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.
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.
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.
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.
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.
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.
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 14–23). 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 [80–83]. A proposed mechanism leading to an increased incidence of AF is coagulation and prothrombotic state [80–83]. Investigators believe that procoagulant and prothrombotic states might be more expressed in patients with chronic AF as compared to those with SR [80–83]. 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
Forest plot of weighted mean difference (WMD) for association between level of AT-III and occurrence of AF.
Forest plot of weighted mean difference (WMD) for association between level of TAT and occurrence of AF.
Forest plot of weighted mean difference (WMD) for association between level of fibrinopeptide and occurrence of AF.
Forest plot of weighted mean difference (WMD) for association between level of sTM and occurrence of AF.
Forest plot of weighted mean difference (WMD) for association between level of D-dimer and occurrence of thromboembolism.
Forest plot of weighted mean difference (WMD) for association between level of fibrinogen and occurrence of thromboembolism.
Forest plot of weighted mean difference (WMD) for association between level of PF1–2 and occurrence of thromboembolism.
Forest plot of weighted mean difference (WMD) for association between level of PF1–2 and occurrence of stroke.
Forest plot of weighted mean difference (WMD) for association between level of TAT and occurrence of stroke.
Forest plot of weighted mean difference (WMD) for association between level of PAI and occurrence of stroke.
Forest plot of weighted mean difference (WMD) for association between level of D-dimer and occurrence of stroke.
Forest plot of weighted mean difference (WMD) for association between level of fibrinogen and occurrence of stroke.
Forest plot of weighted mean difference (WMD) for association between level of AT-III and occurrence of stroke.
Funnel plot for publication bias of studies investigating D-dimer.
Funnel plot for publication bias of studies investigating fibrinogen.
Funnel plot for publication bias of studies investigating PF1–2.
Funnel plot for publication bias of studies investigating of TAT.
Funnel plot for publication bias of studies investigating AT-III.
Funnel plot for publication bias of studies investigating fibrinopeptide-A.
Funnel plot for publication bias of studies investigating t-PA.
Funnel plot for publication bias of studies investigating PAI.
Funnel plot for publication bias of studies investigating vWF.
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
- 1.Macle L, Cairns J, Leblanc K, et al. 2016 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation. Can J Cardiol. 2016;32(10):1170–85. doi: 10.1016/j.cjca.2016.07.591. [DOI] [PubMed] [Google Scholar]
- 2.Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57:e101–98. doi: 10.1016/j.jacc.2010.09.013. [DOI] [PubMed] [Google Scholar]
- 3.Albertsen IE, Rasmussen LH, Overvad TF, et al. Risk of stroke or systemic embolism in atrial fibrillation patients treated with warfarin: A systematic review and meta-analysis. Stroke. 2013;44:1329–36. doi: 10.1161/STROKEAHA.113.000883. [DOI] [PubMed] [Google Scholar]
- 4.Ali-Hassan-Sayegh S, Mirhosseini SJ, Rezaeisadrabadi M, et al. Antioxidant supplementations for prevention of atrial fibrillation after cardiac surgery: An updated comprehensive systematic review and meta-analysis of 23 randomized controlled trials. Interact Cardiovasc Thorac Surg. 2014;18:646–54. doi: 10.1093/icvts/ivu020. [DOI] [PubMed] [Google Scholar]
