Fibrin clot properties in patients with atrial fibrillation: associations with clinical characteristics, biomarkers, and clinical outcomes

Atrial fibrillation (AF) is a common disorder of heart rhythm. While the pathological mechanisms are not completely understood, AF is associated with a substantially elevated stroke risk. Once AF is recognised, the risk of stroke can be estimated and mitigated with anticoagulant medication, such as the factor Xa inhibitor, apixaban. These medications substantially reduce stroke risk, but they also increase bleeding risk. Adjusting treatment intensity depending on an individual’s likelihood of either thrombosis or bleeding may allow clinicians to optimally balance these competing risks.

The propensity of fibrin clots to form in plasma can be measured using various techniques. In this thesis, I iteratively refined a protocol for a tissue factor fibrin clot assay, aiming to maximise its utility in a cohort of patients with AF. I then used this, together with a thrombin assay, to measure fibrin clot properties in 4,350 plasma samples from Apixaban for Reduction In Stroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) participants, with samples taken both before (n = 1,891) and during (n = 2,459) apixaban therapy. Clot properties were then compared with clinical characteristics, biomarkers, outcomes, and treatment effect.

I found that delayed clot formation was associated with diabetes mellitus, renal impairment, and inflammatory biomarkers. Tissue factor-induced lag time was profoundly longer after apixaban was started, but this increase was heterogenous, with a greater difference observed in older individuals and those with increased body mass index.

Additionally, prolonged fibrin clot lysis was associated with female sex, diabetes, increasing BMI, and decreasing age. Lysis time also strongly correlated with inflammatory biomarkers. Of note, people with delayed lysis had fewer bleeding events.

I discuss how these findings provide insight into mechanisms of stroke in patients with AF and how they may influence risk stratification and treatment in the future.