Synthesis prothrombin

The fibrinogen-to-fibrin monomer reaction is catalyzed by the proteolytic enzyme thrombin. Thrombin is in turn produced by the prothrombin-converting factors V, X, and Ca2+ from circulating prothrombin (Phase 2). Prothrombin is a globular protein made in the liver (as is fibrinogen). Vitamin K is an essential factor in its synthesis. Prothrombin-... 

Work in the mid-1970s demonstrated that the vitamin K-dependent step in prothrombin synthesis was the conversion of glutamyl residues to y-carboxyglutamyl residues. Subsequent studies more cleady defined the role of vitamin K in this conversion and have led to the current theory that the vitamin K-dependent carboxylation reaction is essentially a two-step process which first involves generation of a carbanion at the y-position of the glutamyl (Gla) residue. This event is coupled with the epoxidation of the reduced form of vitamin K and in a subsequent step, the carbanion is carboxylated (77—80). Studies have provided thermochemical confirmation for the mechanism of vitamin K and have shown the oxidation of vitamin KH2 (15) can produce a base of sufficient strength to deprotonate the y-position of the glutamate (81—83). 

Generally, nephrotoxicity is not a problem. Some cephalosporins, especially those with the 3-methylthiotetrazole side chain, such as moxalactam (48), show a tendency to promote bleeding. This appears to be due to a reduction in the synthesis of prothrombin and can be a problem especially in elderly patients, patients with renal insufficiency, or patients suffering from malnutrition (219). The same side chain seems to promote a disulfiramlike reaction in patients consuming alcohol following a cephalosporin dose (80,219). 

Progressive liver damage (shock liver) manifests as elevated serum hepatic transaminases and unconjugated bilirubin. Impaired synthesis of clotting factors may increase prothrombin time (PT), international normalized ratio, and activated partial thromboplastin time (aPTT). 

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. 

The last of the fat-soluble vitamins to be identified was vitamin K, found by Dam to be an anti-hemorrhagic factor for young chicks, distinct from vitamin C. Its structure was determined by Dam in collaboration with Karrer. Interest in the vitamin was intensified when it was discovered (Link, 1941) that dicoumarol, present in spoiled sweet clover, was the agent producing hypothrombinemia (giving prolonged blood-clotting time) in cattle. Since vitamin K is structurally similar to dicoumarol, the vitamin was presumptively implicated in thrombin formation. This has been fully substantiated by recent work on the role of vitamin K in the synthesis of prothrombin in the liver. 

Warfarin CoA to mevalonic acid for the synthesis of cholesterol Anticoagulant Inhibits synthesis of clotting factors II (prothrombin), VII, IX,... 

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). 

Parenteral Anticoagulant-induced prothrombin deficiency hypoprothrombinemia secondary to conditions limiting absorption or synthesis of vitamin K (eg, obstructive jaundice, biliary fistula, sprue, ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis of the pancreas, regional enteritis) drug-induced hypoprothrombinemias due to interference with vitamin K metabolism (eg, antibiotics, salicylates) prophylaxis and therapy of hemorrhagic disease of the newborn. 

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. 

Warfarin, a coumarin anticoagulant, is incorporated into commeal for use as a rat poison. Repeated exposure results in sufficient inhibition of prothrombin synthesis to cause fatal internal hemorrhage. 

Vitamin K activity is associated with several quinones, including phylloquinone (vitamin Kj), menadione (vitamin K3), and a variety of menaquinones (vitamin K2). These quinones promote the synthesis of proteins that are involved in the coagulation of blood. These proteins include prothrombin, factor VII (proconvertin), factor IX (plasma thromboplastin), and factor X (Stuart factor). A detailed discussion of blood coagulation is found in Chapter 22. The vitamin K quinones are obtained from three major sources. Vitamin K is present in vari-... 

Twenty to 24 million prescriptions of Coumadin were dispensed in the United States during 2003-2005. Coumadin is an anticoagulant that acts by preventing the synthesis of active vitamin K, a necessary cofactor for synthesizing active clotting factors. Thus, preventing the synthesis of active vitamin K indirectly inhibits the formation of active clotting factors, notably factor II (prothrombin), VII, IX, and X in the liver. Ironically, coumarins, of which Coumadin is a member, are also used as rodenticides. 

Inhibition of synthesis of prothrombin and coagulation factors Vll, IX, and X Inhibition of platelet aggregation in vitro Activation of plasminogen... 

Effect on blood Platelets are the important factors in thrombus formation and aspirin has been shown to inhibit platelet aggregation. They reduce the blood prothrombin level by inhibition of prothrombin synthesis and prothrombin time is prolonged. The aspirin suppresses the synthesis of thromboxane (TXA ) in the platelets. They also prolong the bleeding time due to prevention of platelet aggregation which may be due to inhibition of release of adenosine diphosphate (ADP) from the platelets by salicylates. 

Coumarins are competitive inhibitors of vitamin K, which is required for the formation in the liver of the amino acid, gamma-carboxyglutamic acid. This is necessary for the synthesis of prothrombin and factors VII, IX and X (Figure 17.1). After starting treatment the anticoagulant effect is delayed until the concentration of normal coagulation factors falls (36-72 h). The effects can be reversed by vitamin K (slow maximum effect only after 3-6 h) or by whole blood or plasma (fast). Gut bacteria synthesise vitamin K and thus are an important source of this vitamin. Consequently, antibiotics can cause excessive prolongation of the prothrombin time in patients otherwise adequately controlled on warfarin. 

The physiological role of vitamin K is in blood clotting and is essential for the synthesis of at least four of the proteins (including prothrombin) involved in this process. Vitamin K also plays a role in the synthesis of a protein (osteocalcin) in bone. Vitamin K deficiency is rare but can result from impaired absorption of fat. Vitamin K levels in the body are also reduced if the intestinal flora is killed (e.g. by antibiotics). Vitamin K toxicity is rare but can be caused by excessive intake of vitamin K supplements. Symptoms include erythrocyte haemolysis, jaundice, brain damage and reduced effectiveness of anticoagulants. 

The bis(hydroxycoumarin) derivative dicoumarol (45), which was first identified as the causative agent of sweet clover disease in cattle, is used as an anticoagulant in the treatment of thrombosis. Similar compounds with other linking groups have been used, and warfarin (46), which was first introduced as a rodenticide, is also of value. The hydroxycoumarins interfere with the function of vitamin K in the synthesis of prothrombin and other blood... 

It has been reported that vitamin Kj and several of the vitamin K2 homologues are capable of restoring electron transport in solvent-extracted or irradiated bacterial and mitochondrial preparations. Other reports suggest that vitamin K is concerned with the phosphorylation reactions accompanying oxidative phosphorylation The capacity of these compounds to exist m several forms, e.g., quinone, quinol. chromanol, etc., appears to strengthen the proposal that links them to oxidative phosphorylation. Information has suggested that vitamin K acts to induce prothrombin synthesis. Since prothrombin has been shown to be synthesized only by liver parenchymal cells m the dog, it would appear that the proposed role for vitamin K is not specific for only prothrombin synthesis, but applicable to other proteins. 

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. 

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