Prothrombin Biosynthesis—A Vitamin K-Dependent Reaction

Abstract

The association between vitamin K and hemostasis was first recognized by Dam in the late 1920s when he characterized 2-methyl-3phytyl-1,4-naphthoquinone or vitamin K₁, as an antihemorrhagic factor for chicks. The structures of vitamin K₁ and other compounds relevant to this discussion are shown in Figure 12-1. It was originally thought that the only defect in vitamin K deficiency was a lack of plasma prothrombin. During the 1950s it was recognized that there are a large number of plasma factors in addition to prothrombin associated with thrombin generation; subsequently factors X, IX, and VII were identified and shown to be vitamin K-dependent. A diagrammatic representation of the cascade model for blood coagulation as it is currently understood is shown in Figure 12-2. In this scheme, a series of proteins acts as substrates for proteases that convert them to active proteolytic enzymes, which then become the proteases of the next stage of the cascade. Knowledge of the cellular events responsible for the production of prothrombin, the role of vitamin K in this process, and its antagonism by coumarins has come largely from investigations spanning the last ten years. These studies have shown that prothrombin is formed in the liver by a vitamin K-dependent carboxylation of a liver precursor protein. This process and detailed information on the chemistry and activation of prothrombin have recently been reviewed,¹ and only a limited number of specific references will be provided here.