1–2 and occurrence of AF.

Antithrombin III (AT-3)

A total of 300 patients were included from 6 studies. Of them, 153 cases were allocated to the AF group and 147 cases to the SR group. The mean level of AT-III was 79.39 in AF and 53.30 in SR (details in Tables 1 and 2). Pooled analysis revealed that the mean level of AT-III was significantly higher in the AF group compared to the SR group with WMD of 23.90 (95% CI: 7.51–40.29; p=0.004, Supplementary Figure 1) with significant heterogeneity (I2=94.2%; heterogeneity p<0.001).

Thrombin-antithrombin (TAT)

A total of 501 cases were included from 8 studies, of which 335 cases were allocated to the AF group and 166 to the SR group. The mean level of TAT was 10.22 ng/mL in the AF group and 4.61 ng/mL in the SR group (details in Tables 1 and 2). Pooled analysis revealed that level of TAT was significantly higher in the AF group compared to the SR group with WMD of 5.47 ng/mL (95% CI: 1.77–9.18; p=0.004, Supplementary Figure 2) using a random effect model. There was significant heterogeneity among the studies (I2=99.7%; heterogeneity p<0.001).

Association of fibrinolytic markers with AF

Tissue-type plasminogen activator (t-PA)

A total of 4326 cases were included from 14 studies. Patient populations of the included studies ranged from 36 to 3212 patients. From 4326 cases, 533 were allocated to the AF group and 3793 to the SR group. Mean level of t-PA was 10.97 ng/mL in the AF group and 8.61 ng/mL in the SR group (details in Tables 1 and 2). Pooled assessment analysis indicated that t-PA in patients with AF was significantly higher compared to those with SR with WMD of 2.13 (95% CI: 1.04–3.21; p<0.001, Figure 4) using a random effect model. Significant heterogeneity was observed among the studies (I2=98.3%; heterogeneity p<0.001).

Figure 4.

Figure 4

Forest plot of weighted mean difference (WMD) for association between level of t-PA and occurrence of AF.

Plasminogen activator inhibitor (PAI)

A total of 4267 cases were included from 15 studies, of which 540 cases were in the AF group and 3727 in the SR group. The mean level of PAI was 30.59 ng/mL in AF and 19.58 ng/mL in SR group (details in Tables 1 and 2). Pooled analysis revealed that the level of PAI was significantly higher in the AF group compared to the SR group with WMD of 11.44 ng/mL (95% CI: 6.83–16.05; p<0.001, Figure 5) with significant heterogeneity (I2=99.4%; heterogeneity p<0.001).

Figure 5.

Figure 5

Forest plot of weighted mean difference (WMD) for association between level of PAI and occurrence of AF.

Fibrinopeptide-A

A total of 336 cases were included from 6 studies, whereas 148 cases were allocated to the AF group and 188 to the SR group. The mean level of fibrinopeptide-A was 7.33 ng/ml in AF and 3.18 ng/ml in SR (details in Tables 1 and 2). Pooled analysis showed that the level of fibrinopeptide-A was statistically higher in the AF group compared to SR with WMD of 4.13 ng/mL (95% CI: 0.67–7.60; p=0.01, Supplementary Figure 3) with significant heterogeneity (I2=99.6%; heterogeneity p<0.001).

Association of endothelial markers with AF

von Willebrand factor (vWF)

A total of 18 057 cases were enrolled to the analysis from 32 studies, of which 2607 cases were allocated to the AF group and 15450 to the SR group. The mean level of vWF was 132.38 IU/dL in the AF group and 104.27 IU/dL in the SR group (details in Tables 1 and 2). Pooled analysis revealed a higher level of vWF in patients with AF than in patients with SR with WMD of 27.01 (95% CI: 19.79–34.23; p<0.001, Figure 6) using a random effect model. There was significant heterogeneity among the studies (I2=98.7%; heterogeneity p<0.001).

Figure 6.

Figure 6

Forest plot of weighted mean difference (WMD) for association between level of vWF and occurrence of AF.

Soluble thrombomodulin (sTM)

A total of 591 cases were included from 7 studies. From all cases, 351 were allocated to the AF group and 240 to the SR group. The mean level of sTM was 25.96 ng/mL in the AF group and 22.04 ng/mL in the SR group (details in Tables 1 and 2). Pooled analysis indicated that sTM was significantly higher in the AF group compared to the SR group with WMD of 3.92 (95% CI: 0.53–7.32; p<0.001, Supplementary Figure 4) using a random effect model. There was significant heterogeneity among the studies (I2=91.2%; heterogeneity p<0.001).

Related clinical adverse events of AF

Association of coagulation, fibrinolytic, and endothelial markers with thromboembolic events

Six studies reported the association of markers with thromboembolic events (Table 3). D-dimer, fibrinogen, and PF 1–2 levels were investigated in at least 2 studies and were included in the meta-analysis (Table 2). AT-III and sTM levels were reported in only 1 study and thus were not included in the analysis. Pooled analysis revealed that the level of D-dimer (number of studies=2, WMD of 60.67, 95% CI: 28.61 to 92.73; p<0.001 and I2=0%; heterogeneity p=0.59, Supplementary Figure 5) was significantly higher in patients with thromboembolic events than in patients without thromboembolic events. Pooled analysis showed that the level of fibrinogen (number of studies=3, WMD of 0.61, 95% CI: −0.30 to 1.53; p=0.19 and I2=92.5%; heterogeneity p<0.001, Supplementary Figure 6), and the level of PF1–2 (number of studies=2, WMD of 0.08, 95% CI: −0.06 to 0.22; p=0.18 and I2=0%; heterogeneity p=0.83, Supplementary Figure 7) were not significantly different whether they suffered from thromboembolic events or not.

Table 3.

Characteristics of included studies for meta-analysis of association of biomarkers and clinical adverse events related to AF.

First Author Country and year Study design Number Mean age AC in patients with adverse events AC in patients without adverse events Adverse events NOS
Skov [72] Denmark-2014 Case-control 179 71.6 100% 100% Stroke 8
Zabczyk [73] Poland-2011 Case-control 62 78 81.8% 72.5% Stroke and thromboembolic event 8
Cecchi [36] Italy-2006 Case-control 156 74.4 100% 100% Stroke 7
Loffredo [74] Italy-2005 Case-control 163 72.3 70% 63.4% Stroke 8
Topcuoglu [53] Turkey-2001 Case-control 39 63.6 Stroke 7
Soncini [75] Italy-1998 Case-control 32 71.5 Stroke 7
Kahn [62] Canada-1997 Case-control 75 72.7 100% 100% Stroke 7
Gustafsson [71] Sweden-1990 Case-control 40 70 Stroke 8
Roldan [76] Spain-2003 Case-control 191 72.3 100% 100% Thromboembolic event 8
Feinberg [77] UK-1999 Cohort 726 Thromboembolic event 8
Pongratz [78] Germany-1997 Case-control 60 65.7 Thromboembolic event 6
Black [79] Australia-1993 Case-control 135 50% 28% Thromboembolic event 8
Kumagi [70] Japan-1990 Case-control 49 Thromboembolic event 7

Association of coagulation, fibrinolytic, and endothelial markers with stroke

Eight studies investigated the association of hemostatic markers with stroke (Table 3). D-dimer, fibrinogen, PF1–2, TAT, PAI, and AT-III were examined in at least 2 studies and were included in the meta-analysis (Table 2). Fibrinopeptide-A, tPA, vWF, and sTM levels were reported in only 1 study and were not included in the analysis. Pooled assessment analysis indicated that the level of PF 1–2 (number of studies=2, WMD of 1.06, 95% CI: 0.39 to 1.74; p=0.002 and I2=36.4%%; heterogeneity p=0.21, Supplementary Figure 8), level of TAT (number of studies=2, WMD of 22.28, 95% CI: 4.16 to 40.39; p=0.016 and I2=74.5%; heterogeneity p<0.04, Supplementary Figure 9), and level of PAI (number of studies=2, WMD of 8.60, 95% CI: 4.12 to 13.09; p<0.001 and I2=0%; P-heterogeneity=0.36, Supplementary Figure 10) were significantly higher in patients with stoke as compared to patients without stroke. Pooled analysis showed that the levels of D-dimer (number of studies=3, WMD of 8.08, 95% CI: −32.80 to 48.96; p=0.69 and I2=4.7%%; heterogeneity p=0.35, Supplementary Figure 11), fibrinogen (number of studies=6, WMD of 0.02, 95% CI: −0.22 to 0.25; p=0.88 and I2=79.9%%; heterogeneity p<0.001, Supplementary Figure 12), and AT-III (number of studies=2, WMD of 0.01, 95% CI: −0.01 to 0.03; p=0.51 and I2=0%%; heterogeneity p=0.39, Supplementary Figure 13) did not significantly differ between patients with stroke and patients without stroke.

Publication bias, subgroup analysis, and meta-regression

Begg’s tests suggested that there might be publication bias for studies examining levels of D-dimer, fibrinogen, AT-III, and vWF (Supplementary Figures 1423). Extra details of each study, subgroup analysis, and meta-regression are presented in Supplementary Tables 2 and 3, respectively.

Discussion

For years, finding the pathophysiological mechanisms involved in AF has been an important research area in cardiology and cardiac surgery [8083]. A proposed mechanism leading to an increased incidence of AF is coagulation and prothrombotic state [8083]. Investigators believe that procoagulant and prothrombotic states might be more expressed in patients with chronic AF as compared to those with SR [8083]. In the present study, we investigated a set of coagulation biomarkers to closely examine this possible pathophysiology of AF.

D-dimer is a byproduct of the degeneration of fibrin and reflects thrombin and fibrin turnover [84]. D-dimer is one of the surrogate markers for a hypercoagulable state which is one component of Virchow’s triad [84]. The results of the present study revealed that the level of D-dimer was significantly higher in AF patients compared to those with SR. Generally, increased level of D-dimer is directly associated with an increased incidence of AF; however, it should be noted that there is a significant heterogeneity in our results. The subgroup analysis based on the year of publication, geographic area, design of the studies, age, sex, risk factors of diabetes and hypertension, number of cases, and chronic or non-chronic AF indicated that D-dimer was always considerably higher in AF groups compared with SR groups, despite heterogeneity among studies. A subgroup analysis reported that both paroxysmal and permanent AF had higher levels of D-dimer and the type of AF was not considered a factor of heterogeneity.

Fibrinogen is an acute-phase protein synthesized in the liver, and higher levels are associated with increased risk of cardiovascular diseases [85]. Our results also demonstrate that the level of fibrinogen was considerably higher in the AF group as compared to the SR group. A direct relationship between the level of fibrinogen and the incidence of AF was confirmed; however, this relationship was also associated with a justifiable heterogeneity. The analyses performed on coagulation markers PF1–2, TAT, and AT-III also indicated that the level of these markers was significantly higher in AF groups as compared to SR groups. The results of our study also showed that the type of AF could be a heterogeneity factor in the meta-analysis of D-dimer level. According to the analysis of the available data in our study, the level of D-dimer was strongly and directly related to the occurrence of thromboembolism in AF patients, while fibrinogen and PF1–2 were not. Other coagulation markers, in which no association with stroke and thromboembolism was reported, did not have sufficient data and thus no analysis was carried out.