- 5.Kornej J, Apostolakis S, Bollmann A, Lip GY. The emerging role of biomarkers in atrial fibrillation. Can J Cardiol. 2013;29:1181–93. doi: 10.1016/j.cjca.2013.04.016. [DOI] [PubMed] [Google Scholar]
- 6.Brotman DJ, Deitcher SR, Lip GY, Matzdorff AC. Virchow’s triad revisited. South Med J. 2004;97:213–14. doi: 10.1097/01.SMJ.0000105663.01648.25. [DOI] [PubMed] [Google Scholar]
- 7.Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13. doi: 10.1186/1471-2288-5-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Wells GA SB, O’Connell D, Peterson J, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. 2011. Available: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
- 9.Negreva M, Georgiev S, Vitlianova K. Decreased activity of the protein C anticoagulant pathway in the early hours of paroxysmal atrial fibrillation. Clin Appl Thromb Hemost. :2016. doi: 10.1177/1076029616654262. [Epub ahead of print] [DOI] [PubMed] [Google Scholar]
- 10.Amdur RL, Mukherjee M, Go A, et al. Interleukin-6 is a risk factor for atrial fibrillation in chronic kidney disease: Findings from the CRIC study. PLoS One. 2016;11(2):e0148189. doi: 10.1371/journal.pone.0148189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Yusuf J, Goyal M, Mukhopadhyay S, et al. Effect of heart rate control on coagulation status in patients of rheumatic mitral stenosis with atrial fibrillation – A pilot study. Indian Heart J. 2015;67(Suppl 2):S40–45. doi: 10.1016/j.ihj.2015.06.041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Drabik L, Wołkow P, Undas A. Denser plasma clot formation and impaired fibrinolysis in paroxysmal and persistent atrial fibrillation while on sinus rhythm: Association with thrombin generation, endothelial injury and platelet activation. Thromb Res. 2015;136:408–14. doi: 10.1016/j.thromres.2015.05.028. [DOI] [PubMed] [Google Scholar]
- 13.El Borgi W, Romdhane S, Sdiri W, et al. [Measurement of d-dimers in non-valvular atrial fibrillation. First prospective Tunisian study]. Ann Cardiol Angeiol (Paris) 2015;64:279–84. doi: 10.1016/j.ancard.2015.01.003. [in French] [DOI] [PubMed] [Google Scholar]
- 14.O’Neal WT, Soliman EZ, Howard G, et al. Inflammation and hemostasis in atrial fibrillation and coronary heart disease: The REasons for Geographic and Racial Differences in Stroke study. Atherosclerosis. 2015;243:192–9. doi: 10.1016/j.atherosclerosis.2015.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Erdogan D, Uysal BA, Aksoy F, et al. Strict heart rate control attenuates prothrombotic state and platelet activity in patients with non-valvular permanent atrial fibrillation. Clin Hemorheol Microcirc. 2014;56:219–29. doi: 10.3233/CH-131710. [DOI] [PubMed] [Google Scholar]
- 16.Chen Q, Yan Y, Zhang L, et al. Effect of hyperthyroidism on the hypercoagulable state and thromboembolic events in patients with atrial fibrillation. Cardiology. 2014;127:176–82. doi: 10.1159/000356954. [DOI] [PubMed] [Google Scholar]
- 17.Schnabel RB, Wild PS, Wilde S, et al. Multiple biomarkers and atrial fibrillation in the general population. PLoS One. 2014;9:e112486. doi: 10.1371/journal.pone.0112486. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Ma WH, Sheng L, Gong HP, et al. The application of vWF/ADAMTS13 in essential hypertension. Int J Clin Exp Med. 2014;7:5636–42. [PMC free article] [PubMed] [Google Scholar]
- 19.Xu XF, Jiang FL, Ou MJ, Zhang ZH. The association between mean platelet volume and chronic atrial fibrillation and the presence of thrombotic events. Biomed Rep. 2015;3:388–94. doi: 10.3892/br.2015.418. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Distelmaier K, Maurer G, Goliasch G. Blood count in new onset atrial fibrillation after acute myocardial infarction – a hypothesis generating study. Indian J Med Res. 2014;139:579–84. [PMC free article] [PubMed] [Google Scholar]
