PB0016 - Plasma protein carbonylation is associated with unfavorably altered fibrin clot properties in patients with atrial fibrillation: a novel risk factor of ischemic cerebrovascular events

Background: Atrial fibrillation (AF) is associated with prothrombotic fibrin clot phenotype, which predispose to ischemic stroke. Factors that determine clot phenotype in AF are poorly characterized.

Aims: This study aimed to investigate whether increased oxidative stress, reflected by plasma protein carbonylation (PC), affects fibrin clot properties and the risk of ischemic stroke in anticoagulated AF patients during follow-up.

Methods: In 243 AF patients on anticoagulant therapy (median age, 69 years; median CHA2DS2-VASc=4), we measured PC (Becatti ATVB, 2014), along with plasma clot permeability (Ks) and clot lysis time (CLT). Plasminogen activator inhibitor type 1 (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI) were also determined. Ischemic stroke, major bleeding, and mortality were recorded during a median follow-up of 53 months while on anticoagulation.

Results: Plasma PC (3.16 [2.54-3.99] nM/mg protein) at baseline showed association with age (r=0.36, p< 0.0001) and CHA2DS2-VASc (p=0.003) but not with type of AF. Plasma PC was correlated with CLT (r=0.34, p< 0.0001), and weakly with Ks (r=-0.15, p=0.024), but not with fibrinogen, PAI-1 or TAFI levels. Of note, AF patients with left ventricular ejection fraction < 40% (n=57, 23.5%) had 22.7% higher (p=0.005) PC levels and CLT prolonged by 10% (p=0.044). Ischemic cerebrovascular events were observed in 20 patients (1.9%/year) who had at baseline 36.4% higher PC, 6% reduced Ks, and 15% longer CLT (all p< 0.05), also after adjustment for age. PC did not differ in patients who experienced major bleeding or death compared with the remainder.

Conclusion(s): Our findings suggest that protein carbonylation contributes to the formation of more compact fibrin clots and impaired fibrinolysis in AF, probably due to posttranslational modifications of fibrinogen. We are the first to show that enhanced protein carbonylation in AF patients increases the risk of ischemic cerebrovascular events during anticoagulation, which highlights the role of oxidative stress in thrombotic manifestations of AF.