Vitamin K dependent factors

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... 

Prothrombin time PT is performed by adding thromboplastin (tissue) factor and calcium to citrate-anticoagulated plasma, recalcifying the plasma, and measuring the clotting time. The major utility of PT is to measure the activity of the vitamin K-dependent factors II, VII, and X. The PT is used in evaluation of liver disease, to monitor warfarin anticoagulant effect, and to assess vitamin K deficiency. 

Effect on INR- Coadministration of argatroban and warfarin produces a combined effect on the laboratory measurement of the INR. Cotherapy compared with warfarin monotherapy exerts no additional effect on vitamin K dependent factor Xa activity. 

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. 

Hemorrhagic complications are generally believed to result from decreased synthesis of clotting factors like fibrinogen, vitamin K-dependent factors, and inde-... 

Figure 5.3. Intrinsic and extrinsic blood clotting cascades. Factor I, fibrinogen Factor II, prothrombin (vitamin K-dependent) Factor III, thromboplastin Factor V, proac-celerin Factor VII, proconvertin (vitamin K-dependent) Factor VIII, antihemophilic factor Factor IX, Christmas factor (vitamin K-dependent) Factor X, Stnart factor (vitamin K-dependent) Factor XI, plasma thromboplastin Factor XII, Hageman factor Factor XIII, fibrin-stabilizing factor and Factor XIV, protein C (vitamin K-dependent). What was at one time called Factor IV is calcinm no factor has been assigned nnmber VI.

Vitamin K-dependent factor the intrinstic and extrinsic pathways converge with the activation of factor X to Xa by factor VIII and IX. 

Figure 19-26 Scheme of blood coagulation and fibrinoliisii. a vitamin K-dependent factor inhibition by heparin ard antithrombin III. 

The liver synthesizes fibrinogen factors V, VIII, XI, and XII, and the vitamin K-dependent factors II, VII, IX, and X. Furthermore the liver plays an important role in platelet growth and function. The vitamin K-dependent proteins contain y-carboxy-glutamic acid. Vitamin K is necessary for the carboxylation of these proteins, which facilitate the conversion of prothrombin to thrombin. Patients with severe hepatocellular disease have decreased synthesis of the vitamin K-dependent clotting factors, especially factor VII. Furthermore, patients with cholestatic disease have decreased bile salt secretion, which is necessary for the absorption of vitamin K, leading to failure of activation of factors II, VII, IX, and X. In these patients, unlike those with hepatocellular disease, the prothrombin time can be corrected with an injection of vitamin K. 

C4b binding protein can affect the assay The most common assay is a modified aPTT. Elevated levels of Factor VIII bias the assay results, as do decreased levels of vitamin K-dependent factors. 

Twelve plasma proteins are considered coagulation factors (Table 100-1). The coagulation factors can be divided into three groups on the basis of biochemical properties. These groups include vitamin K-dependent factors (II, VII, IX, and X), contact activation factors... 

The PT, the aPTT, and the thrombin time are useful in screening for a deficiency of fiver-dependent factors. The PT is sensitive to deficiencies in the vitamin K-dependent factors. The aPTT helps to... 

Mechanism Heparin binds to antithrombin III, increasing its serine protease inhibiting activity and resulting in fast inactivation of factors Ila, IXa, Xa, XIa, and XHa. 1 Hepatic synthesis of vitamin K-dependent factors II, VII, IX, X—coumarins prevent y-carboxylation no effect on factors already present. In vivo effects only. 

Vitamin K-dependent factors and vitamin K-independent factors. 

Mechanism and effects Coumarins interfere with the normal posttranslational modification of clotting factors in the liver, a process that depends on vitamin K. The vitamin K-dependent factors include II (thrombin), VII, IX, and X. Because these factors have half-lives of 8-60 hours in the plasma, an anticoagulant effect is observed only after sufficient time has passed for the preformed normal factors to be eliminated. The action of warfarin can be reversed with vitamin K, but recovery requires the synthesis of new normal clotting factors and is therefore slow (6-24 hours). More rapid reversal can be achieved by transfusion with fresh or frozen plasma that contains normal clotting factors. The effect of warfarin is monitored by means of the prothrombin time (PT, or pro time ) test. 

The elevated INR indicates excessive anticoagulation with a high risk of hemorrhage. Warfarin should be discontinued and vitamin Kj administered to accelerate formation of vitamin K-dependent factors. The answer is (E). 

By fluorescence energy transfer, no selectivity is demonstrated for factor Va while its light chain is highly selective for the negatively charged lipids. In contrast, the complex Va - Xa has some selectivity for the zwitterionic lipids. The binding of the vitamin K-dependent factors does not induce phase separation in lipids. A calcium-independent binding is demonstrated and allows to propose a new model for the interaction. 

Energy transfer experiments with vitamin K-dependent factors. Equimolar mixtures of PC-PS were labelled with either PBPC or PBPA, at the same concentration, namely 3.8 %. The transfer efficiency values (Et) are shown in Table II. Since the two probes have identical spectroscopic features ( ), the comparison of Et values for the membranes having similar amounts of label, allows a direct comparison of the lipid environment of the factors. The higher Et value indicates a lower statistical distance and/or a greater number of labelled phospholipids in the neighborhood of the protein. 

The anticoagulant action of coumarins resembles the Symptoms observed in vitamin K deficiency [436], and clinical observations on the reversibility of the coumarin effect by adequate amounts of vitamin K also indicate a competition between these compounds. However, this concept may represent an over-simplification because no single enzyme system has been identified where such a metabolite—anti-metabolite antagonism takes place [437]. It has been suggested that vitamin K and the anticoagulant coumarins exert their action in the liver cell at different levels [438]. They may interact with the regulation of the synthesis of vitamin K-dependent factors [439,440]. 

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