Markers of Activated Coagulation Factor XII Are Inversely Associated with Progression of Atrial Fibrillation in the Race V Study

Background: Paroxysmal atrial fibrillation (PAF) is a common cardiac arrhythmia which may cause stroke and heart failure, especially in case of AF progression. Recent studies have suggested that hypercoagulability may play a significant role in the pathophysiology of PAF by facilitating initiation and progression of PAF. Most evidence for the hypercoagulable state originates from elevated levels of D-dimer, prothrombin fragment 1+2 or thrombin-antithrombin complexes, however whether this originates from the intrinsic (FXII) or the extrinsic (FVII) pathway is not known. Therefore, we aimed to systematically investigate the association of the activation of single coagulation factors with the progression of AF. Methods: In this sub-study of RACE V (Reappraisal of Atrial Fibrillation: Interaction between HyperCoagulability, Electrical Remodelling, and Vascular Destabilisation in the Progression of Atrial Fibrillation, NCT02726698) study, 417 patients with PAF were included. At baseline extensive phenotyping was performed including blood samples drawn. During follow-up continuous monitoring for AF progression defined as either development of persistent or permanent AF during follow-up or an increase of >3% AF burden over the first 6 months or total follow-up, was performed for at least one year. Hypercoagulability was monitored through activated coagulation factors (FXIIa, FXIa, FIXa, FXa, pKa and thrombin) in complex with their natural inhibitors (antithrombin (AT), C1-esterase inhibitor (C1Inh), or alpha-1-antitrypsin (a1AT)) utilizing ELISA. Multivariable logistic regression analysis was used for the association of coagulation markers with AF progression. Results: 51 out of 417 study subjects showed AF progression within the follow-up time period. Patients with AF progression showed significantly lower FXIIa complexes in comparison to patients without AF progression (759 pM [660-879] vs. 886 pM [765-1007]. The activation state of the other coagulation factors showed no statistically significant differences. Multivariate analysis identified that FXIIa complexes (odds ratio [OR] 0.998, 95% confidence intervals [CI] 0.997-0.999, p<.001.) are associated with AF progression. FXIa (OR 0.734, 95%CI 0.521-1.033, p=0.76), FXa (OR 0.532, 95%CI 0.201-1.405, p=0.203), FIXa (OR 1.101, 95%CI 0.789-1.538, p=0.572), thrombin (OR 1.022, 95%CI 0.997-1.048, p=0.086) and kallikrein (OR 0.969, 95%CI 0.903-1.039, p=0.372) showed no relationship with AF-progression. Conclusion: In patients with PAF FXIIa was inversely related to AF progression. Downstream activation of the intrinsic cascade, however, was not related to AF progression. Whether this means that FXII is over-proportionally auto-activated or has a protective role or in AF-progression needs to be further investigated.