The association of coagulation and atrial fibrillation: a systematic review and meta-analysis

Abstract

Aims: While atrial fibrillation (AF) is suggested to induce a prothrombotic state, increasing thrombotic risk, it is also hypothesized that coagulation underlies AF onset. However, conclusive evidence is lacking. With this systematic review and meta-analysis, we aimed to summarize and combine the evidence on the associations between coagulation factors with AF in both longitudinal and cross-sectional studies.

Methods and results: We systematically searched for longitudinal cohort and cross-sectional studies investigating AF and thrombosis. For longitudinal studies, pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. For cross-sectional studies, we determined pooled standardized mean differences (SMDs) and 95% CIs. A total of 17 longitudinal and 44 cross-sectional studies were included. In longitudinal studies, we found significant associations between fibrinogen (HR 1.05, 95% CI 1.00-1.10), plasminogen activator inhibitor 1 (PAI-1) (HR 1.06, 95% CI 1.00-1.12), and D-dimer (HR 1.10, 95% CI 1.02-1.19) and AF incidence. In cross-sectional studies, we found significantly increased levels of fibrinogen (SMD 0.47, 95% CI 0.20-0,74), von Willebrand factor (SMD 0.96, 95% CI 0.28-1.66), P-selectin (SMD 0.31, 95% CI 0.08-0.54), ß-thromboglobulin (SMD 0.82, 95% CI 0.61-1.04), Platelet Factor 4 (SMD 0.42, 95% CI 0.12-0.7), PAI-1 (1.73, 95% CI 0.26-3.19), and D-dimer (SMD 1.74, 95% CI 0.36-3.11) in AF patients, as opposed to controls.

Conclusion: These findings suggest that higher levels of coagulation factors are associated with prevalent and incident AF. These associations are most pronounced with prevalent AF in cross-sectional studies. Limited evidence from longitudinal studies suggests a prothrombotic state underlying AF development.

Keywords: Atrial fibrillation; Coagulation; Haemostasis; Meta-analysis; Tachyarrhythmia; Thrombosis.

Figure 1

Flowchart of the inclusion and exclusion of studies. AF, atrial fibrillation; n, number.

Figure 2

Forest plot of the associations between various coagulation biomarkers and incident AF in longitudinal studies. I² was 71.8% for fibrinogen, 83.9% for von Willebrand factor, 94.5% for ADAMTS13, 0.0% for PAI-1, 0.0% for D-dimer, and 40.4% for P-selectin. ADAMTS13, a desintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; AF, atrial fibrillation; HR, hazard ratio; N, number; PAI-1, plasminogen activator inhibitor 1.

Figure 3

Forest plots of the associations between various coagulation biomarkers and AF presence in cross-sectional studies. (A) Fibrinogen; (B) von Willebrand Factor; (C) P-Selectin; (D) ß-thromboglobulin; (E) platelet factor 4; (F) platelet count; (G) thrombomodulin; (H) TPA. (I) PAI-1; (J) D-dimer. CI, confidence interval; N, number; PAI-1, plasminogen activator inhibitor 1; SD, standard deviation; SMD, standardized mean difference; TAT, thrombin–antithrombin complex; TPA, tissue plasminogen activator.

Figure 3

Forest plots of the associations between various coagulation biomarkers and AF presence in cross-sectional studies. (A) Fibrinogen; (B) von Willebrand Factor; (C) P-Selectin; (D) ß-thromboglobulin; (E) platelet factor 4; (F) platelet count; (G) thrombomodulin; (H) TPA. (I) PAI-1; (J) D-dimer. CI, confidence interval; N, number; PAI-1, plasminogen activator inhibitor 1; SD, standard deviation; SMD, standardized mean difference; TAT, thrombin–antithrombin complex; TPA, tissue plasminogen activator.

Figure 3

Forest plots of the associations between various coagulation biomarkers and AF presence in cross-sectional studies. (A) Fibrinogen; (B) von Willebrand Factor; (C) P-Selectin; (D) ß-thromboglobulin; (E) platelet factor 4; (F) platelet count; (G) thrombomodulin; (H) TPA. (I) PAI-1; (J) D-dimer. CI, confidence interval; N, number; PAI-1, plasminogen activator inhibitor 1; SD, standard deviation; SMD, standardized mean difference; TAT, thrombin–antithrombin complex; TPA, tissue plasminogen activator.