Uses Of Anticoagulants

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Venous disease

Established venous thromboembolism. An anticoagulant is used to prevent extension of an existing thrombus while its size is reduced by natural thrombolytic activity. Effective anticoagulation prevents formation of fresh thrombus, which is more likely to detach and embolise, particularly if it is in large proximal veins; it also helps to recanalise veins and to clear vein valves of thrombus and should thus prevent long-term consequences such as swelling of the leg and stasis ulceration. The site and extent of thrombosis should be established by venous ultrasound. The majority of patients with proximal vein thrombosis or calf vein thrombosis can be treated with outpatient low molecular weight heparin, weight-adjusted and administered once or twice daily according to manufacturer's recommendations. It should be continued for a total of 4-7 days and until the signs of thrombosis (heat, swelling of the limb) have settled. Warfarin should be started at the same time as the heparin. Patients with a symptomatic pulmonary embolism should be treated in hospital with LMW heparin or highdose intravenous unfractionated heparin (above).

In patients with an uncomplicated DVT following a precipitating event (e.g. orthopaedic surgery), warfarin may be necessary for only 6 weeks if the patient has returned to normal mobility and the precipitating factor(s) have been eliminated. The patient should wear a well-fitting compression stocking to increase flow in deep veins, should exercise the leg and should be encouraged to mobilise as soon as the discomfort has settled. The risk of recurrence reduces with passage of time after the initial event. In cases of DVT uncomplicated by pulmonary embolus, 3 months of anticoagulant therapy appears adequate. Where there is evidence of pulmonary embolus it is common practice to continue therapy for 6 to 12 months.

Thrombolytic therapy with streptokinase or urokinase i.v. may be used for life-threatening thrombosis, e.g. major pulmonary embolism with compromised haemodynamics (see p. 580).

Anticoagulant therapy may be life-saving in thromboembolic pulmonary hypertension.

Prevention of venous thrombosis. Oral anticoagulant reduces the risk of thromboembolism in conditions in which there is special hazard, e.g. after surgery. Partly because of the danger of bleeding and partly because of the effort of maintaining control, oral anticoagulants have not been widely adopted. Numerous trials, however, have shown the protective effect of low doses of unfractionated heparin (5000 units every 8-12 h s.c.) and more recently LMW heparin (dose adjusted for body-weight and/or risk) against deep leg vein thrombosis. The significant fact is that it takes a lot less heparin to prevent thrombosis than it does to treat established thrombosis, because heparin acts in low concentration at an early stage in the cascade of coagulation factors which leads to fibrin formation (see above).

Low-dose unfractionated heparin or LMW heparin can be used to prevent venous thromboembolism in other high-risk patients, e.g. those confined to bed and immobilised with strokes, cardiac failure or malignant disease. Spontaneous bleeding has not been a problem with this form of anticoagulant treatment.

Low MW dextrans (see later).

Cardiovascular disease

Acute myocardial infarction. Anticoagulation with heparin is used to reduce the risk of venous thromboembolism, and the risk and size of emboli from mural thrombi following acute myocardial infarction.

Long-term anticoagulation with warfarin to prevent arterial thromboembolism should be considered for any patient who has a large left atrium or a low cardiac output or paroxysmal or established atrial fibrillation (with or without cardiac valvular disease). Where warfarin is considered unsuitable, aspirin may be substituted, for it prevents stroke in patients with atrial fibrillation, though less effectively. The combination of warfarin and aspirin, once regarded as contraindicated, may yet be most effective in patients at high risk of embolism. Heparin is given for 2 h to patients after undergoing angioplasty.

Heparin, aspirin or both are used to prevent myocardial infarction in the acute phase of unstable angina.

Peripheral arterial occlusion. Heparin may prevent extension of a thrombus and hasten its recanalisation; it is commonly used in the acute phase following thrombosis or embolism. There is no case for treating ischaemic peripheral vascular disease with an oral anticoagulant (for prevention, see Antiplatelet drugs).

