Blood clotting factors

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). 

Table 51-1. Numerical system for nomenclature of blood clotting factors. The numbers indicate the order in which the factors have been discovered and bear no relationship to the order in which they act.

Accelerates the actions of several blood clotting factors (VIII, IX, X, XI, and XII)... 

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. 

It has also been proposed that because of sequence and possible structural homology with the blood clotting factors V and VIII [6] that ceruloplasmin may also participate in blood clotting and its regulation [5]. 

Figure 6. Structural relationships between ascorbate oxidase, ceruloplasmin, nitrite reductase, and blood clotting factor VIII.

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... 

Figure 17.1 Summary of the four cascades that result from trauma or bleeding and the reactions they catalyse. These are all activated by the blood clotting factor, Xlla (also known as the Hageman factor). Details of each cascade are presented in Figures 17.2, 17.4 and 17.6. Factor XII is activated by collagen and negatively charged surfaces to form the active form, Xlla.

Bradykinin is a small peptide that is released from a precursor, kininogen, by the action of the proteolytic enzyme kallikrein, which itself is formed from a precursor, prekallikrein, by the action of the blood clotting factor, Xlla (Figure 17.4). Bradykinin is responsible for the pain, vasodilation and increased permeability of the blood vessels by stimulating formation and release of prostaglandins and prostacyclins from the endothelial cells (see Chapter 11). 

Parenteral Solutions, Blood clotting factors, colony-... 

Inhibitors of the blood clotting factor thrombin would in principle prove useful in preventing inappropriate clot formation that potentially leads to stroke and heart attack. Reaction of the carboxylic acid (56-2) with thionyl chloride leads to the corresponding acid chloride (56-3). Treatment of that intermediate with the substituted pyridyl amine (56-1) leads to the amide (56-4). Catalytic hydrogenation of (56-4) reduces the nitro group to the primary amine (56-5). Condensation of that ortho-diamine with the carboxyhc acid (56-6) in the presence of carbonyl diimidazole... 

Table 34-1 Blood Clotting Factors and Drugs That Affect Them.1...

The anticoagulant heparin is a polysaccharide sulfate which can form an electrostatic complex with blood-clotting factors (see ASIDE on blood clotting) and prevent the cascade from progressing. 

A conformational change induced in the protein antithrombin (AT) on binding a specific pentasaccharide S domain allows its interaction with Factor Xa, a blood clotting factor, preventing clotting. 

The principal role of vitamin K is in the post-translational modification of various blood clotting factors, in which it serves as a coenzyme in the carboxylation of certain glutamic acid residues present in these pro teins. Vitamin K exists in several forms, for example, in plants as phyllo quinone (or vitamin K-i), and in intestinal bacterial flora as Inenaquinone (or vitamin K2). For therapy, a synthetic derivative of vita rrri K, menadione, is available. 

A diet high in saturated fats leads to elevated VLDL and LDL levels in the bloodstream. This is undesirable because these lipoproteins tend to form fatty deposits called plaque in the artery walls. Plaque deposits can become inflamed to the point where they rupture, releasing blood-clotting factors into the bloodstream. A blood clot formed around the rupture site is let loose into the bloodstream, where it can become lodged and block the flow of blood to a particular region of the body. When that region is in the heart, the result is a heart attack. When that region is in the brain, the result is a stroke. 

Immunoglobulins, oq-trypsin inhibitor and a2-macroglobulin,k ten or more blood clotting factors and proteins of the complement system all have protective functions that are discussed elsewhere in this book. Hormones, many of them proteins, are present in the blood as they are carried to their target tissues. Many serum proteins have unknown or poorly understood functions. Among these are the acute phase proteins, whose concentrations rise in response to inflammation or other injury. 

One of the goals of synthetic medicinal chemistry is to design potent inilibitors of clinically important proteases. Elastase inhibitors may be useful for treatment of emphysema, pancreatitis, and arthritis,a/b while inhibitors of the angiotensinogen-converting enzyme or of renin (Box 22-D) can help control blood pressure. Inhibition of thrombin, factor Xa, or other blood clotting factors (Fig. 12-17) may prevent blood clots and inhibition of the cytosolic tryptase may provide a new treatment for asthma. Inhibition of the cysteine protease cathepsin K may help combat osteoporosis and inhibition of cysteine proteases of corona viruses may fight the common cold. Cysteine proteases of schistosomes are also targets for protease inhibitors.c... 

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