Another proposed mechanism for the incidence of AF is fibrinolytic activity. PAI is a direct inhibitor of the plasminogen activation system, whereas its interaction with the adhesive glycoprotein plays a role in tissue remodeling [86]. Increased levels of PAI have been associated with an increased risk for coronary artery stenosis and acute coronary syndrome [86]. Our findings suggest a significant direct association between increased level of PAI and the incidence of AF, as patients with AF showed higher levels of PAI compared to those with SR.

Sorted analyses in terms of the year of publication, study design, number of cases, age, sex, diabetes, and hypertension indicated that the level of PAI in the AF group had constantly been higher than in the SR group. None of the above-mentioned criteria appeared to be a factor of heterogeneity. The results of this study predict that with the current heterogeneity in analysis on the level of PAI, history of MI and type of AF (chronic or non-chronic) could be considered factors of heterogeneity. Our results showed that the level of tPA in the AF group was considerably higher than in the SR group. There was a direct correlation between the incidence of AF and the level of tPA from laboratory and clinical studies, although statistically there was a notable heterogeneity. A subgroup analysis revealed that history of MI, type of AF, and geographical area may be considered factors of heterogeneity. Fibrinopeptide-A is also a marker of fibrinolytic activity, and we found that it was clearly higher in the AF group as compared to the SR group. However, we could not find factors of heterogeneity in the subgroup analysis. Owing to insufficient studies on alfa-2 antiplasmin, plasmin-antiplasmin, and urokinase-type plasminogen activator inhibitor, analyzing these markers was not feasible. Although based on the results, this fact is understandable and verifiable from laboratory and clinical studies, not finding a definite factor of heterogeneity of the results might be explained by the fact that other factors had affected the results of the published studies in recent years that have not been taken into account or not been reported on by their authors. Regarding the association of the level of PAI with stroke in AF patients, our results suggest a significant relationship between increased level of PAI and increased risk of stroke. Another mechanism which needs to be examined in AF patients is endothelial activity.

Increased levels of vWF have been found in inflammatory and atherosclerotic vascular diseases that are usually associated with damaged endothelium [87]. The pooled results of our study indicate that the level of vWF was significantly higher in AF patients as compared with the SR group. The results of subgroup analysis suggested that in all types of AF, including paroxysmal, persistent, and permanent, and also in terms of chronic or non-chronic AF, the level of vWF was statistically and clinically higher in the AF group. According to the subgroup analysis, geographic area, design of the studies, and number of cases could be defined as factors of heterogeneity. The findings of this study affirmed that STM, as another marker of endothelial activity, had a significant influence on the incidence of AF, as the level of STM considerably higher in AF patients compared with SR patients. Generally, increased endothelial activity appears to be associated with higher incidence of AF, which is confirmed statistically and through laboratory studies. We conducted a subgroup analysis based on cardiovascular risk factors, whereas one of the most significant cardiac risk factors affecting our results was history of MI. Also, DM, HTN, and smoking were not considered factors of heterogeneity.

Lip et al. argued that using anticoagulants could reduce the levels of D-dimer and PF1–2 in AF patients; therefore, differences in the use of anticoagulants in various studies might be considered confounding factors [68]. In this study, we defined codes for using anticoagulants. Performing a subgroup analysis, we found that on the levels of AT3, tPA, PAI, and STM, the available data about the status of using anticoagulants were confounding factors which possibly could play a part in the incidence of heterogeneity. Heterogeneity is higher in meta-analyses of non-experimental studies, which can be caused by several factors, such as: 1) many confounding factors, 2) less controlled bias, and 3) different definition of outcomes.

Meta-regression was performed on the levels of D-dimer, fibrinogen, PAI, and vWF that had greater number of studies than other markers and could be analyzed based on regression. According to the results of meta-regression on the level of D-dimer, difference in the design of studies, type of AF, and difference in geographical area of the study appeared to be factors of heterogeneity. For the level of fibrinogen, the year of publication (before or after 2000) and geographical area of the study were factors. For the level of vWF, difference in the design of studies and geographical area of the study were factors. For the level of PAI, difference in using anticoagulants was a factor.

Conclusions

Generally, considering the results of this study, we can strongly claim that prothrombotic state has a critical role as a precipitating mechanism in the incidence of AF and clinical complications of thromboembolism and stroke. The levels of coagulation, fibrinolytic, and endothelial markers have been reported to be significantly higher in AF patients than in SR patients. We believe that several other interventions may affect the association of these biomarkers with the incidence of AF; however, they have not been taken into account or mentioned in the series of past and recent studies. High heterogeneity is not the end of trying to find the relation between effective markers in predicting AF, but definitely points out that in future the authors are required to converge the quality of performing studies by observing the factors of heterogeneity and other confounding factors as described in the present study. Finally, emphasizing the association of coagulation, fibrinolytic, and endothelial markers with the incidence of AF and its clinical outcomes, and defining the factors of heterogeneity using subgroup analysis and meta-regression, we believe that in meta-analysis of the relationship of the levels of biomarkers with the incidence of AF, there are real-world associations with heterogeneity. Efforts should be made to find and introduce these associations as well as factors of heterogeneity that affect the results.

Supplementary Files

Supplementary Figure 1

Forest plot of weighted mean difference (WMD) for association between level of AT-III and occurrence of AF.

Supplementary Figure 2

Forest plot of weighted mean difference (WMD) for association between level of TAT and occurrence of AF.

Supplementary Figure 3

Forest plot of weighted mean difference (WMD) for association between level of fibrinopeptide and occurrence of AF.

Supplementary Figure 4

Forest plot of weighted mean difference (WMD) for association between level of sTM and occurrence of AF.

Supplementary Figure 5

Forest plot of weighted mean difference (WMD) for association between level of D-dimer and occurrence of thromboembolism.

Supplementary Figure 6

Forest plot of weighted mean difference (WMD) for association between level of fibrinogen and occurrence of thromboembolism.

Supplementary Figure 7

Forest plot of weighted mean difference (WMD) for association between level of PF1–2 and occurrence of thromboembolism.

Supplementary Figure 8

Forest plot of weighted mean difference (WMD) for association between level of PF1–2 and occurrence of stroke.

Supplementary Figure 9

Forest plot of weighted mean difference (WMD) for association between level of TAT and occurrence of stroke.

Supplementary Figure 10

Forest plot of weighted mean difference (WMD) for association between level of PAI and occurrence of stroke.

Supplementary Figure 11

Forest plot of weighted mean difference (WMD) for association between level of D-dimer and occurrence of stroke.

Supplementary Figure 12

Forest plot of weighted mean difference (WMD) for association between level of fibrinogen and occurrence of stroke.

Supplementary Figure 13

Forest plot of weighted mean difference (WMD) for association between level of AT-III and occurrence of stroke.

Supplementary Figure 14

Funnel plot for publication bias of studies investigating D-dimer.

Supplementary Figure 15

Funnel plot for publication bias of studies investigating fibrinogen.

Supplementary Figure 16

Funnel plot for publication bias of studies investigating PF1–2.

Supplementary Figure 17

Funnel plot for publication bias of studies investigating of TAT.

Supplementary Figure 18

Funnel plot for publication bias of studies investigating AT-III.

Supplementary Figure 19

Funnel plot for publication bias of studies investigating fibrinopeptide-A.

Supplementary Figure 20

Funnel plot for publication bias of studies investigating t-PA.

Supplementary Figure 21

Funnel plot for publication bias of studies investigating PAI.

Supplementary Figure 22

Funnel plot for publication bias of studies investigating vWF.

Supplementary Figure 23

Funnel plot for publication bias of studies investigating sTM.

Supplementary Table 1.

Included, and excluded studies.

Clinical outcomes and biomarkers Studies were identified and screened [n] Studies were excluded according to title, abstract or full text [n] Studies were included [n]
Fibrinogen 315 275 40 approved articles with totally 58 enrolled data for meta-analysis
D-dimer 238 121 30 approved articles with totally 40 enrolled data for meta-analysis
PF1–2 86 79 7 approved articles with totally 9 enrolled data for meta-analysis
AT-III 98 94 4 approved articles with totally 6 enrolled data for meta-analysis
TAT 127 120 7 approved articles with totally 8 enrolled data for meta-analysis
t-PA 437 426 11 approved articles with totally 14 enrolled data for meta-analysis
PAI 91 80 11 approved articles with totally 15 enrolled data for meta-analysis
Alpha-2 antiplasmin 18 18
Fibrinopeptide-A 21 18 3 approved articles with totally 4 enrolled data for meta-analysis
u-PA 29 29
Plasmin-antiplasmin 22 21 1 approved articles with
vWF 185 21 approved articles with totally 32 enrolled data for meta-analysis
sTM 37 31 6 approved articles with totally 7 enrolled data for meta-analysis

Supplementary Table 2.

Extra details of characteristics of each study for exploration of heterogeneity factors.

