13.02.4 Anticoagulants

Heparin is a large (12,000 daltons) endogenous compound found in mast cells. For clinical use, heparin is extracted from porcine intestinal mucosa or bovine lung. Many of the clotting factors are proteases, and heparin inhibits all clotting factor proteases to inhibit clotting quickly. Heparin is precipitated by acid in gut, and not absorbed from gastrointestinal tract, and this means it is ineffective when administered orally. Heparin is used intravenously or subcutaneously.

Low-molecular-weight heparins such as enoxaparin (1-10,000 daltons) are made from heparin. Enoxaparin inhibits the final protease in the coagulation cascade, which is factor Xa to a greater extent than the other proteases in the cascade. Enoxaparin is used subcutaneously. With heparin, and low-molecular weight heparins, the main toxicity is bleeding, which is just an extension of its therapeutic effect. Heparin and low-molecular-weight heparins are beneficial in unstable angina, and very importantly, they are effective immediately, which makes them ideal to use in unstable angina, especially when it is progressing to myocardial infarction, and an immediate anti-coagulant effect is required. Heparins are also used to prevent clotting in surgical and high-risk medical subjects, and in coronary angioplasty.

Warfarin inhibits the formation of vitamin K-dependent factors for coagulation including prothrombin. Warfarin is active after oral administration, and this is a major advantage over heparin, which has to be given intravenously or subcutaneously. However, warfarin is not effective immediately, this is a major disadvantage compared to heparin, which is effective immediately.

Warfarin is only effective when existing vitamin K-dependent clotting factors have been broken down, which usually takes more than 36 hours, but is dependent on levels of vitamin K in the body. If vitamin K levels are low, this alone will inhibit coagulation, and further inhibition of coagulation with warfarin may produce haemorrhage. Clinically, warfarin use is for prolonged anti-coagulation effect (e.g in the prevention of thrombosis, unstable angina). Heparin and warfarin are often used in sequence, heparin to give an immediate anti-coagulant effect, until the anticoagulant effect of warfarin kicks in. The main toxic effect of warfarin is haemorrhage. The antidote to warfarin-induced haemorrhage is vitamin K to build up the vitamin K-dependent factors, and promote coagulation.

Direct thrombin inhibitors, such as dabigatran, have been developed recently, and may take over some of the present roles of the heparins and warfarin. By directly inhibiting thrombin, dabigatran inhibits the conversion of fibrogen (soluble) to fibrin (insoluble) clot. Dabigatran is active after oral administration, and has an immediate effect. Dabigatran is presently used after hip and knee replacement surgery to prevent thromboembolism.

Another group of relatively new anticoagulants are the Factor Xa inhibitors. Fondaparinux is a Factor Xa inhibitor. Fondaparinux is used subcutaneously, and is effective quite quickly. Fondaparinux is used to prevent thromboembolism after hip-fracture, and hip or knee replacement.