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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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A (very rare) genetic deficiency in the production of factor XIII also results in impaired clotting efficacy in affected persons. In this case, covalent links which normally characterize transformation of a soft clot into a hard clot are not formed. Factor XIII preparations, partially purified from human blood, are used to treat individuals with this condition.
372 BIOPHARMACEUTICALS
Table 9.7. Anticoagulants which are used therapeutically or display therapeutic potential. Dicoumarol and related molecules are generally used over prolonged periods, while heparin is used over shorter periods. Hirudin has recently been approved for general medical use, while ancrod remains under clinical investigation
Anticoagulant Structure Source Molecular mass
(Da)
Heparin Glycosaminoglycan Beef lung, pig gastric mucosa 3000-40000
Dicoumarol Coumarin-based Chemical manufacture 336.3
Warfarin Coumarin-based Chemical manufacture 308.4
Hirudin Polypeptide Leech saliva, genetic engineering 7000
Ancrod Polypeptide Snake venom, genetic engineering 35 000
Protein C Glycoprotein Human plasma 62000
Anticoagulants
Although blood clot formation is essential to maintaining haemostasis, inappropriate clotting can give rise to serious, if not fatal, medical conditions. The formation of a blood clot (a thrombus) often occurs inappropriately within diseased blood vessels. This partially or completely obstructs the flow of blood (and hence oxygen) to the tissues normally served by that blood vessel.
Thrombus formation in a coronary artery (the arteries that supply the heart muscle itself with oxygen and nutrients) is termed coronary thrombosis. This results in a heart attack, characterized by the death (infarction) of oxygen-deprived heart muscle — hence the term ‘myocardial infarction’. The development of a thrombus in a vessel supplying blood to the brain can result in development of a stroke. In addition, a thrombus (or part thereof) which has formed at a particular site in the vascular system may become detached. After travelling through the blood, this may lodge in another blood vessel, obstructing blood flow at that point. This process, which can also give rise to heart attacks or strokes, is termed embolism.
Anticoagulants are substances which can prevent blood from clotting and, hence, are of therapeutic use in cases where a high risk of coagulation is diagnosed. They are often administered to patients with coronary heart disease and to patients who have experienced a heart attack or stroke, in an effort to prevent recurrent episodes. The major anticoagulants used for therapeutic purposes are listed in Table 9.7.
Heparin
Proteoglycans are widely distributed throughout the body, being most abundant in connective tissue, where they may contribute up to 30% of that tissue’s dry weight. They consist of a polypeptide backbone to which heteropolysaccharide chains are attached. However, unlike glycoproteins, proteolycans consist of up to, or in excess of, 95% carbohydrate and their properties resemble those of polysaccharides more than those of proteins.
Proteolytic digestion of proteoglycans liberates the carbohydrate side-chains, which are known as glycosaminoglycans (also known as mucopolysaccharides). All the glycosaminogly-cans contain derivatives of glucosamine or galactosamine. Six major groups are known, one of which is heparin.
Heparin (Figure 9.11) is associated with many tissues but is found mainly stored intracellularly as granules in mast cells which line the endothelium of blood vessels. Upon
ÑÍ2ÎÍ
ñîîí
Glucosamine
(2-aminodeoxyglucose)
Glucuronic acid
Iduronic acid
Figure 9.11. Structure of heparin. Heparin preparations, as isolated from natural sources, are a heterogeneous mixture of variably sulphated polysaccharides. The basic repeat structure consists of a D-glucosamine residue linked to a uronic acid, normally L-iduronic acid, less often D-glucuronic acid. Most of the amino groups of the glucosamine residues are modified with N-sulphate groups, while a small proportion are modified with N-acetyl groups. Many of the hydroxyl groups present at positions 2 and 6 of the iduronic ring also carry a sulphate substituent group. Molecular masses of individual molecules can vary considerably, often between 3 and 40 kDa. Individual hydrogens present on the sugar structures above have been omitted for clarity of presentation
BLOOD PRODUCTS AND THERAPEUTIC ENZYMES 373
374 BIOPHARMACEUTICALS
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