First Author Geographic area Total N Total age Total male Total DM Total HTN Total MI Total diuretic Total ACEI Total. statin Total BB AC-code Chronic or not CS
Negreva [9] European 103 59.67 50.45 4.8 68.96 ND ND 28.165 6.805 34.97 1 Acute 14.5
Amdur [10] North America 3762 58.9 54.55 49.8 86.7 ND 64.65 69.85 ND 56.1 4 No detection ND
Yusuf (disease control) [11] Asian 65 31.5 42.85 ND ND ND ND ND ND ND 1 No detection ND
Yusuf (healthy control) [11] Asian 65 30.055 38.55 ND ND ND ND ND ND ND 1 No detection ND
Drabik (persistent) [12] European 97 60.1 64.95 20 48.85 17.35 ND 52.25 53.15 60.6 4 Acute 22.5
Drabik (PAF) [12] European 91 60 55.15 16.4 46.05 26.65 ND 54.05 47.45 57.25 4 Acute 20
Borgi [13] Africa 69 ND ND ND ND ND ND ND ND ND 5 No detection ND
Oneal (with comorbidities) [14] North America 647 69.5 54 32.5 70 ND ND ND 29.5 ND 4 No detection 15
Oneal (with comorbidities) [14] North America 883 64.5 32.5 29.5 54.5 ND ND ND 30 ND 4 No detection 14
Erdogan [15] European 67 69.55 49.275 10 65 ND 18 53.5 ND 43.3 3 Chronic 6
Chen (without comorbidities) [16] Asian 162 53.695 61.03 15 31.5 ND ND ND ND ND 4 Acute ND
Chen (with comorbidities) [16] Asian 207 55.845 64.2 13.5 35.5 ND ND ND ND ND 4 Acute ND
Schnabel [17] European 4998 60.05 54.5 10.15 61.95 8.3 ND ND ND ND 5 No detection 15.3
Wei-Hong Ma [18] Asian 105 58 72.25 0 100 ND ND ND ND ND 2 No detection ND
Xu (without comorbidities) [19] Asian 115 66.85 50.45 37.4 53.1 ND ND 42.6 29.55 43.55 4 Chronic 38.5
Xu (with comorbidities) [19] Asian 115 67.975 51.3 36.5 57.5 ND ND 40.8 26.05 40.95 4 Chronic 31.2
Distelmaier [20] North America 198 73.5 61 24 60.5 25 ND ND ND ND 5 Acute ND
Scridon (PAF) [21] European 69 55.5 78.5 7 39.5 ND ND 18.5 13.5 ND 3 Acute 13
Scridon (persistent) [21] European 53 55 78.5 7 35.5 ND ND 24 15.5 ND 3 Acute 13
Berge [22] European 189 75 71 8 48 ND 19 21 34.5 28 4 No detection ND
Acevedo [23] South America 150 ND ND ND ND ND ND ND ND ND 1 No detection ND
Zorlu [24] European 150 69.5 62 16 33 ND ND 75.5 ND 76 1 No detection ND
Alonso (White) [25] North America 11107 55.7 52.25 12.05 34.85 6.6 ND ND ND ND 1 No detection 26.7
Alonso (African-American) [25] North America 3751 54.8 41.2 26.05 63.65 ND ND ND ND ND 1 No detection 32
Adamsson Eryd [26] European 6031 47.25 100 4.8 6 ND ND ND ND 5 No detection 48
Fu [27] Asian 169 54.45 63.5 ND ND ND ND ND 12.9 6.1 4 No detection 42.5
Hou (disease control) [28] Asian 52 64.85 57.6 0 ND ND ND 40.35 ND 11.45 4 Acute 26.9
Hou (healthy control) [28] Asian 52 65.3 57.6 0 ND ND ND 21.15 ND 7.65 4 Acute 26.9
Schnabel [29] North America 3120 62.05 52.5 ND 38 ND ND ND ND ND 5 No detection ND
Letsas (PAF) [30] European 93 64.4 59 6 60.5 ND ND 43 15.5 34 5 acute ND
Letsas (permanent) [30] European 89 66.6 59.5 11 63 ND ND 52.5 13.5 35.5 5 chronic ND
Gartner [31] Australia 250 59.45 65.5 9 48.5 ND ND ND ND ND 4 No detection ND
Targonski (PAF and PeAF) [32] European 56 63.5 67.7 44.75 69.6 ND 67.7 96.65 87.3 85.4 4 12.4
Targonski (Permanent) [32] European 73 69.3 66.4 33.3 72.2 ND 78.05 90.85 70.6 89.2 4 11.3
Marcus [33] North America 971 70 87.5 22.5 65.5 52 ND 57 59.5 ND 5 No detection 15
Blann [34] European 82 64.5 62.75 ND 27 ND 16.5 19 ND 18.5 3 No detection 12.6
Topaloglu (disease control) [35] European 46 34.5 ND 0 0 ND ND ND ND ND 5 No detection ND
Topaloglu (healthy control) [35] European 38 36 ND 0 0 ND ND ND ND ND 5 No detection ND
Cecchi (with cerebral ischemic) [36] European 192 73.5 60.2 7.25 45.95 ND 18.05 27.3 6.85 6.8 3 No detection 30.1
Cecchi (without cerebral ischemic) [36] European 224 73 59.35 6.4 47.5 ND 20.5 27.05 7.3 8.05 3 No detection 25.9
Turgut (disease control) [37] European 55 66.11 44.7 17.4 67.6 ND ND ND ND ND 4 No detection ND
Turgut (healthy control) [37] European 46 66.56 43.95 3.85 36.55 ND ND ND ND ND 4 No detection ND
Heeringa [38] European 486 77.5 51 17.5 25 22.5 31.65 ND ND 16.55 5 No detection 20.9
Roldan [39] European 265 ND ND ND ND ND ND ND ND ND 4 No detection ND
Marin (acute AF) [40] European 48 63.5 50 0 8.3 8.3 ND 10.4 ND 8.3 4 Acute ND
Marin (chronic AF) [40] European 48 63.5 47.9 14.55 12.5 6.25 ND 6.25 ND 4.15 4 Chronic ND
Inoue (with comorbidities) [41] Asian 251 ND ND ND ND ND ND ND ND ND 5 No detection ND
Inoue (Lone AF) [41] Asian 106 ND ND ND ND ND ND ND ND ND 5 No detection ND
Conway [42] European 147 68 62 7.5 26.5 13.5 ND ND ND ND 3 chronic 16
Hatzinikolaou-Kotsakou (PAF) [43] European 35 59 77.25 8.3 13.85 13.85 ND ND ND ND 5 Acute 20.5
Hatzinikolaou-Kotsakou (persistent) [43] European 34 60 73.5 5.85 20.585 17.6 ND ND ND ND 5 Acute 20.8
Hatzinikolaou-Kotsakou (permanent) [43] European 37 61.5 76.15 5 22.5 15 ND ND ND ND 5 Chronic 24.2
Conway [44] European 74 67.5 70.2 9.45 27 1.35 ND ND ND ND 5 Acute 11.2
Kamath (PAF and PeAF) [45] European 62 63.5 51.6 ND ND ND ND ND ND ND 1 Acute ND
Kamath (permanent AF) [45] European 124 66 52.65 ND ND ND ND ND ND ND 1 Chronic ND
Marin [46] European 80 70.5 55 19.5 52 6.5 ND ND ND 4 4 Chronic ND
Conway [47] European 486 77.5 51.05 8.3 10.595 8.6 ND ND ND ND 1 No detection 10.3
Kamath (PAF) [48] European 58 63 48.235 6.85 24.1 3.4 ND ND ND ND 4 Acute 5.1
Kamath (permanent AF) [48] European 116 65 52.25 5.15 30.45 6.85 ND ND ND ND 4 Chronic 5.1
Kamath [49] European 143 70 63.2 ND ND ND ND ND ND ND 1 No detection 5.9
Wang [50] Asian 3212 60 51.65 23.65 40.6 3.65 ND ND ND ND 5 No detection 32.6
Li-saw-Hee (PAF) [51] European 43 64 77.3 2.15 10.85 6.5 ND ND ND ND 3 Acute 13.4
Li-saw-Hee (PeAF) [51] European 43 64 77.25 2.15 13 4.3 ND ND ND ND 3 Acute 11.5
Li-saw-Hee (permanent) [51] European 43 65 77.25 6.52 23.9 15.2 ND ND ND ND 3 Chronic 11.5
Feng [52] North America 214 62.15 73.5 12.85 36 23.25 ND ND ND ND 6 No detection 16.1
Topcuoglu [53] European 36 62.35 61.87 13.5 42.5 ND ND ND ND ND 1 No detection 20
Mondillo [54] European 80 66.95 82.85 ND ND ND ND ND ND ND 3 Chronic 33.7
Giansante [55] European 105 63.5 55.67 8.5 29.25 ND ND ND ND ND 1 Acute 35.6
Li-saw-Hee [56] European 112 67 77.5 3.85 12.5 11.55 ND ND ND ND 1 Chronic 13.3
Marin (disease control) [57] European 42 53.5 17.35 0 ND ND ND ND ND ND 1 No detection ND
Marin (healthy control) [57] European 38 ND ND 0 ND ND ND ND ND ND 1 No detection ND
Li-saw-Hee [58] European 50 59 20 ND ND ND ND ND ND ND 5 Chronic 20
Roldan [59] European 56 62 ND 0 ND ND ND ND ND ND 1 Chronic ND
Tsai [50] Asian 111 64 74.45 ND ND ND ND ND ND ND 4 Chronic ND
Minamino [61] Asian 90 63 73.3 12.5 23.5 ND ND ND ND 14.5 5 Chronic ND
Kahn [62] North America 81 ND ND ND ND ND ND ND ND ND 1 Chronic ND
Sohara [63] Asian 30 59.1 ND ND ND ND ND ND ND ND 1 Acute ND
Lip (PAF)[64] European 188 59.85 57.8 ND ND ND ND ND ND ND 1 Acute 30
Lip (chronic) [64] European 214 61.8 56.37 ND ND ND ND ND ND ND 1 Chronic 33
Lip [65] European 77 ND ND ND ND ND ND ND ND ND 1 Chronic ND
Mitusch [66] European 97 71 51.35 25 67 ND ND ND ND ND 1 No detection ND
Nagao [67] Asian 36 79.95 44.575 ND ND ND ND ND ND ND 1 No detection ND
Lip [68] European 245 61.15 53.3 ND ND ND ND ND ND ND 5 Chronic ND
Sohara [69] Asian 22 ND ND ND ND ND ND ND ND ND 1 Acute ND
Kumagai [70] Asian 94 62.5 48.15 ND ND ND ND ND ND ND 1 Chronic ND
Gustafsson (with stroke) [71] European 60 77 ND ND ND ND ND ND ND ND 1 No detection 30
Gustafsson (without stroke) [71] European 60 77 ND ND ND ND ND ND ND ND 1 No detection 25

Supplementary Table 3.

Subgroup-analysis and meta-regression.

Subgroup Studies (N) WMD (95% CI) I-squared and P-value respectively P-value of meta-regression
D-dimer

Year of publication 0.845
 >2000 25 243.7 (209.1 to 278.2) 99.8% and 0.001
 ≤2000 16 137.3 (103.6 to 171.1) 99.1% and 0.001

Geographic area 0.008
 Asian 13 144.4 (108.8 to 180.1) 99.7% and 0.001
 European 24 242.5 (199.4 to 285.7) 99% and 0.001
 Africa 1 0.83 (0.28 to 1.38)
 North American 2 65.11 (−62.93 to 193.1) 98.2% and 0.001
 South American
 Australia 1 472 (429.3 to 514.6)

Design of study 0.001
 Cohort 35 176.1 (153.7 to 198.4) 99.7% and 0.001
 Case-control 6 290.2 (189.5 to 390.8) 99.8% and 0.001

Number of population 0.49
 >300 2 65.1 (−62.9 to 193.1) 99.9% and 0.001
 ≤300 39 204.4 (179.9 to 229) 99.4% and 0.001

Mean Age 0.92
 >60 years 26 226.7 (188.6 to 264.8) 99.7% and 0.001
 ≤60 years 9 160.7 (77 to 244.4) 99.6% and 0.001

Male 0.94
 >70% 3 113.7 (22.2 to 205.1) 98.9% and 0.001
 ≤70% 26 227.8 (187.8 to 267.8) 99.6% and 0.001

Diabetes mellitus 0.47
 >30% 2 290 (271.6 to 308.4) 73.3% and 0.001
 ≤30% 20 264.8 (205.7 to 323.8) 99.7% and 0.001

Hypertension 0.96
 >70% 1 96.1 (47.2 to 144.7)
 ≤70% 19 258.6 (194.7 to 321.9) 99.8% and 0.001

History of myocardial infarction 0.95
 >20% 1 −0.16 (−0.42 to 0.107)
 ≤20% 4 761.7 (140.3 to 1383.2) 98.2% and 0.001

Anti-coagulant status codes 0.91
 1 18 215.3 (172 to 258.6) 98.9% and 0.001
 2
 3 2 154 (−110.2 to418.4) 97.6% and 0.001
 4 11 331.3 (225.5 to 437.1) 99.6% and 0.001
 5 10 91.1 (56 to 126.3) 99.9% and 0.001
 6

AF 0.015
 Chronic 14 261.3 (208.9 to 313.8) 99.6% and 0.001
 Non-chronic 11 104.7 (29.6 to 179.8) 99.4% and 0.001

Type of AF 0.254
 Paroxysmal 5 19.6 (12.5 to 26.8) 0.0% and 0.78
 Persistent
 Permanent 4 512.5 (135.3 to 889.8) 99% and 0.001

Cigarette smoking 0.132
 >30% 7 111.1 (106.1 to 116) 99.7% and 0.001
 ≤30% 8 −0.136 (−0.403 to 0.131) 98.3% and 0.001

Fibrinogen

Year of publication 0.02
 >2000 46 0.29 (0.24 to 0.35) 96.1% and 0.001
 ≤2000 12 0.75 (0.54 to 0.96) 96.4% and 0.001

