Persistent Prothrombotic State in Atrial Fibrillation Despite Use of Novel Oral Anti-Coagulants
Authors: Liles Jeffrey , Wanderling Christopher , Otto Abigail M , Liles Jordan , Hoppensteadt Debra , Syed Daneyal , Jabati Sallu , Syed Mushabbar , Fareed Jawed 
Published: November 2019

Abstract
Background: Oral anticoagulants such as warfarin have been conventionally used for the management of atrial fibrillation (AF). Despite the effectiveness of warfarin, its use in AF patients requiring anticoagulation is suboptimal with an even greater underuse seen in elderly patients who are at higher risk of stroke. New oral anticoagulants such as rivaroxaban(R), apixaban (A), dabigitran (D) and edoxaban (E) have been approved to manage thrombotic and cardiovascular disorders including AF. The newer anticoagulants do not require continuous monitoring like warfarin and are much more convenient for patients with AF.
Objective: To profile the baseline level of circulating thrombotic biomarkers plasminogen activator inhibitor (PAI-1), von Willebrand Factor (vWF), microparticle bound tissue factor (MP-TF) and prothrombin fragment 1.2 (F1.2) in patients with AF. Additionally, the effect of novel oral anticoagulants (R, A, D and E) on the levels of thrombotic biomarkers in patients with AF is assessed.
Materials and Methods: Citrated blood samples were drawn from 30 patients (21 male and 9 female; mean age 59.1) prior to ablation surgery for AF at Loyola University Medical Center in Maywood, Illinois. Citrated blood was spun at 3000 rpm to obtain platelet poor plasma. Normal plasma samples from healthy controls (24 male and 24 female; mean age 33) were purchased from a commercial source (George King Biomedical, Overland Park, KS). The plasma samples were analyzed using a biochip array (Randox, London, UK) for metabolic syndrome biomarkers including PAI-1 and ELISA kits for vWF, MP-TF (Hyphen BioMed, Nueville-Sur-Oise, France) and prothrombin F1.2 (Siemens, Newark, DE).
Results: Compared to the control group, circulating levels of vWF, MP-TF and PAI-1 were statistically increased in patients with AF (P<0.0001, P<0.0001, and P=0.0014, respectively). Circulating levels of prothrombin F1.2 showed no difference between the AF and the control group (P=0.2696). AF patients (n=30) were divided into two groups based on their usage (Group 1, n=17) and non-usage (Group 2, n=10) of any novel oral anticoagulant (R, A, D and E). Three patients on warfarin were excluded from this section of data analysis. A statistical increase in vWF (P=0.0018) and MP-TF (P=0.0039) remained in those taking novel oral anticoagulants compared to group 2. No difference was seen in PAI-1 (P=0.333) or F1.2 (P=0.31) between groups 1 and 2. Percent change from the normal mean was also calculated for PAI-1, vWF, MP-TF and F1.2 in group 1 (78%, 61.1%, 142%, 8.9%, respectively) and group 2 (113.6%, 16.9%, 31.7%, 41.4%, respectively) as seen in table 1.
Discussion: Elevated levels of PAI-1, vWF and MP-TF seen in AF patients compared to normal provide insight into an additional risk of thrombogenesis associated with AF which is not targeted by current anticoagulant medications. Most AF patients are assessed using a stroke risk stratification scale (CHA2DS2VASc) to determine if anti-coagulants should be used to prevent stroke associated with AF. Patients in group 1 had a mean CHA2DS2VASc score of 1.15 compared to 2.18 see in group 2. This data supports studies which suggest that including levels of prothrombotic biomarkers to current risk stratification scales could be more effective in assessing the risk of stroke of patients with AF. This data also suggests that although very effective in lowering prothrombin F1.2 levels in AF, the newer anticoagulants, R,A,D and E still leave additional prothrombotic biomarkers unaffected. These unaffected biomarkers could be the potential target of future drug therapies which could lower the risk of stroke in patients with AF even more than the use of newer anticoagulants alone.

Disclosures
No relevant conflicts of interest to declare.