Coagulation

Coagulant Factors and Procoagulants

The liver synthesizes all coagulant factors, except for factors III (tissue thromboplastin), IV (Ca), and VIII (von Willebrand factor). It also makes proteins that modulate fibrinolysis and clotting, such as plasminogen activator inhibitor, antithrombin III, protein C, and protein S. Protein C and protein S, for example, work together to inactivate VIIIa and Va complexes. Thus, severe liver disease not only decreases the synthesis of clotting factors but also increases their consumption.^[115]

Vitamin K as a Cofactor

Vitamin K-dependent proteins include coagulant factors II, VII, IX, and X, protein C, and protein S. Each of these proteins undergoes γ-carboxylation, which is a unique, post-translational modification involving vitamin K-dependent insertion of carboxyl groups into the γ-position of specific glutamic acid residues at the amino terminus.^{[91] [116]} This modification enables the proteins to bind to divalent cations (calcium), which is required for their activation by phospholipids or plasma membranes.^[117] In other words, the liver normally releases γ-carboxylated pro-coagulants (vitamin K-dependent zymogens), whose activation in plasma (to serine proteases) enables their involvement in the clotting cascade.^{[91] [118]}

The γ-carboxylation pathway is complex, involving a series of reactions that use O₂ , CO₂ , NADPH, and vitamin K cofactor. ^[118] There are two major steps. First, γ-carboxylation occurs, a process that uses vitamin K-dependent carboxylase and oxidizes (via microsomal enzymes) vitamin K cofactor (naptho-hydroquinone) to 2,3-epoxide vitamin K. Second, microsomal or cytoplasmic reductases regenerate vitamin K cofactor from the epoxide. ^{[119] [120] [121] [122]} Warfarin works by blocking the second step; through inhibition of hepatic vitamin K epoxidase, warfarin exhausts the supply of vitamin K cofactor. Although this inhibitory action is rapid, the clinical effect of warfarin takes much longer to develop because it requires a decline in the serum prothrombin complex (of clotting factors), which has a half-life of about 14 hours.

The responses of patients to vitamin K administration can help uncover the cause of a prolonged prothrombin time (PT). When PT is prolonged solely because of warfarin or malnutrition, it should be readily corrected by oral or parenteral vitamin K. When the cause is intestinal malabsorption (e.g., cholestasis), the efficacy of vitamin K therapy is dependent on the route of administration, parenteral being superior to enteral. With severe hepatocellular dysfunction (acute hepatitis, cirrhosis), vitamin K therapy is ineffective because the problem is insufficient synthesis of vitamin K-dependent factors, not a shortage of vitamin K.