Geographic area 0.04
 Asian 9 0.35 (0.24 to 0.47) 95% and 0.001
 European 40 0.53 (0.38 to 0.68) 97.9% and 0.001
 Africa
 North American 9 0.10 (0.02 to 0.19) 97.3% and 0.001
 South American
 Australia

Design of study 0.44
 Cohort 15 0.22 (0.15 to 0.29) 98.2% and 0.001
 Case-control 43 0.52 (0.36 to 0.69) 97.4% and 0.001

Number of population 0.053
 >300 11 0.15 (0.05 to 0.25) 98.4% and 0.001
 ≤300 47 0.52 (0.39 to 0.64) 98% and 0.001

Mean Age 0.94
 >60 years 43 0.48 (0.37 to 0.59) 98.7% and 0.001
 ≤60 years 13 0.26 (0.17 to 0.34) 95% and 0.001

Male 0.468
 >70% 13 0.56 (0.35 to 0.77) 93.9% and 0.001
 ≤70% 37 0.40 (0.31 to 0.48) 98.9% and 0.001

Diabetes mellitus 0.97
 >30% 6 0.40 (0.11 to 0.69) 96.5% and 0.001
 ≤30% 37 0.35 (0.28 to 0.43) 97.3% and 0.001

Hypertension 0.60
 >70% 3 0.17 (0.004 to 0.35) 87.1% and 0.001
 ≤70% 40 0.36 (0.29 to 0.43) 97.5% and 0.001

History of myocardial infarction 0.58
 >20% 4 0.01 (−0.11 to 0.13) 75.6% and 0.006
 ≤20% 16 0.42 (0.26 to 0.58) 96.5% and 0.001

Anti-coagulant status codes 0.26
 1 16 0.45 (0.23 to 0.68) 98.5% and 0.001
 2
 3 8 0.62 (0.19 to 1.05) 95.3% and 0.001
 4 16 0.20 (0.14 to 0.25) 92.7% and 0.001
 5 17 0.53 (0.33 to 0.73) 98.6% and 0.001
 6 1 0.05 (−0.13 to 0.23)

AF 0.23
 Chronic 18 0.7 (0.42 to 0.97) 97.6% and 0.001
 Non-chronic 16 0.24 (0.16 to 0.33) 92.6% and 0.001

Type of AF 0.43
 Paroxysmal 8 0.38 (0.18 to 0.58) 83.9% and 0.78
 Persistent 4 0.42 (0.11 to 0.74) 90.2% and 0.001
 Permanent 9 0.54 (0.21 to 0.87) 93.6% and 0.001

Cigarette smoking 0.47
 >30% 11 0.51 (0.47 TO 0.56) 98.3% and 0.001
 ≤30% 26 0.09 (0.78 to 0.103) 96.5% and 0.001

Prothrombotic Factor 1–2

Year of publication
 >2000 7 0.79 (−0.39 to 1.98) 98.1% and 0.001
 ≤2000 2 0.97 (−0.54 to 2.49) 99.8% and 0.001

Geographic area
 Asian 3 0.52 (0.23 to 0.82) 99.7% and 0.001
 European 6 0.47 (0.34 to 0.64) 94.8% and 0.001
 Africa
 North American
 South American
 Australia

Design of study All of them are case–control
 Cohort
 Case-control

Number of population
 >300 1 0.36 (0.33 to 0.39)
 ≤300 8 0.46 (0.29 to 0.62) 99.2% and 0.001

Mean Age
 >60 years 6 0.82 (0.26 to 1.37) 99% and 0.001
 ≤60 years

Male
 >70% 1 1.75 (1.61 to 1.88)
 ≤70% 5 0.58 (0.25 to 0.91) 95.5% and 0.001

Diabetes mellitus
 >30%
 ≤30% 5 0.58 (0.25 to 0.91) 95.5% and 0.001

Hypertension
 >70%
 ≤70% 5 0.38 (0.17 to 0.59) 99.7% and 0.001

History of myocardial infarction
 >20%
 ≤20% 1 0.67 (0.57 to 0.76)

Anti-coagulant status codes
 1 2 0.46 (−0.21 to 1.42) 72.9% and 0.05
 2
 3
 4 5 0.84 (0.31 to 1.36) 99% and 0.001
 5 2 −0.04 (−0.07 to 0.01) 77.1% and 0.03
 6

AF
 Chronic 2 1.20 (0.15 to 2.26) 99.4% and 0.001
 Non-chronic

Type of AF
 Paroxysmal
 Persistent
 Permanent

Cigarette smoking No Data
 >30%
 ≤30%

Thrombin anti thrombin

Year of publication
 >2000 4 5.80 (−1.006 to 12.78) 99.7% and 0.001
 ≤2000 4 4.57 (1.77 to 7.36) 85.4% and 0.001

Geographic area
 Asian 5 6.93 (2.18 to 11.68) 98.1% and 0.001
 European 2 5.46 (3.43 to 7.48) 41.4% and 0.19
 Africa
 North American 1 0.05 (0.01 to 0.093)
 South American
 Australia

Design of study All of them are case–control
 Cohort
 Case-control

Number of population All of them are less than 300 cases
 >300
 ≤300

Mean Age
 >60 years 3 5.79 (3.63 to 7.96) 37.5% and 0.202
 ≤60 years 3 7.89 (2.09 to 13.68) 98.8% and 0.001

Male
 >70%
 ≤70% 5 7.87 (4.43 to 11.32) 98.3% and 0.001

Diabetes mellitus
 >30%
 ≤30% 2 5.46 (3.43 to 7.48) 41.4% and 0.191

Hypertension
 >70%
 ≤70% 2 5.46 (3.43 to 7.48) 41.4% and 0.191

History of myocardial infarction No Data
 >20%
 ≤20%

Anti-coagulant status codes All of them are Code–1
 1
 2
 3
 4
 5
 6

AF
 Chronic
 Non-chronic 2 2.47 (0.55 to 4.39) 27.4% and 0.24

Type of AF
 Paroxysmal 5 2.47 (0.55 to 4.39) 27.4% and 0.24
 Persistent
 Permanent

Cigarette smoking No sufficient data
 >30%
 ≤30%

Anti-thrombin III

Year of publication
 >2000 3 4.26 (−8.76 to 17.28) 91% and 0.001
 ≤2000 3 46.78 (36.8 to 56.70) 0% and 0.833

Geographic area All of them are European
 Asian
 European
 Africa
 North American
 South American
 Australia

Design of study All of them are case–control
 Cohort
 Case-control

Number of population All of studies have less than 300 cases
 >300
 ≤300

Mean Age
 >60 years 2 22.65 (−32.07 to 77.37) 94.2% and 0.001
 ≤60 years 3 18.96 (0.16 to 37.65) 91.1% and 0.001

Male
 >70% 1 −3.80 (−8.98 to 1.38)
 ≤70% 1 43.55 (28.29 to 58.80)

Diabetes mellitus
 >30%
 ≤30% 5 30.21 (11.99 to 48.42) 91.3% and 0.001

Hypertension
 >70%
 ≤70% 2 8.65 (−6.11 to 23.43) 85.3% and 0.009

History of myocardial infarction No data
>20%
≤20%

Anti-coagulant status codes
 1 3 46.78 (36.85 to 56.70) 0.0% and 0.833
 2
 3 1 −3.80 (−8.98 to 1.38)
 4
 5 2 8.65 (−6.11 to 23.43) 85.3% and 0.009
 6

AF
 Chronic 2 22.65 (−32.07 to 77.37) 94.2% and 0.001
 Non-chronic

Type of AF
 Paroxysmal 19.6 (12.5 to 26.8)
 Persistent
 Permanent 1 −3.80 (−8.98 to 1.38)

Cigarette smoking No sufficient data
 >30%
 ≤30%

Fibrinopeptide-A

Year of publication
 >2000 1 10.05 (9.37 to 10.72)
 ≤2000 3 2.17 (−0.72 to 5.07) 99.4% and 0.001

Geographic area
 Asian 1 4.60 (4.28 o 4.91)
 European 3 3.98 (−1.33 to 9.30) 99.7% and 0.001
 Africa
 North American
 South American
 Australia

Design of study All of studies are case–control
 Cohort
 Case-control

Number of population All of studies have less than 300 cases
 >300
 ≤300

Mean Age All of studies have total age higher than 60 years
 >60 years
 ≤60 years

Male
 >70% 1 4.60 (4.28 o 4.91)
 ≤70% 1 10.05 (9.37 to 10.72)

Diabetes mellitus
 >30%
 ≤30% 1 10.05 (9.37 to 10.72)

Hypertension
 >70%
 ≤70% 1 10.05 (9.37 to 10.72)

History of myocardial infarction No data
 >20%
 ≤20%

Anti-coagulant status codes
 1 3 3.98 (−1.33 to 9.30) 99.7% and 0.001
 2
 3
 4 1 4.60 (4.28 to 4.97)
 5
 6

AF
 Chronic 1 4.60 (4.28 to 4.97)
 Non-chronic 1 10.05 (9.37 to 10.72)

Type of AF
 Paroxysmal 1 10.05 (9.37 to 10.72)–
 Persistent
 Permanent

Cigarette smoking
 >30% 2 5.19 (4.78 to 5.63) 99.7% and 0.001
 ≤30% 1 0.42 (0.11 to 0.72)

Tissue plasminogen activator

Year of publication
 >2000 9 3.095 (1.52 to 4.66) 95.5% and 0.001
 ≤2000 5 0.709 (−0.908 to 2.32) 99.2% and 0.001

Geographic area
 Asian 2 3.78 (3.30 to 4.26) 0.0% and 0.86
 European 11 1.86 (0.69 to 3.03) 98.4% and 0.001
 Africa
 North American 1 1.30 (0.013 to 2.58)
 South American
 Australia

Design of study
 Cohort 2 1.89 (−1.82 to 5.62) 98.2% and 0.001
 Case-control 12 2.16 (0.98 to 3.34) 98.2% and 0.001

Number of population
 >300 1 3.80 (3.30 to 4.29)
 ≤300 13 1.95 (0.88 to 3.02) 98.1% and 0.001

Mean Age
 >60 years 10 2.69 (1.56 to 3.83) 96.1% and 0.001
 ≤60 years 3 1.29 (−1.14 to 3.74) 88.8% and 0.001

Male
 >70% 4 3.67 (0.40 to 6.94) 96.3% and 0.001
 ≤70% 6 2.34 (0.56 to 4.13) 99.2% and 0.001

Diabetes mellitus
 >30%
 ≤30% 13 1.60 (0.52 to 2.68) 98.3% and 0.001

Hypertension
 >70%
 ≤70% 10 2.41 (1.47 to 3.51) 93.5% and 0.001

History of myocardial infarction
 >20% 2 1.98 (0.81 to 3.14) 53.3% and 0.143
 ≤20% 2 3.68 (3.26 to 4.10) 0.0% and 0.396

Anti-coagulant status codes
 1 5 0.21 (−1.50 to 1.93) 99.1% and 0.001
 2
 3 1 10.57 (8.055 to 13.085)
 4 3 1.94 (−0.36 to 4.26) 96.8% and 0.001
 5 4 3.48 (2.76 to 4.19) 22.6% and 0.275
 6 1 1.30 (0.013 to 2.58)

AF
 Chronic 3 4.43 (−1.25 to 10.12) 97.6% and 0.001
 Non-chronic 2 2.99 (2.11 to 3.87) 51% and 0.154