- 21.Scridon A, Girerd N, Rugeri L, et al. Progressive endothelial damage revealed by multilevel von Willebrand factor plasma concentrations in atrial fibrillation patients. Europace. 2013;15:1562–66. doi: 10.1093/europace/eut121. [DOI] [PubMed] [Google Scholar]
- 22.Berge T, Ulimoen SR, Enger S, et al. Impact of atrial fibrillation on inflammatory and fibrinolytic variables in the elderly. Scand J Clin Lab Invest. 2013;73:326–33. doi: 10.3109/00365513.2013.780093. [DOI] [PubMed] [Google Scholar]
- 23.Acevedo M, Corbalan R, Braun S, et al. Biochemical predictors of cardiac rhythm at 1 year follow-up in patients with non-valvular atrial fibrillation. J Thromb Thrombolysis. 2012;128:e113–18. doi: 10.1007/s11239-012-0690-1. [DOI] [PubMed] [Google Scholar]
- 24.Zorlu A, Akkaya E, Altay H, et al. The relationship between Ddimer level and the development of atrial fibrillation in patients with systolic heart failure. J Thromb Thrombolysis. 2012;33:343–48. doi: 10.1007/s11239-011-0656-8. [DOI] [PubMed] [Google Scholar]
- 25.Alonso A, Tang W, Agarwal SK, et al. Hemostatic markers are associated with the risk and prognosis of atrial fibrillation: the ARIC study. Int J Cardiol. 2012;155:217–22. doi: 10.1016/j.ijcard.2010.09.051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Adamsson Eryd S, Smith JG, Melander O, et al. Inflammation-sensitive proteins and risk of atrial fibrillation: A population-based cohort study. Eur J Epidemiol. 2011;26:449–55. doi: 10.1007/s10654-011-9565-6. [DOI] [PubMed] [Google Scholar]
- 27.Fu R, Wu S, Wu P, Qiu J. A study of blood soluble P-selectin, fibrinogen, and von Willebrand factor levels in idiopathic and lone atrial fibrillation. Europace. 2011;13:31–36. doi: 10.1093/europace/euq346. [DOI] [PubMed] [Google Scholar]
- 28.Hou J, Liang Y, Gai X, et al. The impact of acute atrial fibrillation on the prothrombotic state in patients with essential hypertension. Clin Biochem. 2010;43:1212–15. doi: 10.1016/j.clinbiochem.2010.07.013. [DOI] [PubMed] [Google Scholar]
- 29.Schnabel RB, Larson MG, Yamamoto JF, et al. Relations of biomarkers of distinct pathophysiological pathways and atrial fibrillation incidence in the community. Circulation. 2010;121:200–7. doi: 10.1161/CIRCULATIONAHA.109.882241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Letsas KP, Weber R, Bürkle G, et al. Pre-ablative predictors of atrial fibrillation recurrence following pulmonary vein isolation: The potential role of inflammation. Europace. 2009;11:158–63. doi: 10.1093/europace/eun309. [DOI] [PubMed] [Google Scholar]
- 31.Gartner W, Zierhut B, Mineva I, et al. Brain natriuretic peptide correlates with the extent of atrial fibrillation-associated silent brain lesions. Clin Biochem. 2008;41:1434–39. doi: 10.1016/j.clinbiochem.2008.09.096. [DOI] [PubMed] [Google Scholar]
- 32.Targonski R, Salczynska D, Sadowski J, Cichowski L. Relationship between inflammatory markers and clinical patterns of atrial fibrillation in patients with congestive heart failure. Kardiol Pol. 2008;66:729–36. discussion 737–39. [PubMed] [Google Scholar]
- 33.Marcus GM, Whooley MA, Glidden DV, et al. Interleukin-6 and atrial fibrillation in patients with coronary artery disease: Data from the Heart and Soul Study. Am Heart J. 2008;155:303–9. doi: 10.1016/j.ahj.2007.09.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Blann AD, Choudhury A, Freestone B, et al. Soluble CD40 ligand and atrial fibrillation: Relationship to platelet activation, and endothelial damage/dysfunction. Int J Cardiol. 2008;127:135–37. doi: 10.1016/j.ijcard.2007.04.028. [DOI] [PubMed] [Google Scholar]
- 35.Topaloglu S, Boyaci A, Ayaz S, et al. Coagulation, fibrinolytic system activation and endothelial dysfunction in patients with mitral stenosis and sinus rhythm. Angiology. 2007;58:85–91. doi: 10.1177/0003319706297917. [DOI] [PubMed] [Google Scholar]
