Venous thromboembolism is a common problem after surgery, particularly in high-risk patients such as elderly patients, those with malignant disease and those with a history of previous thrombosis. The incidence is also high in patients confined to bed following trauma, myocardial infarction or other illnesses. Prevention and treatment of venous thrombosis includes the use of anticoagulants.
HEPARIN is not a single substance but a mixture of polysaccharides. Commercially available un fractionated heparin consists of components with molecular weights varying from 5000 to 35000 and an average of about 13000. It was extracted initially from liver, hence its name, but it is now prepared from porcine gastric mucosa. Heparin has an immediate effect on coagulation by potentiation of the formation of irreversible complexes between AT-III and activated serine protease coagulation factors (thrombin, Xlla, Xla, Xa, IXa and Vila). Low MOLECULARWEIGHT HEPARINS are produced by enzymatic or chemical degradation of standard heparin producing fractions with molecular weights in the range of 2000-8000. Potentiation of thrombin inhibition (anti- IIa activity) requires a minimum length of the heparin molecule with an approximate molecular weight of 5400, whereas the inhibition of factor Xa only requires a smaller heparin molecule with a molecular weight of about 1700. Low molecular weight heparins have the following properties:
1 They have greater activity against factor Xa than against factor IIa, suggesting that they may produce an equivalent anticoagulant effect as standard heparin but have a lower risk of bleeding, although this still awaits confirmation in clinical studies. In addition, low molecular weight heparins cause less inhibition of platelet function.
2 They have a longer half-life than standard heparin and so can be given as a once daily subcutaneous injection instead of every 8-12 hours.
3 They produce little effect on tests of overall coagulation, such as the PTTK at doses recommended for prophylaxis.
4 They are being increasingly used for antithrombotic prophylaxis of high-risk surgical patients. Fixed-dose low molecular weight heparin regimens are being studied for the treatment of established thrombosis. The main complication of treatment with heparin is bleeding. This is managed by stopping heparin. Very occasionally it is necessary to neutralize heparin with protamine. Other complications include osteoporosis with prolonged therapy and thrombocytopenia.
ORAL ANTICOAGULANTS act by interfering with vitamin K metabolism. There are two types of oral anticoagulants, the coumarins and indanediones. The coumarin warfarin is most commonly used because it has a low incidence of side-effects other than bleeding. The dosage is controlled by PT tests. Thromboplastin reagents for PT testing are derived from a variety of sources and give different PT results for the same plasma. It is now standard practice to compare each thromboplastin with an international reference preparation so that they can be assigned an international sensitivity index (tsr). The international normalized ratio (INR) is the ratio of the patient’s PT to a normal control when using the international reference preparation (Information box 6.1).
Each laboratory develops a chart adapted to the ISI of their thromboplastin to convert the patient’s PT to the INR and reports both values. The use of this system :neans that PT tests on a given plasma sample using different thromboplastins result in the same INR and that anticoagulant control is comparable in different hospitals across the world.
Contraindications to the use of oral anticoagulants are seldom absolute and include:
• Severe hypertension
• Non-thrombo-embolic strokes
• Peptic ulceration
• Severe liver and renal disease
• Pre-existing haemostatic defects
• pregnancy. Oral anticoagulants should be avoided in pregnancy because they are teratogenic in the first tremester and may be associated with fetal haernorgerhage later in pregnancy. When anticoagulation is considered essential in pregnancy, self-administered subcotaneous heparin should be used as an alternative, although this may not be as effective for women with prosthetic cardiac valves. Specialist advice should be sought about anticoagulation in pregnancy. manydrugs interact with warfarin . more frequent PT testing should accompany changes in medication, which should occur with the full knowledge of the anticoagulant clinic.
An increased anticoagulant effect due to warfarin (Emergency box 6.1) is usually produced by:
• Drugs causing a reduction in the metabolism of warfarin include tricyclic antidepressants, cimetidine, sulphonamides, phenothiazines and amiodarone .
• Drugs such as clofibrate and quinidine increase the sensitivity of hepatic receptors to warfarin.
• Drugs interfering with vitamin K absorption (such as broad-spectrum antibiotics and cholestyramine) may also potentiate the action of warfarin.
• The displacement of warfarin from its binding site on serum albumin by drugs such as sulphonamides is not usually responsible for clinically important interactions.
• Drugs that inhibit platelet function (such as aspirin) increase the risk of bleeding.
• Alcohol excess, cardiac failure, liver or renal disease, thyrotoxicosis and febrile illnesses may result in potentiation of the effect of warfarin.
A decreased anticoagulant effect due to warfarin is usually produced by drugs that increase the clearance of warfarin by induction of hepatic enzymes that metabolize warfarin, such as rifampicin and barbiturates. Side-effects of warfarin other than bleeding are rare.