| text | Factor Xa (FXa), a cleavage product of coagulation factor X (encoded by the F10 gene), is a vitamin K-dependent glycoprotein able to convert prothrombin (FII) to thrombin (FIIa) during the blood clotting process (Mann KG et al. 1988, 2003; Orfeo T et al. 2004; Stojanovski BM et al., 2024). Calcium ions (Ca2+)-dependent association of FXa with the cofactor FVa on a cell surface greatly increases the ability of FXa to rapidly convert prothrombin (FII) to thrombin (FIIa) (Qureshi SH et al. 2009). The conversion to thrombin entails cleavage at R271 in Lnk3 and R320 in the A chain, along two alternative pathways generating the intermediates prethrombin-2 (cleavage at R271 first) or meizothrombin (cleavage at R320 first) (Krishnaswamy S 2013; Schreuder M et al., 2019; Ruben EA et al., 2022; Di Cera E et al. 2022). An additional autoproteolytic cleavage at R284 produces thrombin. The presence of FVa, in vitro, promotes activation along the meizothrombin pathway. In the absence of FVa, activation proceeds along the prethrombin-2 pathway (Krishnaswamy S 2013; Stojanovski BM et al., 2024). FXa is a target for direct oral anticoagulant (DOAC) drugs that are direct FXa inhibitors (the so-called 'xabans') and used in the treatment and prevention of thromboembolic disorders (Galanis T et al. 2014). Rivaroxaban (brand name Xarelto) binds to and inhibits both free factor Xa and factor Xa bound in the prothrombinase complex (Va:Xa) (Roehrig S et al. 2005). Rivaroxaban was the first medically approved drug of this class (Abrams PJ & Emerson CR 2009, Misselwitz F et al. 2011). In patients with non-valvular atrial fibrillation, 'xabans' appears to be as effective as warfarin in preventing nonhemorrhagic strokes and embolic events (Patel MR et al. 2011, Gomez-Outes A et al. 2013). The most serious side-effect of rivaroxaban is GI bleeding, and with there being no antidote for rivaroxaban, bleeding events can be difficult to manage (Siegal D et al. 2014). Other 'xabans' such as apixaban (Bhanwra S & Ahluwalia K 2014), edoxaban (Minor C et al. 2015), eribaxaban (Bondarenko M et al. 2013) and betrixaban (Zhang P et al. 2009) share a similar mechanism of action to rivaroxaban (Nutescu EA et al. 2016). Unlike warfarin, the 'xabans' exhibit a predictable dose response and do not require routine coagulation monitoring. |
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