Clotting factors, vitamin

Vitamin cycle—metabolic interconversions of vitamin associated with the synthesis of vitamin -dependent clotting factors. Vitamin K1 or K2 is activated by reduction to the hydroquinone form (KH2). Stepwise oxidation to vitamin epoxide ( ) is coupled... 

Vitamin K cycle—metabolic interconversions of vitamin K associated with the synthesis of vitamin K-dependent clotting factors. Vitamin K1 or K2 is activated by reduction to the hydroquinone form (KH2). Stepwise oxidation to vitamin K epoxide (KO) is coupled to prothrombin carboxylation by the enzyme carboxylase. The reactivation of vitamin K epoxide is the warfarin-sensitive step (warfarin). The R on the vitamin K molecule represents a 20-carbon phytyl side chain in vitamin Ki and a 30- to 65-carbon polyprenyl side chain in vitamin K2. 

Vitamin K is an essential cofactor for the synthesis of prothrombin and other blood-clotting factors. Vitamin K deficiency occurs due to liver disease, longterm antimicrobial therapy, and malabsorption. Vitamin K deficiency can lead to hemorrhages in newborns and development of hypoprothrombobinemia. Rapid intravenous injection of emulsified vitamin K produces flushing, breathlessness, hypotension, and may lead to death. 

An example of a biological Friedel-Crafts reaction occurs during the biosynthesis of phylloquinone, or vitamin Kl( the human blood-clotting factor. Phylloquinone is formed by reaction of 1,4-dihydroxynaphthoic acid with phytyl diphosphate. Phytyl diphosphate first dissociates to a resonance-stabilized allylic carbocation, which then substitutes onto the aromatic ring in the typical way. Several further transformations lead to phylloquinone (Figure 16.10). 

Binding calcium ions (Ca2+) is a prerequisite for the activation of seven clotting factors in the coagulation cascade that are dependent on vitamin K. The term cascade indicates, that the factois involved depend from... 

All anticoagulants interfere with the clotting mechanism of the blood. Warfarin and anisindione interfere with the manufacturing of vitamin K-dependent clotting factors... 

In the case of prothrombin and related clotting factors, interruption of the vitamin K cycle leads to the production of nonfunctional, undercarboxylated proteins, which are duly exported from hepatocytes into blood (Thijssen 1995). They are nonfunctional because there is a requirement for the additional carboxyl residues in the clotting process. Ionized carboxyl groups can establish links with negatively charged sites on neighboring phospholipid molecules of cell surfaces via calcium bridges. 

Vitamin E (tocopherol) is the most important antioxidant in the body, acting in the lipid phase of membranes and protecting against the effects of free radicals. Vitamin K functions as cofactor to a carboxylase that acts on glutamate residues of clotting factor precursor proteins to enable them to chelate calcium. 

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. 

The answer is a. (Hardman, pp 1086—1089.) Intolerance of alcohol (disulfiram-like reaction) has been noted only with certain cephalosporins. Cephalosporins with the methylthiotetrazole side chain have been associated with a disulfi ram-like reaction because the methyl thiotetrazole group has a configuration similar to disulfi ram, which blocks the metabolism of alcohol at the acetaldehyde step. Accumulation of acetaldehyde is associated with the symptoms. The methyl thiotetrazole side chain also results in hypopro thrombi nemia by interfering with the synthesis of vitamin K-dependent clotting factors. 

Vitamin K-dependent clotting factor, including factor VII, is affected early. 

Compounds showing vitamin K activity are substituted naphthoquinones. The parent compound, 2-methyl-1,4-naphthoquinone, does show some biological activity as do other similar but synthetic compounds. The production of the complete naturally active forms is thought to depend upon the addition of an isoprene chain at position 3 on the aromatic ring. Differences in this side chain produce the various K vitamins (Figure 12.10). A most important physiological role of vitamin K is in the synthesis of the blood clotting factors, II (prothrombin), VII, IX and X. 

Vitamin K Green leafy vegetables, meats, dairy produce Activation of blood-clotting factors... 

Vitamin K is a component of the carboxylase enzyme that carboxylates the amino acid glutamate in proteins to form y-carboxyglutamate, which binds calcium ions i.e. it catalyses a post-transcriptional modification. Proteins so carboxylated include clotting factors (Factors 11, Vll, IX, and X) and two proteins in bone oesteocalcin (known as matrix-gln-protein) and bone gin protein (BGP). The... 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Oral anticoagulants. Structurally related to vitamin K, 4-hydroxycouma-rins act as false vitamin K and prevent regeneration of reduced (active) vitamin I< from vitamin K epoxide, hence the synthesis of vitamin K-dependent clotting factors. 

The most important adverse effect is bleeding. With coumarins, this can be counteracted by giving vitamin Ki. Coagulability of blood returns to normal only after hours or days, when the liver has resumed synthesis and restored sufficient blood levels of clotting factors. In urgent cases, deficient factors must be replenished directly (e.g., by transfusion of whole blood or of prothrombin concentrate). 

Pharmacology Vitamin K promotes the hepatic synthesis of active prothrombin (factor II), proconvertin (factor VII), plasma thromboplastin component (factor IX), and Stuart factor (factor X). The mechanism by which vitamin K promotes formation of these clotting factors involves the hepatic post-translational carboxylation of specific glutamate residues to gamma-carboxylglutamate residues in proteins involved in coagulation, thus leading to their activation. 

In normal individuals phytonadione and the menaquinones have no activity while in vitamin K deficiency the vitamin promotes the hepatic biosynthesis of factor II (prothrombin), factor VII, factor IX and factor X. Vitamin K functions as an essential cofactor for the enzymatic activation of precursors of these vitamin K dependent clotting factors. The quinone structure of the active form of vitamin K, i.e. reduced vitamin K or hydroquinone. 

L B. Warfarin does not produce an anticoagulant effect in vitro. It inhibits coagulation of blood only in vivo, because the effect depends upon warfarin s effect in the liver on the production of clotting factors. Warfarin does not require conversion into an active drug. It inhibits the post-ribosomal carboxy-lation of glutamic acid residues in the vitamin K-dependent clotting factors. Therefore, heparin rather than warfarin is used when blood is collected from donors and stored. 

Another concern in infants of mothers with epilepsy is a serious hemorrhagic disorder that is associated with a high (25-35%) mortality. This probably results from the finding that many AEDs can act as competitive inhibitors of vitamin K-dependent clotting factors. The competitive inhibition can be overcome by the administration of oral vitamin K supplements to the mother during the last week or 10 days of pregnancy. 

As the plasma levels of T4 and T3 fall after the administration of antithyroid drugs, the catabolism of vitamin K-dependent clotting factors decreases, thus reducing... 

Coumadin (Warfarin) 20.1 (0.9) 24.3 (0.9) 22.6 (1.0) An anticoagulant that acts by preventing the synthesis of active vitamin K, a necessary cofactor for synthesizing active clotting factors. 

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