Type of AF
 Paroxysmal 1 2.50 (1.53 to 3.46)
 Persistent 1 3.40 (2.62 to 4.17)
 Permanent 1 10.57 (8.055 to 13.085)

Cigarette smoking
 >30% 2 4.05 (3.56 to 4.56) 96.3% and 0.001
 ≤30% 4 2.73 (2.18 to 3.27) 61.6% and 0.051

Plasminogen activator inhibitor

Year of publication 0.28
 >2000 10 6.69 (1.79 to 11.59) 99.5% and 0.001
 ≤2000 5 20.72 (7.68 to 33.75) 97.4% and 0.001

Geographic area 0.30
 Asian 4 15.82 (0.49 to 31.14) 99.5% and 0.001
 European 10 10.07 (6.93 to 13.21) 98.4% and 0.001
 Africa
 North American 1 1.009 (−3.05 to 5.07)
 South American
 Australia

Design of study 0.97
 Cohort 1 4.490 (2.71 to 7.08)
 Case-control 14 11.28 (6.70 to 15.86) 99.4% and 0.001

Number of population 0.98
 >300 1 4.490 (2.71 to 7.08)
 ≤300 14 11.28 (6.70 to 15.86) 99.4% and 0.001

Mean Age 0.96
 >60 years 9 6.99 (4.31 to 9.67) 91.7% and 0.001
 ≤60 years 5 10.36 (2.19 to 18.52) 99.8% and 0.001

Male 0.18
 >70% 1 36.42 (32.41 to 40.42)
 ≤70% 8 11.28 (3.14 to 19.42) 99.5% and 0.001

Diabetes mellitus
 >30%
 ≤30% 12 8.93 (6.03 to 11.88) 98.1% and 0.001

Hypertension
 >70%
 ≤70% 9 3.34 (1.30 to 5.39) 96% and 0.001

History of myocardial infarction 0.97
 >20% 2 1.55 (−3.66 to 6.78) 84.5% and 0.011
 ≤20% 2 4.16 (3.29 to 5.03) 0.0% and 0.474

Anti-coagulant status codes 0.014
 1 7 21.28 (11.09 to 31.47) 98.9% and 0.001
 2
 3 1 4.20 (1.09 to 7.31)
 4 2 3.95 (3.27 to 4.64) 0.0% and 0.831
 5 4 1.08 (−0.357 to 2.534) 87.1% and 0.001
 6 1 −1.50 (−5.53 to 2.53)

AF 0.97
 Chronic 3 16.58 (−1.97 to 35.14) 95.6% and 0.001
 Non-chronic 2 3.80 (3.16 to 4.44) 0.0% and 0.448

Type of AF 0.26
 Paroxysmal 1 3.88 (2.87 to 4.88)
 Persistent 1 4.03 (3.08 to 4.97)
 Permanent 1 5.90 (3.49 to 8.31)

Cigarette smoking 0.95
 >30% 2 5.35 (3.73 to 6.97) 0.0% and 0.568
 ≤30% 4 3.80 (3.13 to 4.48) 56.9% and 0.07

von Willebrand Factor

Year of publication 0.98
 >2000 28 27.50 (19.43 to 35.56) 96.3% and 0.001
 ≤2000 4 23.67 (9.80 to 37.53) 99.5% and 0.001

Geographic area 0.01
 Asian 4 15.19 (7.19 to 23.19) 15.4% and 0.315
 European 25 30.91 (22.26 to 39.56) 99% and 0.001
 Africa
 North American 3 13.23 (10.42 to 16.04) 0.0% and 0.423
 South American
 Australia

Design of study 0.05
 Cohort 5 11.70 (6.62 to 16.78) 66.4% and 0.018
 Case-control 27 29.97 (21.49 to 38.44) 98.9% and 0.001

Number of population 0.10
 >300 4 10.32 (5.54 to 15.09) 63.8% and 0.041
 ≤300 28 29.78 (21.48 to 38.08) 98.8% and 0.001

Mean Age 0.703
 >60 years 22 27.88 (18.70 to 37.07) 99.1% and 0.001
 ≤60 years 10 23.95 (16.11 to 31.79) 85.4% and 0.001

Male 0.44
 >70% 13 27.82 (18.23 to 37.41) 87.9% and 0.001
 ≤70% 15 28.74 (17.73 to 39.74) 98% and 0.001

Diabetes mellitus
 >30%
 ≤30% 25 25.34 (16.93 to 33.76) 95.6% and 0.001

Hypertension 0.48
 >70% 2 16.95 (−1.44 to 35.35) 57% and 0.127
 ≤70% 24 27.42 (18.17 to 36.13) 96.7% and 0.001

History of myocardial infarction 0.97
 >20% 3 20.98 (−14.49 to 0.56.4) 98.7% and 0.001
 ≤20% 14 26.61 (14.62 to 38.60) 97.2% and 0.001

Anti-coagulant status codes 0.81
 1 6 9.66 (5.59 to 13.74) 93.5% and 0.001
 2 1 25 (11.14 to 38.85)
 3 8 33.09 (18.72 to 47.47) 90.9% and 0.001
 4 7 34.96 (24.55 to 45.38) 92.4% and 0.001
 5 9 30.16 (13.83 to 46.49) 95.9% and 0.001
 6 1 5.0 (−9.75 to 19.75)

AF 0.65
 Chronic 8 43 (29.03 to 56.97) 93% and 0.001
 Non-chronic 12 26.73 (16.88 to 36.58) 94.7% and 0.001

Type of AF 0.75
 Paroxysmal 4 29.17 (7.99 to 50.34) 96.5% and 0.001
 Persistent 5 25.02 (6.51 to 43.52) 96.1% and 0.001
 Permanent 4 43.01 (10.43 to 75.59) 95.6% and 0.001

Cigarette smoking 0.98
 >30% 4 3.53 (2.48 to 4.58) 95.8% and 0.001
 ≤30% 21 14.60 (13.67 to 15.53) 98.7% and 0.001

Soluble thrombomodulin

Year of Publication
 >2000 6 4.36 (2.79 to 5.93) 86.8% and 0.001
 ≤2000 1 −13.0 (−19.12 to −6.87)

Geographic area
 Asian
 European 6 3.81 (0.35 to 7.27) 92.6% and 0.001
 Africa
 North American
 South American 1 1.81 (1.03 to 2.58)
 Australia

Design of study
 Cohort 1 2.02 (1.88 to 2.15)
 Case-control 6 3.87 (0.31 to 7.43) 90.6% and 0.001

Number of population All of studies have less than 300 cases
 >300
 ≤300

Mean Age
 >60 years 4 6.04 (2.88 to 9.21) 89.5% and 0.001
 ≤60 years 2 −5.16 (−19.87 to 9.54) 95.7% and 0.001

Male
 >70% 2 6.84 (0.02 to 13.65) 86.8% and 0.001
 ≤70% 4 1.68 (−2.13 to 5.50) 94.3% and 0.001

Diabetes mellitus
 >30%
 ≤30% 4 5.10 (2.03 to 8.17) 91.2% and 0.001

Hypertension
 >70%
 ≤70% 4 5.10 (2.03 to 8.17) 91.2% and 0.001

History of myocardial infarction
 >20%
 ≤20% 3 6.18 (4.78 to 7.58) 0.0% and 0.794

Anti-coagulant status codes
 1 3 4.36 (−0.52 to 9.25) 56.9% and 0.09
 2
 3 1 12.28 (6.09 to 18.46)
 4 2 6.02 (4.61 to 7.50) 0.0% and 0.839
 5 1 −5.27 (−19.76 to 9.21)
 6

AF
 Chronic 4 3.38 (−5.27 to 12.04) 92.6% and 0.001
 Non-chronic 2 2.85 (1.52 to 4.17) 88.7% and 0.001

Type of AF
 Paroxysmal 1 2.02 (1.88 to 2.15)
 Persistent
 Permanent 1 12.28 (6.09 to 18.46)

Cigarette smoking
 >30% 1 12.28 (6.09 to 18.46)
 ≤30% 3 2.01 (1.88 to 2.14) 56.3% and 0.101

Footnotes

Declaration of interest

The authors declare that there is no conflict of interest.

Source of support: Departmental sources

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Figure 1

Forest plot of weighted mean difference (WMD) for association between level of AT-III and occurrence of AF.

Supplementary Figure 2

Forest plot of weighted mean difference (WMD) for association between level of TAT and occurrence of AF.

Supplementary Figure 3

Forest plot of weighted mean difference (WMD) for association between level of fibrinopeptide and occurrence of AF.

Supplementary Figure 4

Forest plot of weighted mean difference (WMD) for association between level of sTM and occurrence of AF.

Supplementary Figure 5

Forest plot of weighted mean difference (WMD) for association between level of D-dimer and occurrence of thromboembolism.

Supplementary Figure 6

Forest plot of weighted mean difference (WMD) for association between level of fibrinogen and occurrence of thromboembolism.

Supplementary Figure 7

Forest plot of weighted mean difference (WMD) for association between level of PF1–2 and occurrence of thromboembolism.

Supplementary Figure 8

Forest plot of weighted mean difference (WMD) for association between level of PF1–2 and occurrence of stroke.

Supplementary Figure 9

Forest plot of weighted mean difference (WMD) for association between level of TAT and occurrence of stroke.

Supplementary Figure 10

Forest plot of weighted mean difference (WMD) for association between level of PAI and occurrence of stroke.

Supplementary Figure 11

Forest plot of weighted mean difference (WMD) for association between level of D-dimer and occurrence of stroke.

Supplementary Figure 12

Forest plot of weighted mean difference (WMD) for association between level of fibrinogen and occurrence of stroke.

Supplementary Figure 13

Forest plot of weighted mean difference (WMD) for association between level of AT-III and occurrence of stroke.

Supplementary Figure 14

Funnel plot for publication bias of studies investigating D-dimer.

Supplementary Figure 15

Funnel plot for publication bias of studies investigating fibrinogen.

Supplementary Figure 16

Funnel plot for publication bias of studies investigating PF1–2.

Supplementary Figure 17

Funnel plot for publication bias of studies investigating of TAT.

Supplementary Figure 18

Funnel plot for publication bias of studies investigating AT-III.

Supplementary Figure 19

Funnel plot for publication bias of studies investigating fibrinopeptide-A.

Supplementary Figure 20

Funnel plot for publication bias of studies investigating t-PA.

Supplementary Figure 21

Funnel plot for publication bias of studies investigating PAI.

Supplementary Figure 22

Funnel plot for publication bias of studies investigating vWF.

Supplementary Figure 23

Funnel plot for publication bias of studies investigating sTM.

Supplementary Table 1.

Included, and excluded studies.

Clinical outcomes and biomarkers Studies were identified and screened [n] Studies were excluded according to title, abstract or full text [n] Studies were included [n]
Fibrinogen 315 275 40 approved articles with totally 58 enrolled data for meta-analysis
D-dimer 238 121 30 approved articles with totally 40 enrolled data for meta-analysis
PF1–2 86 79 7 approved articles with totally 9 enrolled data for meta-analysis
AT-III 98 94 4 approved articles with totally 6 enrolled data for meta-analysis
TAT 127 120 7 approved articles with totally 8 enrolled data for meta-analysis
t-PA 437 426 11 approved articles with totally 14 enrolled data for meta-analysis
PAI 91 80 11 approved articles with totally 15 enrolled data for meta-analysis
Alpha-2 antiplasmin 18 18
Fibrinopeptide-A 21 18 3 approved articles with totally 4 enrolled data for meta-analysis
u-PA 29 29
Plasmin-antiplasmin 22 21 1 approved articles with
vWF 185 21 approved articles with totally 32 enrolled data for meta-analysis
sTM 37 31 6 approved articles with totally 7 enrolled data for meta-analysis

Supplementary Table 2.

