Pre-Existence of Prothrombotic State in Patients with Atrial Fibrillation Despite Therapy with New and Traditional Anti-Coagulant Drugs
Authors: Liles Jeffrey Paul , Wanderling Christopher , Liles Jordan Lee , Hoppensteadt Debra , Fareed Jawed , Syed Daneyal , Syed Mushabbar 
Published: October 2019

Abstract
Background: Oral anticoagulants such as warfarin (W) have been conventionally used for the management of atrial fibrillation (AF). Despite the effectiveness of W, 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) and apixaban (A) have been approved to manage thrombotic and cardiovascular disorders including AF. The newer anticoagulants do not require continuous monitoring like W does and are much more convenient for patients with AF.
Objective: To profile the baseline level of circulating thrombogenic biomarkers von Willebrand Factor (vWF), prothrombin fragment 1.2 (F1+2), microparticle bound tissue factor (MP-TF) and plasminogen activator inhibitor (PAI-1) in patients with AF. Additionally, the effect of both newer (R and A) and traditional (W) anticoagulants on the levels of thrombogenic biomarkers in patients with AF will be assessed.
Materials: Citrated blood was drawn from thirty AF patients prior to ablation surgery and spun at 3000 rpm to obtain platelet poor plasma. Normal plasma samples from healthy controls 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: Circulating levels of vWF, MP-TF and PAI-1 were statistically increased in patients with AF compared to normal (P<0.0001, P<0.0001, and P=0.0014, respectively). Circulating levels of prothrombin F1+2 showed no difference between the AF and normal group (P=0.2696). AF patients (n=30) were divided into two groups based on their usage (Group 1, n=21) and non-usage (Group 2, n=9) of any anticoagulant. Furthermore, those on anticoagulants were divided based on their use of newer (R and A, Group 3, n=16) or traditional (W, Group 4, n=4) anticoagulants. A statistical increase in vWF (P<0.0001), MP-TF (P<0.0001) and PAI-1 (P=0.011) remained in Group 1 compared to normal while a statistical increase in prothrombin F1+2 (P=0.0343) and PAI-1 (P=0.0040) were noted in Group 2 compared to normal. vWF (P=0.0036) and MP-TF (P=0.0059) were elevated in Group 1 compared to Group 2 while prothrombin F1+2 (P=0.0697) and PAI-1 (P=0.4548) showed no difference between the two groups. Furthermore, there was no statistical difference in the level of any thrombogenic biomarker in AF patients between Group 3 (R and A) and Group 4 (W). (Table 1)
Discussion: Elevated levels of vWF, MP-TF and PAI-1 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 patients are assessed using a stroke risk stratification scale (CHA2DS2VASc, CHADS2, CHADS-VASC, or CHADS) to determine if anti-coagulants should be used to prevent stroke associated with AF. Of the 30 patients examined in this study, 8/9 (89%) patients who were not on anticoagulants had a stroke risk stratification score of 0 while 20/21(95%) patients who were on anticoagulants had a score of >1. This data supports studies which suggest that adding 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 and A, and the traditional anticoagulant, W, 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/traditional anticoagulants alone.Table 1.Biomarkers of Thrombogenesis in AF and Normal GroupsGroupvWF (concentration %)Prothrombin F1+2 (pmol/L)MP-TF (pg/mL)PAI-1 (ng/mL)Normal4140 ± 919 n=46106.1 ± 52.7 n=500.38 ± 0.25 n=483.21 ± 4.13 n=25AF Group 1 Anticoagulant n=216616 ± 1173107.9 ± 61.20.93 ± 0.715.69 ± 4.15Group 2 Non-Anticoagulant n=94788 ± 1338162.5 ± 93.30.51 ± 0.136.49 ± 3.14Group 3 New Anticoagulants (R and A) n=166721 ± 1127103.5 ± 37.60.76 ± 0.345.68 ± 4.53Group 4 Traditional Anticoagulants (W) n=46387 ± 158075.2 ± 52.60.94 ± 0.335.63 ± 3.52

Disclosures
No relevant conflicts of interest to declare.