Factors II, VII, IX and

Coagulation Factors II, III, VII, IX, X, XI, and Xlla fragments, thrombin, and plasmin are classified as serine proteases because each possesses a serine residue with neighboring histidine and asparagine residues at its enzymatically active site (Table 3). Factors II, VII, IX, and X, Protein C, Protein S, and Protein Z are dependent on the presence of vitamin K [84-80-0] for their formation as biologically functionally active procoagulant glycoproteins. 

For activity, factors II, VII, IX, and X and proteins C and S require vitamin K-dependent y-carboxylation of certain glutamate residues, a process that is inhibited by the anticoagulant warfarin. 

PCCs contain the vitamin K-dependent factors II, VII, IX, and X. These agents represent another attempt to bypass the factor at which the antibody is directed (see Fig. 64-2). However, PCCs carry the risk of serious thrombotic complications. Porcine factor VIII is most useful when the inhibitor titer is less than 50 BU (see Fig. 64-2 for dose and frequency). Owing to its similarity to human factor VIII, porcine factor VIII participates in the coagulation cascade. However, most inhibitors have very weak neutralizing activity against it. Porcine factor VIII is a third-line agent (only after factor Vila and a PCC have failed) owing to a 15% incidence of cross-reactivity.15... 

Vitamin K is a fat-soluble vitamin cofactor for the activation of factors II, VII, IX, and X in the liver. Almost all neonates are vitamin K-deficient at as a result of (1) insignificant transplacental vitamin K crossover, (2) lack of colonization of the colon by vitamin K-producing bacteria, and (3) inadequate dietary vitamin K intake (especially in breast-fed infants because human milk contains less vitamin K than infant formula or cow s milk). Vitamin K-deficiency bleeding (VKDB) refers to bleeding attributable to vitamin K deficiency within first 6 months of life. It occurs in three general time frames early (0-24 hours), classic (1-7 days), and late (2-12 weeks). Early onset occurs rarely and usually is associated with maternal ingestion of anticonvulsants, rifampin, isoniazid, and warfarin. Classic vitamin K-dependent bleeding usually results from the lack of prophylactic vitamin K administration in... 

The levels of vitamin K-dependent coagulation factors are physiologically low in neonates. Absence of vitamin K impairs y-carboxylation, and the inactive precursors of factors II, VII, IX, and X accumulate in the plasma, unable to bind calcium and cell membranes. Consequently, the precursor levels may decline further, impairing coagulation and potentially leading to VKDB. 

The most commonly used oral anticoagulant drug in the U.S. is warfarin. It acts by altering vitamin K so that it is unavailable to participate in synthesis of vitamin K-dependent coagulation factors in the liver (coagulation factors II, VII, IX, and X). Because of the presence of preformed clotting factors in the blood, the full antithrombotic effect of warfarin therapy may require 36 to 72 h. 

Several substances that contribute to the blood coagulation process are formed in the liver. These include fibrinogen, prothrombin, and several of the blood clotting factors (II, VII, IX, and X). Deficiency in any of these substances leads to impaired blood coagulation. 

Administration of high levels of a mixture of clotting factors II, VII, IX and X, which works effectively in 50 per cent of treated patients. 

Vitamin K promotes the hepatic y-car-boxylation of glutamate residues on the precursors of factors II, VII, IX, and X, as well as that of other proteins, e.g., protein C, protein S, or osteocalcin. Carboxyl groups are required for Ca +-mediat-ed binding to phospholipid surfaces (p, 142). There are several vitamin K derivatives of different origins Ichlorophyllous plants I<2 from gut bacteria and I<3 (menadione) synthesized chemically. All are hydrophobic and require bile acids for absorption. 

Mechanism of Action A coumarin derivative that interferes with hepatic synthesis of vitamin K-dependent clotting factors, resulting in depletion of coagulation factors II, VII, IX, and X. Therapeutic Effect Prevents further extension of formed existing clot prevents new clot formation or secondary thromboembolic complications. Pharmacokinetics ... 

FIGURE 25-2 Role of vitamin K in the synthesis of vitamin K-dependent clotting factors (II, VII, IX and X). Vitamin K catalyzes the reaction necessary for completion of clotting factor synthesis, but it is oxidized in the process to vitamin K epoxide. Regeneration of vitamin K occurs via vitamin K epoxide reductase. Oral anticoagulants such as warfarin (Coumadin) block the regeneration of the vitamin K, thus halting the further synthesis of the vitamin K-dependent factors. 

Shikata E, leiri I, Ishiguru S, et al. Association of pharmacokinetics (CYP2C9) and pharmacodynamics (factors II, VII, IX, and X protein S and C and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity. Blood 2004 103 2630-2635. 

Q4 Vitamin K is a fat-soluble vitamin which is composed of a number of related compounds known as quinones. Most of the protein clotting factors in blood are produced in the liver and depend on the presence of adequate vitamin K for their synthesis. Some of the necessary vitamin K is present in the diet (in green, leafy vegetables), but most is synthesized by bacteria in the intestine. Vitamin K is particularly important in maintaining blood levels of coagulation factors II, VII, IX and X. 

Superwarfarins lower the blood concentrations of the vitamin K-dependent clotting factors II, VII, IX and X this results in prolongation of prothrombin time (PT) and partial thromboplastin time (PTT). PT and PTT should be repeated at least twice daily until a normal PT and PTT are established. Also, the blood clotting time and the bleeding time should be measured. Blood is often demonstrable in the excreta. Secondary hypochromic or microcytic anemia may be marked (Goldfrank et al, 2002 Nelson et al, 2006). 

Coagulation factors I, II, V, VII, IX-XIII are synthesized in hepato-cytes. To a minor extent, factor I is also synthesized in the intrahepatic RES, while factor Vlll is formed exclusively in the RES. Formation of factors II, VII, IX and X as well as of the two inhibitor proteins C and S depends on vitamin K, the absence of which will cause the synthesis to decline. Factors 1, V, XI, XII and Xni are formed without the mediation of vitamin K. Proteolytic enzymes convert coagulation factors into active factors in the plasma, (s. tab. 5.12)... 

Method Intravenous administration of 10 mg vitamin K in cases with a Quick s value of <70%. Diagnostically, a return to normal levels of >75% within 24 hours excludes liver disease, but favours vitamin K deficiency. A non-increase in the value indicates liver disease, since the synthesis of factors II, VII, IX and X does not depend on the administration of vitamin K. 

The conmarins act as competitive inhibitors of vitamin K epoxide rednctase, which is responsible for regenerating rednced vitamin K from vitamin K epoxide after it has been consnmed as a co-factor in the synthesis of coagulation factors II, VII, IX, and X. 

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