Active FXI Can Independently Predict Ischemic Stroke in Anticoagulated Atrial Fibrillation Patients: A Cohort Study

Abstract

Background Atrial fibrillation (AF) is associated with a prothrombotic state. Presence of active tissue factor (TF), activated factor IX (FIXa) and FXIa in circulating blood contributes to thrombosis. We investigated a prognostic value of these factors in AF patients. Methods In this cohort study, 284 AF patients (aged 63.3 ± 8.8 years) treated with oral anticoagulants were enrolled. Plasma levels of active coagulation factors were evaluated using thrombin generation assay. Concentrations of fibrinogen, D-dimer, interleukin-6 (IL-6), and endothelial damage markers, including von Willebrand factor (VWF) and soluble (s)E-selectin, were also measured. Ischemic stroke and cardiovascular death, analyzed separately or as a composite endpoint, were recorded during a mean follow-up of 47 months. Results Cerebrovascular events were observed in 20 patients (1.8%/year) who had at baseline higher fibrinogen, D-dimer, and VWF levels. Active TF and FXIa at enrollment were detectable in 12 (60%) and 15 (75%) patients who experienced ischemic stroke during follow-up. The composite endpoint observed in 23 patients (2.1%/year) was associated with increased concentrations of the above laboratory variables, along with 26% higher IL-6 levels. sE-selectin did not differ between the studied groups. On multivariable regression analysis, advanced age, anticoagulation discontinuation, and detectable FXIa, but not active TF, independently predicted the composite endpoint. No associations of FIXa with the study endpoints were observed. Conclusion FXIa present in circulating blood is associated with increased risk of ischemic stroke and cardiovascular death in anticoagulated AF patients during long-term follow-up. FXIa inhibition could be useful in cardiovascular prevention in AF beyond the current oral anticoagulation.

Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis

“…Atrial Fibrillation (AF) is the most common sustained cardiac rhythm disorder and is associated with a prothrombotic state. It was shown in a cohort study that in long-term follow-up, FXIa level in circulating blood has been associated with poor prognosis such as IS and cardiovascular death in AF patients on anticoagulants (45). Recently, the FXIa inhibitor asundexian at two doses (20 and 50mg daily) showed lower bleeding rates than the active comparator, the FXa inhibitor apixaban 5mg, in a phase II trial in AF at risk for stroke.…”

“…It was shown in a cohort study that in long-term follow-up, the FXIa level in circulating blood has been associated with poor prognosis such as IS and cardiovascular death in AF patients on anticoagulants. 48 Recently, the FXIa inhibitor asundexian at two doses (20 and 50 mg daily) showed lower bleeding rates than the active comparator, the FXa inhibitor apixaban 5 mg, in a phase II trial in AF at risk for stroke. However, it still remains to be further investigated to what extent inhibition of FXI(a) is equally or more effective than established direct oral anticoagulants (DOACs) to prevent thrombotic events and if they could improve long-term prognosis of AF.…”

Persistently High Levels of Coagulation Factor XI as a Risk Factor for Venous Thrombosis

“…A study by Suri MF et al [15] found a threefold increased risk of ischaemic stroke, and Yang DT et al [16] reported a fivefold increased risk of stroke or transient ischaemic attack (TIA) in patients with elevated FXI levels. Z ąbczyk MT et al [17] recently found that circulating FXIa is associated with increased risk of ischaemic stroke and cardiovascular death in patients with atrial fibrillation (AF) undergoing anticoagulant therapy during long-term follow-up. Finally, elevated FXI levels have been associated with higher risk of all-cause mortality after the first ischaemic stroke [16].…”

Elevated plasma factor XI predicts cardiovascular events in patients with type 2 diabetes: a long-term observational study

“…We have shown recently, that in patients with advanced CAD, FXIa was an independent predictor of MI, stroke, or CV death in long-term follow-up [ 20 ]. In patients with atrial fibrillation FXIa was an independent predictor of stroke or CV mortality which occurred despite oral anticoagulation [ 21 ]. The persistent generation of FXIa in the plasma is likely driven by oxidative stress, inflammation, and endothelial injury [ 14 ], all of which are involved in the pathophysiology of DM, suggesting a possible FXI upregulation in diabetic patients.…”