Prothrombin and

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). 

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. 

Prothrombin and several other proteins of the blood clotting system (Factors VII, IX and X, and proteins C and S) each contain between four and six y-carboxygluta-mate residues which chelate calcium ions and so permit the binding of the blood clotting proteins to membranes. In vitamin K deficiency or in the presence of warfarin, an abnormal precursor of prothrombin (preprothrombin) containing little or no y-carboxyglutamate, and incapable of chelating calcium, is released into the circulation. 

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. 

This enzyme catalyzes the vitamin K-dependent post-translational carboxylation of specific glutamic acid residues in prothrombin and other blood coagulation proteins to form 4-glutamylcarboxylate side chains. 

Warfarin acts as a vitamin K antagonist and suppresses the hepatic formation of prothrombin and of factors VII, IX, and X, causing a markedly reduced prothrombin activity of the blood.Warfarin also causes dilatation and engorgement of blood vessels and an increase in capillary fragility. The two effects can combine to produce hematomas, severe blood... 

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

In the absence of the vitamin, the blood-clotting time increases, since the post-translational carboxylation of several glutamate residues in prothrombin and other factors involved in blood clotting is impaired. In humans, this disorder is unknown except in cases of faulty vitamin K absorption, since the normal diet covers the need generously. 

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. 

Vitamin confers biologic activity upon prothrombin and factors VII, IX, and X by participating in their postribosomal modification. Vitamin is a fat-soluble substance found primarily in leafy green vegetables. The dietary requirement is low, because the vitamin is additionally synthesized by bacteria that colonize the human intestine. Two natural forms exist vitamins Ki and K2. Vitamin K1 (phytonadione Figure 34-5) is found in food. Vitamin K2 (menaquinone) is found in human tissues and is synthesized by intestinal bacteria. 

In addition to the 20 common amino acids, proteins may contain residues created by modification of common residues already incorporated into a polypeptide (Fig. 3-8a). Among these uncommon amino acids are 4-hydroxyproline, a derivative of proline, and 5-hydroxylysine, derived from lysine. The former is found in plant cell wall proteins, and both are found in collagen, a fibrous protein of connective tissues. 6-N-Methyllysine is a constituent of myosin, a contractile protein of muscle. Another important uncommon amino acid is y-carboxyglutamate, found in the bloodclotting protein prothrombin and in certain other proteins that bind Ca2+ as part of their biological function. More complex is desmosine, a derivative of four Lys residues, which is found in the fibrous protein elastin. 

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... 

The most obvious effect of a deficiency in vitamin K in animals is delayed blood clotting, which has been traced to a decrease in the activity of prothrombin and of clotting factors VII, IX, and X (Chapter 12, Fig. 12-17). Prothrombin formed by the liver in the absence of vitamin K lacks the ability to chelate calcium ions essential for the binding of prothrombin to phospholipids and to its activation to thrombin. The structural differences between this abnormal protein and the normal prothrombin have been pinpointed at the N terminus of the 560 residue glycoprotein.e f Tryptic peptides from the N termini differed in electrophoretic mobility. As detailed in Chapter 12, ten residues within the first 33, which were identified as glutamate residues by the sequence analysis on normal prothrombin, are actually y-carboxyglutamate (Gla). The same amino acid is present near the N termini of clotting factors VII, IX, and X. 

Interaction of Prothrombin and Ca++ with Phospholipid Monolayers Containing Phosphatidyl Serine... 

In the present work we studied the interaction of prothrombin with lipid monolayers in the presence of Ca++. The stoichiometric relations of the interacting components were determined by measuring surface radioactivity of 3H-labelled prothrombin and 45Ca. The penetration was inferred from the effect of the interaction on the capacitance of the surface layer. 

Figure 7. A schematic model of the interaction between prothrombin and the PS monolayer in the presence of calcium on one side, the hydrocarbon chain is in contact with the air or the mercury drop on the other side, the layer of prothrombin protrudes in the aqueous solution. The prothrombin schematic configuration is according to Ref. 8.

We particularly thank R. Benarous and J. Elion for their purified prothrombin and for the discussions. This work was supported by a grant from the Volkswagen Foundation. Dr. LeCompte was supported by an EMBO Fellowship. 

The BBB also prevents many macromolecules from entering the brain. The total protein content of CSF when compared to plasma is very low and markedly different from that of plasma (Table 27.1). Plasma proteins such as albumin, prothrombin, and plasminogen are... 

No correlation between decarboxylated prothrombin and vitamin K levels in 11 week old infants and CDD and CDF TEQ levels in breast milk 13.7-62.6 (mean of 29.4) Pluim et al. 1994b... 

Schematic view of the role of coagulation factor Xa in arterial thrombosis. After endothelial injury, platelets adhere to the subendothelial matrix. The procoagulant activity of the arterial clot can be attributed to the formation of the prothrombinase complex on the platelet surface which cleaves prothrombin and produces thrombin. Thrombin subsequently acts as a strong agonist of further platelet aggregation.

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