Extra details of characteristics of each study for exploration of heterogeneity factors.

First Author Geographic area Total N Total age Total male Total DM Total HTN Total MI Total diuretic Total ACEI Total. statin Total BB AC-code Chronic or not CS
Negreva [9] European 103 59.67 50.45 4.8 68.96 ND ND 28.165 6.805 34.97 1 Acute 14.5
Amdur [10] North America 3762 58.9 54.55 49.8 86.7 ND 64.65 69.85 ND 56.1 4 No detection ND
Yusuf (disease control) [11] Asian 65 31.5 42.85 ND ND ND ND ND ND ND 1 No detection ND
Yusuf (healthy control) [11] Asian 65 30.055 38.55 ND ND ND ND ND ND ND 1 No detection ND
Drabik (persistent) [12] European 97 60.1 64.95 20 48.85 17.35 ND 52.25 53.15 60.6 4 Acute 22.5
Drabik (PAF) [12] European 91 60 55.15 16.4 46.05 26.65 ND 54.05 47.45 57.25 4 Acute 20
Borgi [13] Africa 69 ND ND ND ND ND ND ND ND ND 5 No detection ND
Oneal (with comorbidities) [14] North America 647 69.5 54 32.5 70 ND ND ND 29.5 ND 4 No detection 15
Oneal (with comorbidities) [14] North America 883 64.5 32.5 29.5 54.5 ND ND ND 30 ND 4 No detection 14
Erdogan [15] European 67 69.55 49.275 10 65 ND 18 53.5 ND 43.3 3 Chronic 6
Chen (without comorbidities) [16] Asian 162 53.695 61.03 15 31.5 ND ND ND ND ND 4 Acute ND
Chen (with comorbidities) [16] Asian 207 55.845 64.2 13.5 35.5 ND ND ND ND ND 4 Acute ND
Schnabel [17] European 4998 60.05 54.5 10.15 61.95 8.3 ND ND ND ND 5 No detection 15.3
Wei-Hong Ma [18] Asian 105 58 72.25 0 100 ND ND ND ND ND 2 No detection ND
Xu (without comorbidities) [19] Asian 115 66.85 50.45 37.4 53.1 ND ND 42.6 29.55 43.55 4 Chronic 38.5
Xu (with comorbidities) [19] Asian 115 67.975 51.3 36.5 57.5 ND ND 40.8 26.05 40.95 4 Chronic 31.2
Distelmaier [20] North America 198 73.5 61 24 60.5 25 ND ND ND ND 5 Acute ND
Scridon (PAF) [21] European 69 55.5 78.5 7 39.5 ND ND 18.5 13.5 ND 3 Acute 13
Scridon (persistent) [21] European 53 55 78.5 7 35.5 ND ND 24 15.5 ND 3 Acute 13
Berge [22] European 189 75 71 8 48 ND 19 21 34.5 28 4 No detection ND
Acevedo [23] South America 150 ND ND ND ND ND ND ND ND ND 1 No detection ND
Zorlu [24] European 150 69.5 62 16 33 ND ND 75.5 ND 76 1 No detection ND
Alonso (White) [25] North America 11107 55.7 52.25 12.05 34.85 6.6 ND ND ND ND 1 No detection 26.7
Alonso (African-American) [25] North America 3751 54.8 41.2 26.05 63.65 ND ND ND ND ND 1 No detection 32
Adamsson Eryd [26] European 6031 47.25 100 4.8 6 ND ND ND ND 5 No detection 48
Fu [27] Asian 169 54.45 63.5 ND ND ND ND ND 12.9 6.1 4 No detection 42.5
Hou (disease control) [28] Asian 52 64.85 57.6 0 ND ND ND 40.35 ND 11.45 4 Acute 26.9
Hou (healthy control) [28] Asian 52 65.3 57.6 0 ND ND ND 21.15 ND 7.65 4 Acute 26.9
Schnabel [29] North America 3120 62.05 52.5 ND 38 ND ND ND ND ND 5 No detection ND
Letsas (PAF) [30] European 93 64.4 59 6 60.5 ND ND 43 15.5 34 5 acute ND
Letsas (permanent) [30] European 89 66.6 59.5 11 63 ND ND 52.5 13.5 35.5 5 chronic ND
Gartner [31] Australia 250 59.45 65.5 9 48.5 ND ND ND ND ND 4 No detection ND
Targonski (PAF and PeAF) [32] European 56 63.5 67.7 44.75 69.6 ND 67.7 96.65 87.3 85.4 4 12.4
Targonski (Permanent) [32] European 73 69.3 66.4 33.3 72.2 ND 78.05 90.85 70.6 89.2 4 11.3
Marcus [33] North America 971 70 87.5 22.5 65.5 52 ND 57 59.5 ND 5 No detection 15
Blann [34] European 82 64.5 62.75 ND 27 ND 16.5 19 ND 18.5 3 No detection 12.6
Topaloglu (disease control) [35] European 46 34.5 ND 0 0 ND ND ND ND ND 5 No detection ND
Topaloglu (healthy control) [35] European 38 36 ND 0 0 ND ND ND ND ND 5 No detection ND
Cecchi (with cerebral ischemic) [36] European 192 73.5 60.2 7.25 45.95 ND 18.05 27.3 6.85 6.8 3 No detection 30.1
Cecchi (without cerebral ischemic) [36] European 224 73 59.35 6.4 47.5 ND 20.5 27.05 7.3 8.05 3 No detection 25.9
Turgut (disease control) [37] European 55 66.11 44.7 17.4 67.6 ND ND ND ND ND 4 No detection ND
Turgut (healthy control) [37] European 46 66.56 43.95 3.85 36.55 ND ND ND ND ND 4 No detection ND
Heeringa [38] European 486 77.5 51 17.5 25 22.5 31.65 ND ND 16.55 5 No detection 20.9
Roldan [39] European 265 ND ND ND ND ND ND ND ND ND 4 No detection ND
Marin (acute AF) [40] European 48 63.5 50 0 8.3 8.3 ND 10.4 ND 8.3 4 Acute ND
Marin (chronic AF) [40] European 48 63.5 47.9 14.55 12.5 6.25 ND 6.25 ND 4.15 4 Chronic ND
Inoue (with comorbidities) [41] Asian 251 ND ND ND ND ND ND ND ND ND 5 No detection ND
Inoue (Lone AF) [41] Asian 106 ND ND ND ND ND ND ND ND ND 5 No detection ND
Conway [42] European 147 68 62 7.5 26.5 13.5 ND ND ND ND 3 chronic 16
Hatzinikolaou-Kotsakou (PAF) [43] European 35 59 77.25 8.3 13.85 13.85 ND ND ND ND 5 Acute 20.5
Hatzinikolaou-Kotsakou (persistent) [43] European 34 60 73.5 5.85 20.585 17.6 ND ND ND ND 5 Acute 20.8
Hatzinikolaou-Kotsakou (permanent) [43] European 37 61.5 76.15 5 22.5 15 ND ND ND ND 5 Chronic 24.2
Conway [44] European 74 67.5 70.2 9.45 27 1.35 ND ND ND ND 5 Acute 11.2
Kamath (PAF and PeAF) [45] European 62 63.5 51.6 ND ND ND ND ND ND ND 1 Acute ND
Kamath (permanent AF) [45] European 124 66 52.65 ND ND ND ND ND ND ND 1 Chronic ND
Marin [46] European 80 70.5 55 19.5 52 6.5 ND ND ND 4 4 Chronic ND
Conway [47] European 486 77.5 51.05 8.3 10.595 8.6 ND ND ND ND 1 No detection 10.3
Kamath (PAF) [48] European 58 63 48.235 6.85 24.1 3.4 ND ND ND ND 4 Acute 5.1
Kamath (permanent AF) [48] European 116 65 52.25 5.15 30.45 6.85 ND ND ND ND 4 Chronic 5.1
Kamath [49] European 143 70 63.2 ND ND ND ND ND ND ND 1 No detection 5.9
Wang [50] Asian 3212 60 51.65 23.65 40.6 3.65 ND ND ND ND 5 No detection 32.6
Li-saw-Hee (PAF) [51] European 43 64 77.3 2.15 10.85 6.5 ND ND ND ND 3 Acute 13.4
Li-saw-Hee (PeAF) [51] European 43 64 77.25 2.15 13 4.3 ND ND ND ND 3 Acute 11.5
Li-saw-Hee (permanent) [51] European 43 65 77.25 6.52 23.9 15.2 ND ND ND ND 3 Chronic 11.5
Feng [52] North America 214 62.15 73.5 12.85 36 23.25 ND ND ND ND 6 No detection 16.1
Topcuoglu [53] European 36 62.35 61.87 13.5 42.5 ND ND ND ND ND 1 No detection 20
Mondillo [54] European 80 66.95 82.85 ND ND ND ND ND ND ND 3 Chronic 33.7
Giansante [55] European 105 63.5 55.67 8.5 29.25 ND ND ND ND ND 1 Acute 35.6
Li-saw-Hee [56] European 112 67 77.5 3.85 12.5 11.55 ND ND ND ND 1 Chronic 13.3
Marin (disease control) [57] European 42 53.5 17.35 0 ND ND ND ND ND ND 1 No detection ND
Marin (healthy control) [57] European 38 ND ND 0 ND ND ND ND ND ND 1 No detection ND
Li-saw-Hee [58] European 50 59 20 ND ND ND ND ND ND ND 5 Chronic 20
Roldan [59] European 56 62 ND 0 ND ND ND ND ND ND 1 Chronic ND
Tsai [50] Asian 111 64 74.45 ND ND ND ND ND ND ND 4 Chronic ND
Minamino [61] Asian 90 63 73.3 12.5 23.5 ND ND ND ND 14.5 5 Chronic ND
Kahn [62] North America 81 ND ND ND ND ND ND ND ND ND 1 Chronic ND
Sohara [63] Asian 30 59.1 ND ND ND ND ND ND ND ND 1 Acute ND
Lip (PAF)[64] European 188 59.85 57.8 ND ND ND ND ND ND ND 1 Acute 30
Lip (chronic) [64] European 214 61.8 56.37 ND ND ND ND ND ND ND 1 Chronic 33
Lip [65] European 77 ND ND ND ND ND ND ND ND ND 1 Chronic ND
Mitusch [66] European 97 71 51.35 25 67 ND ND ND ND ND 1 No detection ND
Nagao [67] Asian 36 79.95 44.575 ND ND ND ND ND ND ND 1 No detection ND
Lip [68] European 245 61.15 53.3 ND ND ND ND ND ND ND 5 Chronic ND
Sohara [69] Asian 22 ND ND ND ND ND ND ND ND ND 1 Acute ND
Kumagai [70] Asian 94 62.5 48.15 ND ND ND ND ND ND ND 1 Chronic ND
Gustafsson (with stroke) [71] European 60 77 ND ND ND ND ND ND ND ND 1 No detection 30
Gustafsson (without stroke) [71] European 60 77 ND ND ND ND ND ND ND ND 1 No detection 25

Supplementary Table 3.