Long-term anticoagulant prophylaxis

The decision to use warfarin long-term must take into account nondrug factors. The patient should be told of the risks of haemorrhage, including those introduced by taking other drugs, and of the signs of bleeding into the alimentary or urinary tracts. All patients should carry a card stating that they are receiving an oral anticoagulant. Such therapy should be withheld from a patient who is considered to be unlikely or unable to comply with the requirements of regular medication and blood testing. The incidence of haemorrhagic complications is directly related to the level of anticoagulation; safety and good results can be obtained only by close attention to detail. The INR should be monitored at a maximum interval of 8 weeks in patients on a stable maintenance dose and more frequently in patients with an unstable INR.

Surgery in patients receiving anticoagulant therapy

For elective surgery warfarin may be withdrawn about 5 days before the operation and resumed about 3 days later if conditions seem appropriate; heparin may be used in the intervening period. In patients with mechanical prosthetic valves, heparin is substituted at full dosage 4 days before surgery, and restarted 12-24 h after the operation. Warfarin is restarted when the patient resumes oral intake. Emergency surgery: proceed as for bleeding (p. 571). For dental extractions: omission of warfarin for 1-2 days to adjust the INR to the lower limit of the therapeutic range is adequate (INR should be tested just prior to the procedure). The usual dose of warfarin can be resumed the day after extraction.

Aspirin, taken prophylactically for thromboembolic disorders (see below), is commonly discontinued 2 weeks before elective procedures and restarted when oral intake permits.

Contraindications to anticoagulant therapy

Contraindications relate mostly to conditions in which there is a tendency to bleed, and are relative rather than absolute, the dangers being balanced against the possible benefits. They include:

• Behavioural: inability or unwillingness to cooperate, dependency on alcohol

• Neurological: stroke within 3 weeks, or surgery to the brain or eye

• Alimentary: active peptic ulcer, active inflammatory bowel disease, oesophageal varices, uncompensated hepatic cirrhosis

• Cardiovascular: severe uncontrolled hypertension

• Renal: if function is severely impaired

• Pregnancy: in early pregnancy the fetal warfarin syndrome is a hazard and bleeding may cause fetal death in late pregnancy

• Haematological: pre-existing bleeding disorder.

Emerging anticoagulant drugs

Recent strategies have sought to develop substances that act at different sites in the coagulation cascade and agents that inhibit thrombin, or prevent thrombin generation, or block initiation of the coagulation process or enhance endogenous anticoagulation have reached the clinical arena.

Novel delivery systems, using synthetic amino acids (e.g. SNAC) to facilitate absorption, allow the oral administration of unfractionated or LMW heparins sufficient to prolong the APTT. These are being evaluated.

Direct inhibitors of thrombin inactivate fibrin-bound thrombin which may promote thrombus extension (as opposed to heparin which acts indirectly through antithrombin) as follows:

Hirudin, a polypeptide originally isolated from the salivary glands of the medicinal leech Hirudo medicalis, is now produced by recombinant technology. It is a potent and specific inhibitor of thrombin with which it forms an almost irreversible complex. It is cleared predominantly by the kidneys and has a t1/ of 40 minutes after i.v. administration. No antidote is available for a bleeding patient. It has been used successfully in patients with heparin-induced thrombocytopenia (HIT), thromboprophylaxis in elective hip arthroplasty, unstable angina and myocardial infarction.

Bivalirudin is a semisynthetic bivalent thrombin inhibitor which contains an analogue of the C-terminal of hirudin; this binds to thrombin but having a lower affinity, produces only transient inhibition and hence may be safer. It has been used in patients undergoing coronary angioplasty.

Argatroban, a carboxylic acid derivative, binds noncovalently to the active site of thrombin and is an effective alternative to heparin in patients with HIT.

Other highly selective agents in clinical development include blockers of:

factor IXa, an essential factor for amplification of the coagulation cascade (by active-site-blocked factor IXa or monoclonal antibodies against the factor), the factor Vila/tissue factor pathway, the initiating step of coagulation [with recombinant tissue factor pathway inhibitor (TFPI) the analogue of the natural inhibitor], and factor X or factor Xa and inhibition of factor Vila within the factor Vila/tissue factor complex (by NAPc2, a recombinant nematode anticoagulant peptide).

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