Granulocyte-stimulating activity of the anticoagulant warfarin in rats

whose biological activity is based on vitamin K (vit. K) antagonism and subsequent inhibition of the vitamin K-dependent (VKD) step in the complete synthesis of a number of blood coagulation factors required for normal hemostasis (S h e a r e r , 1990). Based on these activities, hydroxycoumarin anticoagulants have found wide application as anticoagulant rodenticides (L u n d, 1988) and in prophylactic medicine to prevent thromboembolic disorders for more than 50 years (F u r i e , 2000). Warfarin (WF) and its analogs inhibit vit. K epoxide reductase (VKOR), leading to depletion of the hydroquinone form of vit. K, a cofactor for γ-glutamyl carboxylase which mediates posttranslational modification (carboxylation) of nascent glutamyl (Gla) residues needed for biological activity of coagulation factors (W a l l i n and H u t s o n, 2004). Prevention of normal production of these essential blood clotting factors by hydroxycoumarin anticoagulants leads to increase of clotting time up to the point where no clotting occurs. By inhibiting VKOR, however, WF affects the generation of biologically active VKD proteins required for biological processes other than hemostasis, including proteins involved in the regulation of bone growth and calcification (bone Gla protein, BGP/osteocalcin and matrix Gla protein, MGP) (P r i c e, 1988) and proteins involved in mesangial and vascular smooth muscle cell growth and signaling (N a k a n o et al., 1997; Y a n a g i t a et al., 1999). Data which demonstrated WF effects on proteins not dependent on vit. K (non-VKD proteins), including molecules involved in signal transduction (K a t e r et al., 2002), and the discovery of VKD proteins with as yet unknown function (S h e a r e r, 2006) imply broader effects of hydroxycoumarin-type anticoagulant rodenticides on cell/tissue physiology.