Subgroup-analysis and meta-regression.

Subgroup Studies (N) WMD (95% CI) I-squared and P-value respectively P-value of meta-regression
D-dimer

Year of publication 0.845
 >2000 25 243.7 (209.1 to 278.2) 99.8% and 0.001
 ≤2000 16 137.3 (103.6 to 171.1) 99.1% and 0.001

Geographic area 0.008
 Asian 13 144.4 (108.8 to 180.1) 99.7% and 0.001
 European 24 242.5 (199.4 to 285.7) 99% and 0.001
 Africa 1 0.83 (0.28 to 1.38)
 North American 2 65.11 (−62.93 to 193.1) 98.2% and 0.001
 South American
 Australia 1 472 (429.3 to 514.6)

Design of study 0.001
 Cohort 35 176.1 (153.7 to 198.4) 99.7% and 0.001
 Case-control 6 290.2 (189.5 to 390.8) 99.8% and 0.001

Number of population 0.49
 >300 2 65.1 (−62.9 to 193.1) 99.9% and 0.001
 ≤300 39 204.4 (179.9 to 229) 99.4% and 0.001

Mean Age 0.92
 >60 years 26 226.7 (188.6 to 264.8) 99.7% and 0.001
 ≤60 years 9 160.7 (77 to 244.4) 99.6% and 0.001

Male 0.94
 >70% 3 113.7 (22.2 to 205.1) 98.9% and 0.001
 ≤70% 26 227.8 (187.8 to 267.8) 99.6% and 0.001

Diabetes mellitus 0.47
 >30% 2 290 (271.6 to 308.4) 73.3% and 0.001
 ≤30% 20 264.8 (205.7 to 323.8) 99.7% and 0.001

Hypertension 0.96
 >70% 1 96.1 (47.2 to 144.7)
 ≤70% 19 258.6 (194.7 to 321.9) 99.8% and 0.001

History of myocardial infarction 0.95
 >20% 1 −0.16 (−0.42 to 0.107)
 ≤20% 4 761.7 (140.3 to 1383.2) 98.2% and 0.001

Anti-coagulant status codes 0.91
 1 18 215.3 (172 to 258.6) 98.9% and 0.001
 2
 3 2 154 (−110.2 to418.4) 97.6% and 0.001
 4 11 331.3 (225.5 to 437.1) 99.6% and 0.001
 5 10 91.1 (56 to 126.3) 99.9% and 0.001
 6

AF 0.015
 Chronic 14 261.3 (208.9 to 313.8) 99.6% and 0.001
 Non-chronic 11 104.7 (29.6 to 179.8) 99.4% and 0.001

Type of AF 0.254
 Paroxysmal 5 19.6 (12.5 to 26.8) 0.0% and 0.78
 Persistent
 Permanent 4 512.5 (135.3 to 889.8) 99% and 0.001

Cigarette smoking 0.132
 >30% 7 111.1 (106.1 to 116) 99.7% and 0.001
 ≤30% 8 −0.136 (−0.403 to 0.131) 98.3% and 0.001

Fibrinogen

Year of publication 0.02
 >2000 46 0.29 (0.24 to 0.35) 96.1% and 0.001
 ≤2000 12 0.75 (0.54 to 0.96) 96.4% and 0.001

Geographic area 0.04
 Asian 9 0.35 (0.24 to 0.47) 95% and 0.001
 European 40 0.53 (0.38 to 0.68) 97.9% and 0.001
 Africa
 North American 9 0.10 (0.02 to 0.19) 97.3% and 0.001
 South American
 Australia

Design of study 0.44
 Cohort 15 0.22 (0.15 to 0.29) 98.2% and 0.001
 Case-control 43 0.52 (0.36 to 0.69) 97.4% and 0.001

Number of population 0.053
 >300 11 0.15 (0.05 to 0.25) 98.4% and 0.001
 ≤300 47 0.52 (0.39 to 0.64) 98% and 0.001

Mean Age 0.94
 >60 years 43 0.48 (0.37 to 0.59) 98.7% and 0.001
 ≤60 years 13 0.26 (0.17 to 0.34) 95% and 0.001

Male 0.468
 >70% 13 0.56 (0.35 to 0.77) 93.9% and 0.001
 ≤70% 37 0.40 (0.31 to 0.48) 98.9% and 0.001

Diabetes mellitus 0.97
 >30% 6 0.40 (0.11 to 0.69) 96.5% and 0.001
 ≤30% 37 0.35 (0.28 to 0.43) 97.3% and 0.001

Hypertension 0.60
 >70% 3 0.17 (0.004 to 0.35) 87.1% and 0.001
 ≤70% 40 0.36 (0.29 to 0.43) 97.5% and 0.001

History of myocardial infarction 0.58
 >20% 4 0.01 (−0.11 to 0.13) 75.6% and 0.006
 ≤20% 16 0.42 (0.26 to 0.58) 96.5% and 0.001

Anti-coagulant status codes 0.26
 1 16 0.45 (0.23 to 0.68) 98.5% and 0.001
 2
 3 8 0.62 (0.19 to 1.05) 95.3% and 0.001
 4 16 0.20 (0.14 to 0.25) 92.7% and 0.001
 5 17 0.53 (0.33 to 0.73) 98.6% and 0.001
 6 1 0.05 (−0.13 to 0.23)

AF 0.23
 Chronic 18 0.7 (0.42 to 0.97) 97.6% and 0.001
 Non-chronic 16 0.24 (0.16 to 0.33) 92.6% and 0.001

Type of AF 0.43
 Paroxysmal 8 0.38 (0.18 to 0.58) 83.9% and 0.78
 Persistent 4 0.42 (0.11 to 0.74) 90.2% and 0.001
 Permanent 9 0.54 (0.21 to 0.87) 93.6% and 0.001

Cigarette smoking 0.47
 >30% 11 0.51 (0.47 TO 0.56) 98.3% and 0.001
 ≤30% 26 0.09 (0.78 to 0.103) 96.5% and 0.001

Prothrombotic Factor 1–2

Year of publication
 >2000 7 0.79 (−0.39 to 1.98) 98.1% and 0.001
 ≤2000 2 0.97 (−0.54 to 2.49) 99.8% and 0.001

Geographic area
 Asian 3 0.52 (0.23 to 0.82) 99.7% and 0.001
 European 6 0.47 (0.34 to 0.64) 94.8% and 0.001
 Africa
 North American
 South American
 Australia

Design of study All of them are case–control
 Cohort
 Case-control

Number of population
 >300 1 0.36 (0.33 to 0.39)
 ≤300 8 0.46 (0.29 to 0.62) 99.2% and 0.001

Mean Age
 >60 years 6 0.82 (0.26 to 1.37) 99% and 0.001
 ≤60 years

Male
 >70% 1 1.75 (1.61 to 1.88)
 ≤70% 5 0.58 (0.25 to 0.91) 95.5% and 0.001

Diabetes mellitus
 >30%
 ≤30% 5 0.58 (0.25 to 0.91) 95.5% and 0.001

Hypertension
 >70%
 ≤70% 5 0.38 (0.17 to 0.59) 99.7% and 0.001

History of myocardial infarction
 >20%
 ≤20% 1 0.67 (0.57 to 0.76)

Anti-coagulant status codes
 1 2 0.46 (−0.21 to 1.42) 72.9% and 0.05
 2
 3
 4 5 0.84 (0.31 to 1.36) 99% and 0.001
 5 2 −0.04 (−0.07 to 0.01) 77.1% and 0.03
 6

AF
 Chronic 2 1.20 (0.15 to 2.26) 99.4% and 0.001
 Non-chronic

Type of AF
 Paroxysmal
 Persistent
 Permanent

Cigarette smoking No Data
 >30%
 ≤30%

Thrombin anti thrombin

Year of publication
 >2000 4 5.80 (−1.006 to 12.78) 99.7% and 0.001
 ≤2000 4 4.57 (1.77 to 7.36) 85.4% and 0.001

Geographic area
 Asian 5 6.93 (2.18 to 11.68) 98.1% and 0.001
 European 2 5.46 (3.43 to 7.48) 41.4% and 0.19
 Africa
 North American 1 0.05 (0.01 to 0.093)
 South American
 Australia

Design of study All of them are case–control
 Cohort
 Case-control

Number of population All of them are less than 300 cases
 >300
 ≤300

Mean Age
 >60 years 3 5.79 (3.63 to 7.96) 37.5% and 0.202
 ≤60 years 3 7.89 (2.09 to 13.68) 98.8% and 0.001

Male
 >70%
 ≤70% 5 7.87 (4.43 to 11.32) 98.3% and 0.001

Diabetes mellitus
 >30%
 ≤30% 2 5.46 (3.43 to 7.48) 41.4% and 0.191

Hypertension
 >70%
 ≤70% 2 5.46 (3.43 to 7.48) 41.4% and 0.191

History of myocardial infarction No Data
 >20%
 ≤20%

Anti-coagulant status codes All of them are Code–1
 1
 2
 3
 4
 5
 6

AF
 Chronic
 Non-chronic 2 2.47 (0.55 to 4.39) 27.4% and 0.24

Type of AF
 Paroxysmal 5 2.47 (0.55 to 4.39) 27.4% and 0.24
 Persistent
 Permanent

Cigarette smoking No sufficient data
 >30%
 ≤30%

Anti-thrombin III

Year of publication
 >2000 3 4.26 (−8.76 to 17.28) 91% and 0.001
 ≤2000 3 46.78 (36.8 to 56.70) 0% and 0.833

Geographic area All of them are European
 Asian
 European
 Africa
 North American
 South American
 Australia

Design of study All of them are case–control
 Cohort
 Case-control

Number of population All of studies have less than 300 cases
 >300
 ≤300

Mean Age
 >60 years 2 22.65 (−32.07 to 77.37) 94.2% and 0.001
 ≤60 years 3 18.96 (0.16 to 37.65) 91.1% and 0.001

Male
 >70% 1 −3.80 (−8.98 to 1.38)
 ≤70% 1 43.55 (28.29 to 58.80)

Diabetes mellitus
 >30%
 ≤30% 5 30.21 (11.99 to 48.42) 91.3% and 0.001

Hypertension
 >70%
 ≤70% 2 8.65 (−6.11 to 23.43) 85.3% and 0.009

History of myocardial infarction No data
>20%
≤20%

Anti-coagulant status codes
 1 3 46.78 (36.85 to 56.70) 0.0% and 0.833
 2
 3 1 −3.80 (−8.98 to 1.38)
 4
 5 2 8.65 (−6.11 to 23.43) 85.3% and 0.009
 6

AF
 Chronic 2 22.65 (−32.07 to 77.37) 94.2% and 0.001
 Non-chronic

Type of AF
 Paroxysmal 19.6 (12.5 to 26.8)
 Persistent
 Permanent 1 −3.80 (−8.98 to 1.38)

Cigarette smoking No sufficient data
 >30%
 ≤30%

Fibrinopeptide-A

Year of publication
 >2000 1 10.05 (9.37 to 10.72)
 ≤2000 3 2.17 (−0.72 to 5.07) 99.4% and 0.001

Geographic area
 Asian 1 4.60 (4.28 o 4.91)
 European 3 3.98 (−1.33 to 9.30) 99.7% and 0.001
 Africa
 North American
 South American
 Australia