- 36.Cecchi E, Marcucci R, Poli D, et al. Hyperviscosity as a possible risk factor for cerebral ischemic complications in atrial fibrillation patients. Am J Cardiol. 2006;97:1745–48. doi: 10.1016/j.amjcard.2006.01.034. [DOI] [PubMed] [Google Scholar]
- 37.Turgut N, Akdemir O, Turgut B, et al. Hypercoagulopathy in stroke patients with nonvalvular atrial fibrillation: Hematologic and cardiologic investigations. Clin Appl Thromb Hemost. 2006;12:15–20. doi: 10.1177/107602960601200104. [DOI] [PubMed] [Google Scholar]
- 38.Heeringa J, Conway DS, van der Kuip DA, et al. A longitudinal population-based study of prothrombotic factors in elderly subjects with atrial fibrillation: The Rotterdam Study 1990–1999. J Thromb Haemost. 2006;4:1944–49. doi: 10.1111/j.1538-7836.2006.02115.x. [DOI] [PubMed] [Google Scholar]
- 39.Roldan V, Marin F, Martinez JG, et al. Relation of interleukin-6 levels and prothrombin fragment 1+2 to a point-based score for stroke risk in atrial fibrillation. Am J Cardiol. 2005;95:881–82. doi: 10.1016/j.amjcard.2004.12.016. [DOI] [PubMed] [Google Scholar]
- 40.Marín F, Roldán V, Climent VE, et al. Plasma von Willebrand factor, soluble thrombomodulin, and fibrin D-dimer concentrations in acute onset non-rheumatic atrial fibrillation. Heart. 2004;90:1162–66. doi: 10.1136/hrt.2003.024521. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Inoue H, Nozawa T, Okumura K, et al. Prothrombotic activity is increased in patients with nonvalvular atrial fibrillation and risk factors for embolism. Chest. 2004;126:687–92. doi: 10.1378/chest.126.3.687. [DOI] [PubMed] [Google Scholar]
- 42.Conway DS, Buggins P, Hughes E, Lip GY. Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in chronic atrial fibrillation. J Am Coll Cardiol. 2004;43:2075–82. doi: 10.1016/j.jacc.2003.11.062. [DOI] [PubMed] [Google Scholar]
- 43.Hatzinikolaou-Kotsakou E, Kartasis Z, Tziakas D, et al. Atrial fibrillation and hypercoagulability: Dependent on clinical factors or/and on genetic alterations? J Thromb Thrombolysis. 2003;16:155–61. doi: 10.1023/B:THRO.0000024053.45693.fc. [DOI] [PubMed] [Google Scholar]
- 44.Conway DS, Buggins P, Hughes E, Lip GY. Relation of interleukin-6, C-reactive protein, and the prothrombotic state to transesophageal echocardiographic findings in atrial fibrillation. Am J Cardiol. 2004;93:1368–73. A1366. doi: 10.1016/j.amjcard.2004.02.032. [DOI] [PubMed] [Google Scholar]
- 45.Kamath S, Blann AD, Chin BS, Lip GY. Platelet activation, haemorheology and thrombogenesis in acute atrial fibrillation: A comparison with permanent atrial fibrillation. Heart. 2003;89:1093–1095. doi: 10.1136/heart.89.9.1093. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Marin F, Roldan V, Climent V, et al. Is thrombogenesis in atrial fibrillation related to matrix metalloproteinase-1 and its inhibitor, TIMP-1? Stroke. 2003;34:1181–86. doi: 10.1161/01.STR.0000065431.76788.D9. [DOI] [PubMed] [Google Scholar]
- 47.Conway DS, Heeringa J, Van Der Kuip DA, et al. Atrial fibrillation and the prothrombotic state in the elderly: The Rotterdam Study. Stroke. 2003;34:413–17. doi: 10.1161/01.str.0000051728.85133.32. [DOI] [PubMed] [Google Scholar]
- 48.Kamath S, Chin BS, Blann AD, Lip GY. A study of platelet activation in paroxysmal, persistent and permanent atrial fibrillation. Blood Coagul Fibrinolysis. 2002;13:627–36. doi: 10.1097/00001721-200210000-00008. [DOI] [PubMed] [Google Scholar]
- 49.Kamath S, Blann AD, Chin BS, et al. A study of platelet activation in atrial fibrillation and the effects of antithrombotic therapy. Eur Heart J. 2002;23:1788–95. doi: 10.1053/euhj.2002.3259. [DOI] [PubMed] [Google Scholar]
