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Direct oral anticoagulants (DOACs) are known to prevent thrombosis but there is limited information about their activity on the clot formation and lysis cascade. This study assesses the role of apixaban, one of the four licenced DOACs, on clot dynamics in patients with atrial fibrillation (AF). We compared haemostatic and clot lysis characteristics between a group of patients with AF (n = 47) and a "disease control" group with ischaemic heart disease but in sinus rhythm (n = 39). Subsequently, we conducted clot structure studies in 3 groups of patients with AF on different antithrombotic drugs: warfarin (n = 60), apixaban (n = 60) or antiplatelets (n = 62) and in patients with AF naïve to oral anticoagulants before and after 3-months treatment with apixaban (n = 32). Haemostasis was investigated by a viscoelastic, whole blood technique (Thromboelastography/TEG), a "microplate-reader based", citrated plasma technique (microplate assay), immunoassays to determine plasma concentrations of plasminogen activator inhibitor-1 (PAI-1), tissue-Plasminogen Activator (t-PA), D-dimer and finally platelet derived and apoptotic microparticles. Patients with AF have more potent thrombogenesis based on microplate assay indices [Rate of clot formation (p = 0.03, ƞ2 = 0.06), Maximum optical density (p < 0.001, ƞ2 = 0.05)] and delayed fibrinolysis [Rate of clot dissolution (p = 0.005, ƞ2 = 0.17)] with increased levels of apoptotic microparticles (p = 0.02, ƞ2 = 0.06) compared with the 'disease control' group. Apixaban was more effective in attenuating prothrombotic characteristics assessed by TEG {R (ε2 = 0.21), K (ε2 = 0.16) and angle [mean difference (MD), 95% Confidence Intervals (CI), vs warfarin 5, 0.96–8.6 and 8, 3.8–11.4 vs antiplatelets], (p < 0.001 for all indices)} compared with the other treatment groups. Patients on apixaban had lower D-dimer (p < 0.001, ε2 = 0.17) and tPA (p = 0.03, MD 90, 95%CI 6–150 vs warfarin and MD 90, 95% CI 4–150 vs antiplatelets) levels. From the microplate assay analysis, warfarin and apixaban demonstrated comparable activity based on multiple indices, both superior to antiplatelets. However, warfarin was associated with reduced fibrin network robustness (Max. optical density p < 0.001, ε2 = 0.1). Apixaban inhibited thrombosis, amplified fibrinolysis and decreased D-dimer (p = 0.001, r = 0.4) levels in the follow up study. Patients with AF have impaired haemostasis and elevated levels of apoptotic microparticles. Apixaban appears to affect plasma prothrombotic characteristics in a distinctive manner compared with warfarin and to reduce biomarkers associated with adverse cardiovascular events. • Clot structure characteristics in atrial fibrillation reflect elevated prothrombotic potential. • Atrial fibrillation is associated with higher levels of apoptotic microparticles. • Apixaban affects haemostasis differently compare with warfarin and antiplatelets. • Apixaban reduces biomarker levels related with adverse cardiovascular events. • Clot structure characteristics may be useful to tailor anticoagulation therapy. [ABSTRACT FROM AUTHOR]