Anticoagulants

Although blood clot formation is essential to maintaining haemostasis, inappropriate clotting can give rise to serious, sometimes 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) that 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 that 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

Table 12.3 Anticoagulants that are used therapeutically or display therapeutic potential

Anticoagulant3

Structure

Source

Molecular mass (Da)

Heparin

Glycosaminoglycan

Beef lung, pig gastric mucosa

3 000-40 000

Dicoumarol

Coumarin-based

Chemical manufacture

336.3

Warfarin

Coumarin-based

Chemical manufacture

308.4

Hirudin

Polypeptide

Leech saliva, genetic

7 000

engineering

Ancrod

Polypeptide

Snake venom, genetic

35 000

engineering

Protein C

Glycoprotein

Human plasma

62 000

aDicoumarol and related molecules are generally used over prolonged periods, whereas heparin is used over shorter periods. Hirudin has recently been approved for general medical use, while ancrod remains under clinical investigation.

aDicoumarol and related molecules are generally used over prolonged periods, whereas heparin is used over shorter periods. Hirudin has recently been approved for general medical use, while ancrod remains under clinical investigation.

stroke (in an effort to prevent recurrent episodes). The major anticoagulants used for therapeutic purposes are listed in Table 12.3.

Heparin is a carbohydrate-based (glycosaminoglycan) anticoagulant associated with many tissues, but mainly found stored intracellularly as granules in mast cells that line the endothelium of blood vessels. Upon release into the bloodstream, heparin binds to and thereby activates an additional plasma protein, namely antithrombin. The heparin-antithrombin complex then binds a number of activated clotting factors (including Ila, IXa, Xa, XIa and XlIa), thereby inactivating them. The heparin now disassociates from the complex and combines with another antithrombin molecule, thereby initiating another turn of this inhibitory cycle.

Heparin was originally extracted from liver (hence its name), but commercial preparations are now obtained by extraction from beef lung or porcine gastric mucosa.

Although the product has proven to be an effective (and relatively inexpensive) anticoagulant, it does suffer from a number of clinical disadvantages, including the need for a cofactor (antithrombin III) and poorly predictable dose responses. Despite such disadvantages, however, heparin still enjoys widespread clinical use.

The vitamin K antimetabolites dicoumarol and warfarin are related coumarin-based anticoagulants which, unlike heparin, may be administered orally. These compounds induce their anticoagulant effect by preventing the vitamin K-dependent y-carboxylation of certain blood factors, specifically factors II, VII, IX and X. Upon initial hepatic synthesis of these coagulation factors, a specific carboxylase catalyses the y-carboxylation of several of their glutamate residues (for example, 10 of the first 33 residues present in prothrombin are y-carboxygluta-mate). This post-translational modification is required in order to allow these factors to bind Ca2+ ions, which is a prerequisite to their effective functioning. Vitamin K is an essential cofactor for the carboxylase enzyme, and its replacement with the antimetabolite dicoumarol renders this enzyme inactive. As a consequence, defective blood factors are produced that hinder effective functioning of the coagulation cascade. The only major side effect of these oral anticoagulants is prolonged bleeding; thus, the dosage levels are chosen with care. Dicou-marol was first isolated from spoiled sweet clover hay, as the agent that promoted haemorrhage disease in cattle. Both dicoumarol and warfarin have also been utilized (at high doses) as rat poisons.

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