Design of study All of studies are case–control
 Cohort
 Case-control

Number of population All of studies have less than 300 cases
 >300
 ≤300

Mean Age All of studies have total age higher than 60 years
 >60 years
 ≤60 years

Male
 >70% 1 4.60 (4.28 o 4.91)
 ≤70% 1 10.05 (9.37 to 10.72)

Diabetes mellitus
 >30%
 ≤30% 1 10.05 (9.37 to 10.72)

Hypertension
 >70%
 ≤70% 1 10.05 (9.37 to 10.72)

History of myocardial infarction No data
 >20%
 ≤20%

Anti-coagulant status codes
 1 3 3.98 (−1.33 to 9.30) 99.7% and 0.001
 2
 3
 4 1 4.60 (4.28 to 4.97)
 5
 6

AF
 Chronic 1 4.60 (4.28 to 4.97)
 Non-chronic 1 10.05 (9.37 to 10.72)

Type of AF
 Paroxysmal 1 10.05 (9.37 to 10.72)–
 Persistent
 Permanent

Cigarette smoking
 >30% 2 5.19 (4.78 to 5.63) 99.7% and 0.001
 ≤30% 1 0.42 (0.11 to 0.72)

Tissue plasminogen activator

Year of publication
 >2000 9 3.095 (1.52 to 4.66) 95.5% and 0.001
 ≤2000 5 0.709 (−0.908 to 2.32) 99.2% and 0.001

Geographic area
 Asian 2 3.78 (3.30 to 4.26) 0.0% and 0.86
 European 11 1.86 (0.69 to 3.03) 98.4% and 0.001
 Africa
 North American 1 1.30 (0.013 to 2.58)
 South American
 Australia

Design of study
 Cohort 2 1.89 (−1.82 to 5.62) 98.2% and 0.001
 Case-control 12 2.16 (0.98 to 3.34) 98.2% and 0.001

Number of population
 >300 1 3.80 (3.30 to 4.29)
 ≤300 13 1.95 (0.88 to 3.02) 98.1% and 0.001

Mean Age
 >60 years 10 2.69 (1.56 to 3.83) 96.1% and 0.001
 ≤60 years 3 1.29 (−1.14 to 3.74) 88.8% and 0.001

Male
 >70% 4 3.67 (0.40 to 6.94) 96.3% and 0.001
 ≤70% 6 2.34 (0.56 to 4.13) 99.2% and 0.001

Diabetes mellitus
 >30%
 ≤30% 13 1.60 (0.52 to 2.68) 98.3% and 0.001

Hypertension
 >70%
 ≤70% 10 2.41 (1.47 to 3.51) 93.5% and 0.001

History of myocardial infarction
 >20% 2 1.98 (0.81 to 3.14) 53.3% and 0.143
 ≤20% 2 3.68 (3.26 to 4.10) 0.0% and 0.396

Anti-coagulant status codes
 1 5 0.21 (−1.50 to 1.93) 99.1% and 0.001
 2
 3 1 10.57 (8.055 to 13.085)
 4 3 1.94 (−0.36 to 4.26) 96.8% and 0.001
 5 4 3.48 (2.76 to 4.19) 22.6% and 0.275
 6 1 1.30 (0.013 to 2.58)

AF
 Chronic 3 4.43 (−1.25 to 10.12) 97.6% and 0.001
 Non-chronic 2 2.99 (2.11 to 3.87) 51% and 0.154

Type of AF
 Paroxysmal 1 2.50 (1.53 to 3.46)
 Persistent 1 3.40 (2.62 to 4.17)
 Permanent 1 10.57 (8.055 to 13.085)

Cigarette smoking
 >30% 2 4.05 (3.56 to 4.56) 96.3% and 0.001
 ≤30% 4 2.73 (2.18 to 3.27) 61.6% and 0.051

Plasminogen activator inhibitor

Year of publication 0.28
 >2000 10 6.69 (1.79 to 11.59) 99.5% and 0.001
 ≤2000 5 20.72 (7.68 to 33.75) 97.4% and 0.001

Geographic area 0.30
 Asian 4 15.82 (0.49 to 31.14) 99.5% and 0.001
 European 10 10.07 (6.93 to 13.21) 98.4% and 0.001
 Africa
 North American 1 1.009 (−3.05 to 5.07)
 South American
 Australia

Design of study 0.97
 Cohort 1 4.490 (2.71 to 7.08)
 Case-control 14 11.28 (6.70 to 15.86) 99.4% and 0.001

Number of population 0.98
 >300 1 4.490 (2.71 to 7.08)
 ≤300 14 11.28 (6.70 to 15.86) 99.4% and 0.001

Mean Age 0.96
 >60 years 9 6.99 (4.31 to 9.67) 91.7% and 0.001
 ≤60 years 5 10.36 (2.19 to 18.52) 99.8% and 0.001

Male 0.18
 >70% 1 36.42 (32.41 to 40.42)
 ≤70% 8 11.28 (3.14 to 19.42) 99.5% and 0.001

Diabetes mellitus
 >30%
 ≤30% 12 8.93 (6.03 to 11.88) 98.1% and 0.001

Hypertension
 >70%
 ≤70% 9 3.34 (1.30 to 5.39) 96% and 0.001

History of myocardial infarction 0.97
 >20% 2 1.55 (−3.66 to 6.78) 84.5% and 0.011
 ≤20% 2 4.16 (3.29 to 5.03) 0.0% and 0.474

Anti-coagulant status codes 0.014
 1 7 21.28 (11.09 to 31.47) 98.9% and 0.001
 2
 3 1 4.20 (1.09 to 7.31)
 4 2 3.95 (3.27 to 4.64) 0.0% and 0.831
 5 4 1.08 (−0.357 to 2.534) 87.1% and 0.001
 6 1 −1.50 (−5.53 to 2.53)

AF 0.97
 Chronic 3 16.58 (−1.97 to 35.14) 95.6% and 0.001
 Non-chronic 2 3.80 (3.16 to 4.44) 0.0% and 0.448

Type of AF 0.26
 Paroxysmal 1 3.88 (2.87 to 4.88)
 Persistent 1 4.03 (3.08 to 4.97)
 Permanent 1 5.90 (3.49 to 8.31)

Cigarette smoking 0.95
 >30% 2 5.35 (3.73 to 6.97) 0.0% and 0.568
 ≤30% 4 3.80 (3.13 to 4.48) 56.9% and 0.07

von Willebrand Factor

Year of publication 0.98
 >2000 28 27.50 (19.43 to 35.56) 96.3% and 0.001
 ≤2000 4 23.67 (9.80 to 37.53) 99.5% and 0.001

Geographic area 0.01
 Asian 4 15.19 (7.19 to 23.19) 15.4% and 0.315
 European 25 30.91 (22.26 to 39.56) 99% and 0.001
 Africa
 North American 3 13.23 (10.42 to 16.04) 0.0% and 0.423
 South American
 Australia

Design of study 0.05
 Cohort 5 11.70 (6.62 to 16.78) 66.4% and 0.018
 Case-control 27 29.97 (21.49 to 38.44) 98.9% and 0.001

Number of population 0.10
 >300 4 10.32 (5.54 to 15.09) 63.8% and 0.041
 ≤300 28 29.78 (21.48 to 38.08) 98.8% and 0.001

Mean Age 0.703
 >60 years 22 27.88 (18.70 to 37.07) 99.1% and 0.001
 ≤60 years 10 23.95 (16.11 to 31.79) 85.4% and 0.001

Male 0.44
 >70% 13 27.82 (18.23 to 37.41) 87.9% and 0.001
 ≤70% 15 28.74 (17.73 to 39.74) 98% and 0.001

Diabetes mellitus
 >30%
 ≤30% 25 25.34 (16.93 to 33.76) 95.6% and 0.001

Hypertension 0.48
 >70% 2 16.95 (−1.44 to 35.35) 57% and 0.127
 ≤70% 24 27.42 (18.17 to 36.13) 96.7% and 0.001

History of myocardial infarction 0.97
 >20% 3 20.98 (−14.49 to 0.56.4) 98.7% and 0.001
 ≤20% 14 26.61 (14.62 to 38.60) 97.2% and 0.001

Anti-coagulant status codes 0.81
 1 6 9.66 (5.59 to 13.74) 93.5% and 0.001
 2 1 25 (11.14 to 38.85)
 3 8 33.09 (18.72 to 47.47) 90.9% and 0.001
 4 7 34.96 (24.55 to 45.38) 92.4% and 0.001
 5 9 30.16 (13.83 to 46.49) 95.9% and 0.001
 6 1 5.0 (−9.75 to 19.75)

AF 0.65
 Chronic 8 43 (29.03 to 56.97) 93% and 0.001
 Non-chronic 12 26.73 (16.88 to 36.58) 94.7% and 0.001

Type of AF 0.75
 Paroxysmal 4 29.17 (7.99 to 50.34) 96.5% and 0.001
 Persistent 5 25.02 (6.51 to 43.52) 96.1% and 0.001
 Permanent 4 43.01 (10.43 to 75.59) 95.6% and 0.001

Cigarette smoking 0.98
 >30% 4 3.53 (2.48 to 4.58) 95.8% and 0.001
 ≤30% 21 14.60 (13.67 to 15.53) 98.7% and 0.001

Soluble thrombomodulin

Year of Publication
 >2000 6 4.36 (2.79 to 5.93) 86.8% and 0.001
 ≤2000 1 −13.0 (−19.12 to −6.87)

Geographic area
 Asian
 European 6 3.81 (0.35 to 7.27) 92.6% and 0.001
 Africa
 North American
 South American 1 1.81 (1.03 to 2.58)
 Australia

Design of study
 Cohort 1 2.02 (1.88 to 2.15)
 Case-control 6 3.87 (0.31 to 7.43) 90.6% and 0.001

Number of population All of studies have less than 300 cases
 >300
 ≤300

Mean Age
 >60 years 4 6.04 (2.88 to 9.21) 89.5% and 0.001
 ≤60 years 2 −5.16 (−19.87 to 9.54) 95.7% and 0.001

Male
 >70% 2 6.84 (0.02 to 13.65) 86.8% and 0.001
 ≤70% 4 1.68 (−2.13 to 5.50) 94.3% and 0.001

Diabetes mellitus
 >30%
 ≤30% 4 5.10 (2.03 to 8.17) 91.2% and 0.001

Hypertension
 >70%
 ≤70% 4 5.10 (2.03 to 8.17) 91.2% and 0.001

History of myocardial infarction
 >20%
 ≤20% 3 6.18 (4.78 to 7.58) 0.0% and 0.794

Anti-coagulant status codes
 1 3 4.36 (−0.52 to 9.25) 56.9% and 0.09
 2
 3 1 12.28 (6.09 to 18.46)
 4 2 6.02 (4.61 to 7.50) 0.0% and 0.839
 5 1 −5.27 (−19.76 to 9.21)
 6

AF
 Chronic 4 3.38 (−5.27 to 12.04) 92.6% and 0.001
 Non-chronic 2 2.85 (1.52 to 4.17) 88.7% and 0.001

Type of AF
 Paroxysmal 1 2.02 (1.88 to 2.15)
 Persistent
 Permanent 1 12.28 (6.09 to 18.46)

Cigarette smoking
 >30% 1 12.28 (6.09 to 18.46)
 ≤30% 3 2.01 (1.88 to 2.14) 56.3% and 0.101

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