Vitamin K and Vitamin K Antagonists

Vitamin Κ was discovered by Henrik Dam in 1929 in studies of sterol metabolism in chicks fed fat-free diets (1). The antihemorrhagic fat-soluble agent was called vitamin Κ, Κ being short for "Koagulation" (the German word for coagulation). Since then there have been two major eras of extensive research on this vitamin. The first era was in the 1930s and it culminated in 1939 with the characterization and synthesis of vitamin (phylloquinone) and a year later of "vitamin Κ 2" (menaquinone-7). The chemical structures of the different vitamins Κ are shown in Figure 1. During this period it was shown that the hemorrhagic disease associated with vitamin Κ deficiency was due to the absence of prothrombin activity in plasma, and shortly thereafter, it was demonstrated that a combination therapy with vitamin Κ and bile salts was effective in the treatment of hemorrhagic tendency in patients with obstructive jaundice and diseases of the liver. Thus the relationship between vitamin Κ, liver function, and blood coagulation became established. The second era of extensive research on vitamin Κ has focused on its function. It started in the late 1960s and it culminated, at least temporarily, in the mid-1970s, when the product of post-translational vitamin K-dependent carboxylation, γ-carboxyglutamic acid (Gla), was identified (2—4). It was demonstrated that this modified amino acid gave the vitamin K-dependent clotting factors the calcium binding properties which are necessary for their normal function in blood coagulation. In the years between these two eras, several vitamin Κ antagonists, such as dicumarol, warfarin, phenpro Figure 1 <target id="page_430" target-type="page">430</target>Chemical structures of phylloquinone (vitamin K₁), menaquinone (vitamin K₂), and menadione (vitamin K₃). The particular form of menaquinone shown has four prenyl units, hence menaquinone-4. A menaquinone with six prenyl units would be called menaquinone-6 https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781003065128/89f109c1-44e9-4ebf-9d1d-1b1a46b4b267/content/fig2_12_1.tif"/> coumon, and phenidione, were identified and their place in therapeutics was established (i.e., in the prevention of thrombosis).