Mean SEM from 5 impartial experiments. activated cells. In contrast procoagulant activity associated to monocytes and macrophages was dose dependently inhibited by rivaroxaban, but not significantly by fondaparinux. These results could explain why patients undergoing major orthopedic surgery with rivaroxaban prophylaxis were able to achieve significant reductions in venous thromboembolism, compared with drugs commonly used, i.e. fondaparinux and low molecular weight heparin. In addition, rivaroxaban and fondaparinux suppressed some chemokine secretion produced by activated macrophages. This may also contribute to their antithrombotic effect in clinic. strong class=”kwd-title” Keywords: Coagulant, Fondaparinux, Rivaroxaban, Monocyte, Cytokine Background Newer antithrombotic Etoricoxib D4 drugs have been developed to improve efficacy and safety for prevention and treatment of venous and arterial thrombosis. Drug candidates are designed to achieve a direct specific inhibition of coagulation factors that are presumed to play an important role in thrombogenesis. Among them, there are new orally active antithrombotic agents targeting thrombin or factor Xa that have previously been approved in therapeutics [1]. Fondaparinux (Arixtra?) is usually a synthetic penta saccharide that selectively binds to antithrombin III, potentiating factor Xa neutralization thus inhibiting thrombin formation [2, 3]. Rivaroxaban (Xarelto?) is usually a direct factor Xa inhibitor which binds directly to the Xa active site, blocking its activity [4]. Rivaroxaban is usually 100,000-fold more selective for FXa than for other biological proteases such as thrombin, plasmin, factor VIIa or factor IXa. Both, fondaparinux and rivaroxaban inhibit thrombin generation in plasma when the coagulation cascade is usually triggered by tissue factor (TF). Activated coagulation factor X (FXa) is usually a major target for designing anticoagulant drugs: it is located at the THSD1 convergence of the intrinsic and extrinsic coagulation cascade, and activation of one molecule of factor X results in the generation of 1000 molecules of thrombin [5, 6]. Factor Xa assembled along with factor Va around the cell surface results in prothrombinase complex formation, a potent activator of prothrombin. This complex enhances factor Xa catalytic efficacy by several orders of magnitude in the rate of factor II activation into thrombin [7]. It is well established that in thrombosis, FXa generation results from an activation of coagulation cascade initiated by TF expressed on activated endothelial cells and activated monocytes/macrophages [8], while under physiological conditions, endothelial cells and monocytes /macrophages do not express TF and TF activity is usually Etoricoxib D4 counterbalanced by TFPIs [9]. Endothelial cells secrete TFPI and express TFPI around the cell surface and TFPIs was found bound to the surfaces of monocytes [10]. TFPI and TFPI inhibit both TF-factor VIIa-dependent factor Xa (FXa) generation and free FXa. TFPI inhibits prothrombinases in the presence of Protein S and factor Va [9, 10]. In some pathological conditions, TF is usually over-expressed by a variety of cells, including monocytes and tumor cells, and the correct balance between TF and TFPI is usually disrupted [9, 11, 12]. Monocytes and macrophages are the major cell type developing pro-coagulant activity through TF expression induced by inflammatory stimuli [13C17]. Monocyte thrombogenic activity could contribute to thrombotic risk in surgery [18] and cancer [19, 20]. In fact, tumor associated macrophages express a significantly higher level Etoricoxib D4 of TF than control cells [21]. Clinical studies have confirmed the major contribution of TF expressed on activated monocytes in thrombosis [22C24]. After plaque injury, as observed in angioplasty, exposure of cellular and extracellular TF to circulating blood play a pivotal role in mediating fibrin-rich thrombus formation leading to acute coronary syndromes [25]. TF expressed on monocytes/macrophages is usually up-regulated by inflammatory cytokines and oxidized lipids from the plaque [26]. Moreover, activated macrophages also acquire other functional properties, including cytokine production that may significantly participate in autocrine and paracrine signaling among leukocytes and vascular endothelial cells [27, 28]. In addition to the extrinsic activation mediated by tissue Etoricoxib D4 factor-factor VIIa, after inflammatory stimuli, monocytes can initiate coagulation in an option procoagulant response due to the binding of the zymogen factor X to the integrin Mac-1 (CD11b/CD18) triggering monocyte degranulation and cathepsin G activation of factor X, which catalyzes the cleavage of FX at a novel Leu177- Leu178 peptide bond to form an active protease [21, 28C31]. The newly generated factor Xa remains associated with the monocyte membrane, and promotes procoagulant activity and thrombin formation [9, 21, 28C31]. Finally, several lines of evidence.