Thromb Haemost 2008; 100: 527–529 Vitamin K or vitamin “Koagulation” (German spelling for coagulation) was discovered by the 1943 Nobel Prize winners Henrik Dam and Edward A. Doisy, as a fat soluble substance, the deficiency of which caused bleeding disorders.Vitamin K in its reduced form is required as a cofactor for the γ-glutamyl carboxylase enzyme that catalyses the γ-carboxylation of specific glutamic acid (Glu) residues of a subclass of proteins (1). This subclass of proteins was then termed vitamin K-dependent proteins (VKDP), or γ-carboxylated proteins or simply Gla-proteins. The enzymatic reaction generates γ-carboxyglutamate (Gla) and vitamin K 2,3,-epoxide which is then recycled back to the hydroquinone form by a reductase enzyme (1). Warfarin (3-[α-acetonyl-benzyl-4-hydroxycoumarin]) inhibits the activity of the vitamin K epoxide reductase blocking the vitamin K cycle.This property of warfarin has led to its widespread use in anticoagulant therapy (2). In 2000, warfarin was ranked among the top-selling drugs with a turnover estimated at 500 million dollars. The γ-carboxylation process appears to be required for the activities of all Gla-proteins studied to date. Carboxylase substrates synthesised in the presence of warfarin are undercarboxylated and have impaired biological activities (3). In the present theme issue, Shearer and Newman stress the importance of exploring vitamin K metabolism and catabolism pathways for a better understanding of pathologies linked to vitamin K deficiency (4). The occurrence of such pathologies is established in bone and arteries, two tissues that express many VKDP, whereby expression is hypothesised in others. The various molecular forms of vitamin K are different not only with regard to their co-factor activities but also with regard to their absorption, transport, cellular uptake, tissue distribution, turnover and catabolism.This paper provides a clear description of the nomenclature and chemical structure of K vitamins, namely phylloquinone (vitamin K1) and menaquinones (vitamins K2) as well as their dietary sources. Further research is certainly needed in this area to determine to what extent bacterially fermented food as well as intestinal flora contribute to the maintenance of vitamin K status. The effects of other putative non-cofactor functions of vitamin K, which potentially include the suppression of inflammation, prevention of brain oxidative damage and a role in sphingolipid synthesis as well as the possible existence of a receptor for vitamin K, are important issues that require long-term basic research to be clarified. The full consequences of dietary vitamin K deficiency on tissue distribution and metabolism of K vitamins as well as the consequences of oral anticoagulants on the metabolism of K vitamins remains to be assessed in the light of new findings on VKDP. Only few proteins are known to contain Gla residues. These include: (i) certain proteins of the blood coagulation system: prothrombin, factors VII, IX and X, protein C, protein S and protein Z; (ii) the protein encoded by the growth arrest specific gene GAS6, which presents strong structural homology with protein S; (iii) Gla proteins expressed in mineralised tissues: osteocalcin and matrix Gla-protein (MGP); (iv) Gla-containing snake venom proteins and conotoxins; (v) four transmembrane Gla-proteins PRGP1, PRGP2, TMG3 and TMG4 whose functions are as yet unknown; (vi) some members of the connexin family of proteins (5). The precise role of the γ-carboxylation modification for connexin protein function is not as yet known. Except for protein S and protein Z, VKDP of the blood-clotting cascade are serine protease zymogens and are activated by serine proteases. The role of protein Z in blood clotting is not fully clarified and neither cellular effects nor a specific pathology have been as yet associated with protein Z. The review by Vasse et al. (6) in the present issue covers this topic. Two further contributions in the present theme issue relate to the therapeutic functions of VKDP in haemostasis. In her concise review Ulla Hedner concentrates on the therapeutic use of factor VIIa in bleeding associated pathologies (7). The paper by Paul Monahan reviews the data obtained from factor IX knockout mice and other haemophilia B mouse models (8). Such mouse models have not only enabled a better understanding of the role of factor IX in haemostasis, thrombosis and wound healing but also pro-