ANTICOAGULANTS

2010

ANTICOAGULANTS are agents that prevent the clotting of blood. Blood coagulation involves the conversion of fluid blood to a solid gel or a clot. The formation of a clot contributes to the process of haemostasis (see HAEMOSTATICS). The formation of fibrin filament, together with the adhesion and activation of platelets, helps form the haemostatic plug, which serves to block the damaged blood vessel wall. The actual elements of the clot, insoluble strands of fibrin, are the end-product of a cascade largely involving serine protease enzymes, notably thrombin, and blood-borne proteins. A thrombus is the generally unwanted formation of a haemostatic plug or thrombus within blood vessels, often within the veins or arteries of the heart, commonly in pathological conditions associated with arterial disease or where there is stasis. The formation of a thrombus occurs only in vivo (unlike blood clots which can form in vitro). Pieces of the thrombus may break off and form an embolism, which may lodge in vessels in the lungs or brain, causing damage to the tissues supplied. Thrombolytic drugs are able to dissolve thrombi (see FIBRINOLYTIC AGENTS), whereas antiplatelet drugs are not thrombolytic drugs but diminish the adhesion of platelets and their contribution to thrombus formation (see PLATELET AGGREGATION INHIBITING AGENTS). In some situations, e.g. myocardial infarction, the three classes of drug — anticoagulants, antiplatelets and thrombolytics — may be used in concert.

Heparins. Normally, the processes leading to coagulation, and those inhibiting it, are in balance. A natural anticoagulant found in the body is the basic glycosaminoglycan heparin (actually a family of sulphated mucopolysaccharides in a range of molecular weights from 3000 to 40,000). In tissues, heparin is found in mast cells (as polymers of MW 750,000), and also in the blood and the endothelium of blood vessels. Commercially, for medical use, it is extracted from bovine lung or porcine intestinal mucosa. It must be injected or used by infusion. The mechanism of action of heparin is complex, but it is sometimes referred to as an indirect-acting antithrombin, in as much as it works to inhibit the action of thrombin in the coagulation cascade by enhancing the action of the naturally occurring inhibitor antithrombin III. Heparin also modifies platelet aggregation, which is an important part of the coagulation process. A related glycosaminoglycan, heparan sulphate, occurs extracellularly in several tissues, including the endothelium of blood vessels. Like heparin, it acts along with factor II, and is thought to be an important anticoagulant in the microcirculation. Low-molecular weight heparins (LMWHs) are now available in fragments of different sizes (range 4000-15,000), with slightly different anticoagulant activity (e.g. certoparin, dalteparin, enoxaparin and tinzaparin). Further, heparinoids (e.g. danaparoid) are under investigation.

Antithrombin-III-independent anticoagulants. All the heparins need to be given by injection, so there is considerable interest in new classes of anticoagulants effective when given orally. The first such agent, arose from the original observation of bleeding disease in cattle fed on bruised clover. A number of analogues, bishydroxycoumarins, have been developed, most notably warfarin. These agents work by interfering with post-translational Ύ-carboxylation of glutamic acid residues in clotting factors II, VII, IX, and X. They do this by preventing the reduction of vitamin K, which is necessary for its action as a cofactor of the decarboxylase. Thus they act essentially as vitamin K antagonists, preventing its role in the formation of clotting factors. The effect of these drugs on fibrin formation takes several days to develop. Related anticoagulants such as nicoumalone and phenindione are now rarely used.

Directly acting antithrombins. A number of agents work directly as antithrombins, rather than indirectly like heparin and warfarin (see ANTITHROMBINS). An anticoagulant found in the medicinal leech, hirudin, works by direct interaction with both the catalytic site and the fibrinogen recognition site on thrombin. It is now made by recombinant DNA techniques. Unlike heparin, it causes little bleeding at clinically effective doses, but it does have to be given by injection. Hirugen is a synthetic dodecapeptide, an analogue of hirudin; it binds to thrombin and blocks access of substrates. Argatroban is a weak competitive inhibitor of thrombin.

Ancrod is an effective anticoagulant, and is a protease obtained from the venom of the Malaysian pit viper. It works by acting directly on fibrinogen to produce an unstable form that is cleared from the blood, resulting in depletion of fibrinogen. Its therapeutic use, by intravenous injection, is in the treatment of deep-vein thrombosis, especially the sort that occurs following surgery, or to prevent thrombosis. It is no longer commonly used.

Because calcium ions are required for several stages of the clotting process, agents that bind or chelate Ca2+ are effective anticoagulants. This approach is not used clinically in vivo in humans because of the vital importance of Ca2+ in all bodily processes, but in vitro, agents such as sodium citrate or sodium oxalate are routinely added as anticoagulants to prevent clotting of blood specimens.