- 50.Wang TD, Chen WJ, Su SS, et al. Increased levels of tissue plasminogen activator antigen and factor VIII activity in nonvalvular atrial fibrillation: Relation to predictors of thromboembolism. J Cardiovasc Electrophysiol. 2001;12:877–84. doi: 10.1046/j.1540-8167.2001.00877.x. [DOI] [PubMed] [Google Scholar]
- 51.Li-Saw-Hee FL, Blann AD, Gurney D, Lip GY. Plasma von Willebrand factor, fibrinogen and soluble Pselectin levels in paroxysmal, persistent and permanent atrial fibrillation. Effects of cardioversion and return of left atrial function. Eur Heart J. 2001;22:1741–47. doi: 10.1053/euhj.2000.2531. [DOI] [PubMed] [Google Scholar]
- 52.Feng D, D’Agostino RB, Silbershatz H, et al. Hemostatic state and atrial fibrillation (the Framingham Offspring Study) Am J Cardiol. 2001;87:168–71. doi: 10.1016/s0002-9149(00)01310-2. [DOI] [PubMed] [Google Scholar]
- 53.Topcuoglu MA, Haydari D, Ozturk S, et al. Plasma levels of coagulation and fibrinolysis markers in acute ischemic stroke patients with lone atrial fibrillation. Neurol Sci. 2000;21:235–40. doi: 10.1007/s100720070082. [DOI] [PubMed] [Google Scholar]
- 54.Mondillo S, Sabatini L, Agricola E, et al. Correlation between left atrial size, prothrombotic state and markers of endothelial dysfunction in patients with lone chronic nonrheumatic atrial fibrillation. Int J Cardiol. 2000;75:227–32. doi: 10.1016/s0167-5273(00)00336-3. [DOI] [PubMed] [Google Scholar]
- 55.Giansante C, Fiotti N, Miccio M, et al. Coagulation indicators in patients with paroxysmal atrial fibrillation: effects of electric and pharmacologic cardioversion. Am Heart J. 2000;140:423–29. doi: 10.1067/mhj.2000.108520. [DOI] [PubMed] [Google Scholar]
- 56.Li-Saw-Hee FL, Blann AD, Lip GY. A cross-sectional and diurnal study of thrombogenesis among patients with chronic atrial fibrillation. J Am Coll Cardiol. 2000;35:1926–31. doi: 10.1016/s0735-1097(00)00627-6. [DOI] [PubMed] [Google Scholar]
- 57.Marín F, Roldán V, Monmeneu JV, et al. Prothrombotic state and elevated levels of plasminogen activator inhibitor-1 in mitral stenosis with and without atrial fibrillation. Am J Cardiol. 1999;84:862–64. A869. doi: 10.1016/s0002-9149(99)00453-1. [DOI] [PubMed] [Google Scholar]
- 58.Li-Saw-Hee FL, Blann AD, Goldsmith I, Lip GY. Indexes of hypercoagulability measured in peripheral blood reflect levels in intracardiac blood in patients with atrial fibrillation secondary to mitral stenosis. Am J Cardiol. 1999;83:1206–9. doi: 10.1016/s0002-9149(99)00060-0. [DOI] [PubMed] [Google Scholar]
- 59.Roldan V, Marin F, Marco P, et al. Hypofibrinolysis in atrial fibrillation. Am Heart J. 1998;136:956–60. doi: 10.1016/s0002-8703(98)70149-8. [DOI] [PubMed] [Google Scholar]
- 60.Tsai LM, Chen JH, Tsao CJ. Relation of left atrial spontaneous echo contrast with prethrombotic state in atrial fibrillation associated with systemic hypertension, idiopathic dilated cardiomyopathy, or no identifiable cause (lone) Am J Cardiol. 1998;81:1249–52. doi: 10.1016/s0002-9149(98)00131-3. [DOI] [PubMed] [Google Scholar]
- 61.Minamino T, Kitakaze M, Sato H, et al. Plasma levels of nitrite/nitrate and platelet cGMP levels are decreased in patients with atrial fibrillation. Arterioscler Thromb Vasc Biol. 1997;17:3191–95. doi: 10.1161/01.atv.17.11.3191. [DOI] [PubMed] [Google Scholar]
- 62.Kahn SR, Solymoss S, Flegel KM. Nonvalvular atrial fibrillation: Evidence for a prothrombotic state. CMAJ. 1997;157:673–81. [PMC free article] [PubMed] [Google Scholar]
- 63.Sohara H, Amitani S, Kurose M, Miyahara K. Atrial fibrillation activates platelets and coagulation in a time-dependent manner: A study in patients with paroxysmal atrial fibrillation. J Am Coll Cardiol. 1997;29:106–12. doi: 10.1016/s0735-1097(96)00427-5. [DOI] [PubMed] [Google Scholar]
- 64.Lip GY, Lowe GD, Rumley A, Dunn FG. Fibrinogen and fibrin D-dimer levels in paroxysmal atrial fibrillation: evidence for intermediate elevated levels of intravascular thrombogenesis. Am Heart J. 1996;131:724–30. doi: 10.1016/s0002-8703(96)90278-1. [DOI] [PubMed] [Google Scholar]
