4-Hydroxycoumarins belong to a class of vitamin K antagonist anticoagulant drug molecules derived from coumarin, a bitter-tasting but sweet-smelling natural substance made by plants. It itself doesn't affect coagulation, but is transformed in mouldy feeds or silages by a number of fungi into active dicumarol, a substance that does have anticoagulant properties. Identified in 1940, dicumarol became the prototypical drug of the 4-hydroxycoumarin anticoagulant drug class but has been superceded by warfarin since the 1950's (Norn et al. 2014). Phenindione was introduced in the early 1950s and acts similarly to warfarin, but it has been associated with hypersensitivity reactions so is now rarely used (Naisbitt et al. 2005). Other coumarin-derivatives commonly prescribed in Europe and other regions are long-acting phenprocoumon (half-life 140 hours) and short-acting acenocoumarol (half-life 11 hours) (Gadisseur et al. 2002). Warfarin, the more potent form of dicumarol and initially used as rat poison, was introduced as an oral anticoagulant in the 1950s and is currently the most widely used oral anticoagulant. Although the working mechanism of the 4-Hydroxycoumarin drugs is similar, there are some important differences in pharmacokinetics between them (Verhoef et al. 2014).

The reduction of vitamin K 2,3-epoxide (MK4 epoxide) by VKORC1 is essential to sustain gamma-carboxylation of vitamin K-dependent proteins such as the clotting factors II, VII, IX and X. The anticoagulant drug warfarin inhibits VKORC1 (Whitlon et al. 1978), thereby reducing clotting ability (Choonara et al. 1985, 1988), which is used as a treatment for thrombotic disorders such as deep vein thrombosis (DVT), pulmonary embolism and to prevent stroke (Ageno et al. 2012). A common side-effect of warfarin anticoagulation is bleeding which can be counteracted by vitamin K supplementation (Ageno et al. 2012). The exact mechanism by which warfarin inhibits VKORC1 remains elusive. Several recent mechanistic studies suggest competitive binding of a key residue in VKORC1 (Czogalla et al. 2017) or blockage of a dynamic electron-transfer process in VKORC1 (Shen et al. 2017). New oral anticoagulants (NOAC; rivaroxaban, dabigatran, apixaban) have become available as an alternative to warfarin anticoagulation. Unlike warfarin, they are fast-acting and don't require routine coagulation monitoring (Gomez-Outes et al. 2013). The regeneration of reduced vitamin K (vitamin K hydroquinone) from vitamin K epoxide is catalyzed by vitamin K epoxide reductase (VKORC1) (Sadler 2004). Two important features of this reaction remain unclear. First, dithiothreitol functions efficiently as a reductant in vitro (Wallin & Martin 1985), but the in vivo reductant remains unknown. Second, while people homozygous for mutations in VKORC1 protein lack epoxide reductase activity (Rost et al. 2004) and cultured insect cells transfected with the cloned human VKORC1 gene express vitamin K epoxide reductase activity (Li et al. 2004), the possibility that the active form of the enzyme is a complex with other proteins cannot be formally excluded.