Introduction Thrombotic disorders including ischemic heart d

Introduction Thrombotic disorders including ischemic heart disease, deep venous thrombosis, and ischemic stroke represent one of the most common causes of death in the world [1]. All these conditions relate to states accompanied by a shift of hemostasis balance into a coagulation side because of various genetic or/and acquired factors. The pathologic formation of thrombi of vessels, the leading pathogenic process of thrombotic diseases, can obstruct blood flow causing serious tissue damage (e.g. damage of tlr inhibitor cells) due to insufficient oxygen supply. Thrombosis can be associated with some pathology as a secondary disorder. For example, atrial fibrillation may be followed by systemic embolization, a severe life-threating complication [2]. The above-mentioned conditions is treated and prevented by administration of anticoagulants. Currently available oral anticoagulants are divided into two groups: vitamin K antagonists (VKA), non-vitamin K antagonist oral anticoagulants (NOAC). VKA indirectly influence on calcium-dependent clotting factors by hampering their gamma carboxylation and thereby make them incapable of binding to the vascular endothelium and performing their biological function. The most famous member of VKA is warfarin which until 2010 was the only oral anticoagulant medication available [3]. However, owing to a narrow therapeutic index, drug-drug interactions and a need for close monitoring of the degree of anticoagulation therapy VKA is considered to be a difficult and inconvenient therapeutic option. NOAC achieve their anticoagulant effect through two different mechanisms: inhibition of thrombin (FIIa) in the case of dabigatran and inhibition of factor Xa (FXa) in the case of apixaban, edoxaban, and rivaroxaban. It has been shown that all NOAC possess a superior benefit/risk ratio in terms of bleeding and mortality and cause fewer adverse effects in comparison to VKA [4]. Despite superiority over vitamin K antagonists the existing NOAC show several disadvantages related to their adverse effects. For example, treatment with rivaroxaban and dabigatran may be associated with an elevated bleeding risk [5] and edoxaban can cause impaired kidney function [6,7]. Moreover, in some cases therapy with NOAC can lead to uncontrollable bleeding which requires administration of the specific reversal agents [8]. Thus, currently, discovery and development of more safe anticoagulants remains an actual task. Studies which generalize data of meta-analyses published in the last decade show that inhibition of FXa is more optimal therapeutic strategy than inhibition of FIIa [9]. For instance, the RE-LY trial demonstrated that therapy with dabigatran is associated with an enhanced risk for myocardial infarction, whereas administration of FXa inhibitors, in contrast, might reduce the risk of this disease [9]. The increased risk of myocardial infarction caused by inhibition of FIIa is attributed to enhancement of platelet reactivity which, in turn, may arise due to several potential mechanisms, for example, through augmented thrombin glycoprotein Ibα signaling. The mechanisms underlying decline of this risk in the case of FXa inhibitors therapy are unknown. The coagulation cascade consists of approximately 30 different proteins [10]. Most of them are serine proteases activation of which occurs consistently: upstream proteins activate its downstream substrates which, in turn, represent precursors for the next reactions and so on. This apparent redundancy is aimed at two goals: signal amplification and general control over the coagulation process. There exist two major initiation factors which divide the cascade into two branches: the intrinsic pathway and the extrinsic pathway. The first pathway is initiated with an activation of coagulation factor XII which occurs at contact with negatively charged surfaces or platelet polyphosphates. The extrinsic pathway begins with vascular trauma which causes a release of tissue factor, the leading initiation factor of this pathway. After initiation both pathways lead to factor X activation and the activated form of this protein (FXa) forms the prothrombinase complex which subsequently generates thrombin from prothrombin. Thrombin, the final and crucial element of the cascade, induces fibrin formation and performs other functions related to positive and negative feedbacks. Thus, two branches of the clotting cascade converge on FX and its inhibition results in effective prevention of thrombosis due to initial stopping of the amplification stage. This allows to use smaller doses of an anticoagulant to treat thrombotic disorders [11].