- 65.Lip GY, Lip PL, Zarifis J, et al. Fibrin D-dimer and beta-thromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation. Effects of introducing ultra-low-dose warfarin and aspirin. Circulation. 1996;94:425–31. doi: 10.1161/01.cir.94.3.425. [DOI] [PubMed] [Google Scholar]
- 66.Mitusch R, Siemens HJ, Garbe M, et al. Detection of a hypercoagulable state in nonvalvular atrial fibrillation and the effect of anticoagulant therapy. Thromb Haemost. 1996;75:219–23. [PubMed] [Google Scholar]
- 67.Nagao T, Hamamoto M, Kanda A, et al. Platelet activation is not involved in acceleration of the coagulation system in acute cardioembolic stroke with nonvalvular atrial fibrillation. Stroke. 1995;26:1365–68. doi: 10.1161/01.str.26.8.1365. [DOI] [PubMed] [Google Scholar]
- 68.Lip GY, Lowe GD, Rumley A, Dunn FG. Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment. Br Heart J. 1995;73:527–33. doi: 10.1136/hrt.73.6.527. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Sohara H, Miyahara K. Effect of atrial fibrillation on the fibrino-coagulation system – study in patients with paroxysmal atrial fibrillation. Jpn Circ J. 1994;58:821–26. doi: 10.1253/jcj.58.821. [DOI] [PubMed] [Google Scholar]
- 70.Kumagai K, Fukunami M, Ohmori M, et al. Increased intracardiovascular clotting in patients with chronic atrial fibrillation. J Am Coll Cardiol. 1990;16:377–80. doi: 10.1016/0735-1097(90)90589-h. [DOI] [PubMed] [Google Scholar]
- 71.Gustafsson C, Blomback M, Britton M, et al. Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation. Stroke. 1990;21:47–51. doi: 10.1161/01.str.21.1.47. [DOI] [PubMed] [Google Scholar]
- 72.Skov J, Sidelmann JJ, Bladbjerg EM, et al. Lysability of fibrin clots is a potential new determinant of stroke risk in atrial fibrillation. Thromb Res. 2014;134:717–22. doi: 10.1016/j.thromres.2014.06.031. [DOI] [PubMed] [Google Scholar]
- 73.Zabczyk M, Majewski J, Lelakowski J. Thromboembolic events are associated with prolonged clot lysis time in patients with permanent atrial fibrillation. Pol Arch Med Wewn. 2011;121:400–7. [PubMed] [Google Scholar]
- 74.Loffredo L, Violi F, Fimognari FL, et al. The association between hyperhomocysteinemia and ischemic stroke in patients with non-valvular atrial fibrillation. Haematologica. 2005;90:1205–11. [PubMed] [Google Scholar]
- 75.Soncini M, Casazza F, Mattioli R, et al. Hypercoagulability and chronic atrial fibrillation: The role of markers of thrombin generation. Minerva Med. 1997;88:501–5. [PubMed] [Google Scholar]
- 76.Roldán V, Marín F, Blann AD, et al. Interleukin-6, endothelial activation and thrombogenesis in chronic atrial fibrillation. Eur Heart J. 2003;24:1373–80. doi: 10.1016/s0195-668x(03)00239-2. [DOI] [PubMed] [Google Scholar]
- 77.Feinberg WM, Pearce LA, Hart RG, et al. Markers of thrombin and platelet activity in patients with atrial fibrillation: correlation with stroke among 1531 participants in the stroke prevention in atrial fibrillation III study. Stroke. 1999;30:2547–53. doi: 10.1161/01.str.30.12.2547. [DOI] [PubMed] [Google Scholar]
- 78.Pongratz G, Brandt-Pohlmann M, Henneke KH, et al. Platelet activation in embolic and preembolic status of patients with nonrheumatic atrial fibrillation. Chest. 1997;111:929–33. doi: 10.1378/chest.111.4.929. [DOI] [PubMed] [Google Scholar]
- 79.Black IW, Chesterman CN, Hopkins AP, et al. Hematologic correlates of left atrial spontaneous echo contrast and thromboembolism in nonvalvular atrial fibrillation. J Am Coll Cardiol. 1993;21:451–57. doi: 10.1016/0735-1097(93)90688-w. [DOI] [PubMed] [Google Scholar]
- 80.Colkesen Y, Acil T, Abayli B, et al. Mean platelet volume is elevated during paroxysmal atrial fibrillation: A marker of increased platelet activation? Blood Coagul Fibrinolysis. 2008;19:411–14. doi: 10.1097/MBC.0b013e3283049697. [DOI] [PubMed] [Google Scholar]
