Clotting factors vitamin K-dependent

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

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. 

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. 

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... 

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 ... 

They act by interfering with synthesis of vitamin K dependent clotting factors in liver. They act as competitive antagonists of vitamin K and reduce plasma levels of clotting factors in a dose dependent manner. They act by interfering with regeneration of active form of vitamin K. Factor VII levels are reduced first followed by factor IX, X and II. 

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. 

Deficiencies in vitamin K and the related synthesis of the vitamin K-dependent clotting factors are treated by administering exogenous vitamin K.20 Various commercial forms of this vitamin are available for oral or parenteral (intramuscular or subcutaneous) administration. Specifically, individuals with a poor diet, intestinal disease, or impaired intestinal absorption may require vitamin K to maintain proper hemostasis. 

Vitamin E has received much publicity as one of several antioxidants that may be useful in treating a variety of disorders, including cardiovascular disease. Vitamin E may inhibit the oxidation of reduced vitamin K. Vitamin K oxidation is necessary for carboxylation of vitamin-K-dependent clotting factors, which must occur for these clotting factors to be fully functional. Increased prothrombin times, induced by combined vitamin E and warfarin therapy, may be managed by discontinuing vitamin E and, if necessary, by administering vitamin K. 

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. 

The increased susceptibility to bleeding observed in patients with liver failure (raised INR) results from depressed fibrinogen levels and the reduced synthesis of clotting factors by the cirrhotic liver. In addition, the absorption of fat-soluble vitamin K is impaired in cholestasis and subsequently the synthesis of vitamin K-dependent clotting factors is reduced. 

The first report of an experimentally-induced deficiency was by Doisy (1) who fed two subjects a formula diet that was deficient in vitamin K. One of the subjects developed a slight reddening of the hair, a scaly, transient dermatitis, depressed vitamin K-dependent clotting factors, and hypocholesterolemia. The symptoms were unresponsive to vitamin K but disappeared when a normal diet was resumed. When Doisey recalculated his purified diet, he realized that he had inadvertently omitted the manganese. The diet had contained a manganese level of only 0.34 mg/day and apparently had produced a manganese deficiency. 

Prothrombin, also produced by the liver, is a clotting factor essential for normal coagulation. Prothrombin is one of the vitamin K-dependent clotting factors, which means that it has no coagulating properties unless vitamin K is present to transform it. Consequently, reduced intake or absorption of fat-soluble vitamin K will increase the time taken for blood to clot. 

Newborn infants present a special problem with respect to vitamin K. They have low plasma levels of prothrombin and the other vitamin K-dependent clotting factors (about 30% to 60% of the adult concentrations, depending on gestational age). To a great extent, this is the result of the relatively late development of liver glutamate carboxylase, but they are also short of vitamin K, as a result of the placental barrier that limits fetal uptake of the vitamin. This is probably a way of regulating the activity of Gas6 and other vitantin K-dependent proteins in development and differentiation (Section 5.3.4 Israels et al., 1997). 

The usual method of assessing vitamin K nutritional status, or monitoring the efficacy of anticoagulant therapy, is a functional test of blood clotting, and hence the ability to synthesize the vitamin K-dependent clotting factors. 

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). 

Withdrawal of oral anticoagulant. The balance of evidence is that abrupt, as opposed to gradual withdrawal of therapy does not of itself add to the risk of thromboembolism, for renewed synthesis of functional vitamin K dependent clotting factors takes several days. 

Sex hormones and hormone antagonists. Oestrogens increase the synthesis of some vitamin K dependent clotting factors and progestogen-only contraceptives are preferred. The hormone antagonists danazol, flutamide and tamoxifen enhance the effect of warfarin. 

Increased turnover of vitamin K-dependent clotting factors... 

Increased sensitivity to drugs is also encountered in liver disease. The use of anticoagulants increases the risk of bleeding due to the reduced absorption of vitamin K or decreased production of vitamin K-dependent clotting factors. There is an enhanced risk for respiratory depression and hepatic encephalopathy due to morphine or barbiturates in patients with severe liver disease. Vigorous use of diuretics can precipitate hepatic coma due to potassium loss in liver disease. There is an increased risk of hypoglycemia with... 

Many androgens and anabolic steroids reduce the dose of oral anticoagulant that a patient requires, sometimes by as much as 25% (73), and hemorrhage has sometimes resulted from their use. From the results of a study in which stanozolol reduced warfarin requirements, the investigators concluded that stanozolol increased fibrinolysis, reduced the production of vitamin K-dependent clotting factors, and increased the amount of the natural anticoagulant antithrombin III (74). 

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