- 81.Tan C, OuYang M, Kong D, Zhou X. Association between the left atrial and left atrial appendages systole strain rate in patients with atrial fibrillation. Med Sci Monit. 2016;22:4974–77. doi: 10.12659/MSM.901831. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82.Hu X, Jiang J, Ma Y, Tang A. Novel P wave indices to predict atrial fibrillation recurrence after radiofrequency ablation for paroxysmal atrial fibrillation. Med Sci Monit. 2016;22:2616–23. doi: 10.12659/MSM.896675. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Jia W, Qi X, Li Q. Association between Rs3807989 polymorphism in Caveolin-1 (CAV1) gene and atrial fibrillation: A meta-analysis. Med Sci Monit. 2016;22:3961–66. doi: 10.12659/MSM.896826. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.Boisclair MD, Ireland H, Lane DA. Assessment of hypercoagulable states by measurement of activation fragments and peptides. Blood Rev. 1990;4:25–40. doi: 10.1016/0268-960x(90)90014-j. [DOI] [PubMed] [Google Scholar]
- 85.Danesh J, Lewington S, Thompson SG, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: An individual participant meta-analysis. JAMA. 2005;294:1799–809. doi: 10.1001/jama.294.14.1799. [DOI] [PubMed] [Google Scholar]
- 86.Jankun J, Skrzypczak Jankun E. Yin and yang of the plasminogen activator inhibitor. Pol Arch Med Wewn. 2009;119:410–17. [PubMed] [Google Scholar]
- 87.Hernández-Romero D, Marín F, Roldán V, Lip GY. Subclinical atherosclerotic endothelial damage as predictor for bleeding in anticoagulated atrial fibrillation patients. J Intern Med. 2012;272:409. doi: 10.1111/j.1365-2796.2012.02565.x. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Forest plot of weighted mean difference (WMD) for association between level of AT-III and occurrence of AF.
Forest plot of weighted mean difference (WMD) for association between level of TAT and occurrence of AF.
Forest plot of weighted mean difference (WMD) for association between level of fibrinopeptide and occurrence of AF.
Forest plot of weighted mean difference (WMD) for association between level of sTM and occurrence of AF.
Forest plot of weighted mean difference (WMD) for association between level of D-dimer and occurrence of thromboembolism.
Forest plot of weighted mean difference (WMD) for association between level of fibrinogen and occurrence of thromboembolism.
Forest plot of weighted mean difference (WMD) for association between level of PF1–2 and occurrence of thromboembolism.
Forest plot of weighted mean difference (WMD) for association between level of PF1–2 and occurrence of stroke.
Forest plot of weighted mean difference (WMD) for association between level of TAT and occurrence of stroke.
Forest plot of weighted mean difference (WMD) for association between level of PAI and occurrence of stroke.
Forest plot of weighted mean difference (WMD) for association between level of D-dimer and occurrence of stroke.
Forest plot of weighted mean difference (WMD) for association between level of fibrinogen and occurrence of stroke.
Forest plot of weighted mean difference (WMD) for association between level of AT-III and occurrence of stroke.
Funnel plot for publication bias of studies investigating D-dimer.
Funnel plot for publication bias of studies investigating fibrinogen.
Funnel plot for publication bias of studies investigating PF1–2.
Funnel plot for publication bias of studies investigating of TAT.
Funnel plot for publication bias of studies investigating AT-III.
Funnel plot for publication bias of studies investigating fibrinopeptide-A.
Funnel plot for publication bias of studies investigating t-PA.
Funnel plot for publication bias of studies investigating PAI.
Funnel plot for publication bias of studies investigating vWF.
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 |