The blood clotting process
When blood is lost or clotting is initiated in some other way, a complex cascade of biochemical reactions is set in motion, which ends in the formation of a network or clot of insoluble protein threads enmeshing the blood cells. These threads are produced by the polymerisation of the molecules of fibrinogen (a soluble protein present in the plasma) into threads of insoluble fibrin. The penultimate step in the chain of reactions requires the presence of an enzyme, thrombin, which is produced from its precursor prothrombin, already present in the plasma. This is initiated by factor III
(tissue thromboplastin), and subsequently involves various factors including activated factor VII, IX, X, XI and XII, and is inhibited by antithrombin III. Platelets are also involved in the coagulation process.
Fibrinolysis is the mechanism of dissolution of fibrin clots, which can be promoted with thrombolytics. For further information on platelet aggregation and clot dissolution, see ‘Antiplatelet drugs and thrombolytics’, (p.697).
When blood is lost or clotting is initiated in some other way, a complex cascade of biochemical reactions is set in motion, which ends in the formation of a network or clot of insoluble protein threads enmeshing the blood cells. These threads are produced by the polymerisation of the molecules of fibrinogen (a soluble protein present in the plasma) into threads of insoluble fibrin. The penultimate step in the chain of reactions requires the presence of an enzyme, thrombin, which is produced from its precursor prothrombin, already present in the plasma. This is initiated by factor III
(tissue thromboplastin), and subsequently involves various factors including activated factor VII, IX, X, XI and XII, and is inhibited by antithrombin III. Platelets are also involved in the coagulation process.
Fibrinolysis is the mechanism of dissolution of fibrin clots, which can be promoted with thrombolytics. For further information on platelet aggregation and clot dissolution, see ‘Antiplatelet drugs and thrombolytics’, (p.697).
Mode of action of the anticoagulants
Anticoagulants may be divided into direct anticoagulants, which have an immediate effect, and the indirect anticoagulants, which inhibit the formation of coagulation factors, so have a delayed effect as they do not inactivate coagulation factors already formed. See ‘Table 12.1’, (p.359), for a list.
(a) Direct anticoagulants
The direct anticoagulants include heparin, which principally enhances the effect of antithrombin III, thereby inhibiting the effect of thrombin (factor IIa) and activated factor X (factor Xa). Low-molecular-weight heparins are salts of fragments of heparin and act similarly, except that they have a
greater effect on factor Xa than factor IIa. They have a longer duration of action than heparin and usually require less monitoring. The heparinoids (such as danaparoid) are similar. A more recent introduction is the synthetic polysaccharide fondaparinux, which is an inhibitor of factor Xa.
The other group of direct anticoagulants are the thrombin inhibitors, which bind to the active thrombin site. These include recombinant forms or synthetic analogues of hirudin such as bivalirudin and lepirudin. Megalatran and its oral prodrug ximelagatran act similarly, but have been withdrawn because of liver toxicity.
The direct anticoagulants include heparin, which principally enhances the effect of antithrombin III, thereby inhibiting the effect of thrombin (factor IIa) and activated factor X (factor Xa). Low-molecular-weight heparins are salts of fragments of heparin and act similarly, except that they have a
greater effect on factor Xa than factor IIa. They have a longer duration of action than heparin and usually require less monitoring. The heparinoids (such as danaparoid) are similar. A more recent introduction is the synthetic polysaccharide fondaparinux, which is an inhibitor of factor Xa.
The other group of direct anticoagulants are the thrombin inhibitors, which bind to the active thrombin site. These include recombinant forms or synthetic analogues of hirudin such as bivalirudin and lepirudin. Megalatran and its oral prodrug ximelagatran act similarly, but have been withdrawn because of liver toxicity.
(b) Indirect anticoagulants
The indirect anticoagulants inhibit the vitamin K-dependent synthesis of factors VII, IX, X and II (prothrombin) in the liver, and may also be referred to as vitamin K antagonists. The most commonly used are the coumarins, principally warfarin, but also acenocoumarol and phenprocoumon. The indanediones such as phenindione are now less frequently used. The indirect anticoagulants have the advantage over currently available direct anticoagulants in that they are orally active. They are often therefore referred to as oral anticoagulants, but this term may become misleading with the development of direct-acting oral anticoagulants, such as ximelegatran, which have different monitoring requirements and interactions.
Coagulation tests
During anticoagulant therapy the aim is to give protection against intravascular clotting, without running the risk of bleeding. To achieve this, doses of heparin and oral anticoagulants should be individually titrated until the desired response is attained. With the coumarin and indanedione oral anticoagulants, this procedure normally takes several days because they do not act directly on the blood clotting factors already in circulation, but on the rate of synthesis of new factors by the liver. The successful titration is determined by one of a number of different but closely related laboratory tests, see ‘Table 12.2’, (p.360) and below. Note that routine monitoring of anticoagulant effect is not required for low-molecular weight heparins or heparinoids, except in patients at increased risk of bleeding, such as those with renal impairment or who are overweight. Also, note that these tests cannot be used to monitor the anticoagulant effect of fondaparinux or the direct thrombin inhibitors, and these require no routine monitoring.
(a) Prothrombin timeThe prothrombin time test (PT, Pro-Time, tissue factor induced coagulation time) is the most common method employed in clinical situations. It measures the time taken for a fibrin clot to form in a citrated plasma sample containing calcium ions and tissue thromboplastin. The PT is usually reported as the International Normalised Ratio (INR).
1. International normalised ratio (INR). The INR was adopted by the WHO in 1982 to standardise (using the International Sensitivity Index) oral anticoagulant therapy to take into account the sensitivities of the different thromboplastins used in laboratories across the world. The formula for calculating the INR is as follows:
INR = (patient’s prothrombin time in seconds/mean normal prothrombin time in seconds)ISI
The PT values obtained from the patient’s sample are compared to a control, and this gives the INR. The higher the INR, the higher the PT value so if the patient’s ratio is 2, this means the PT (and therefore clotting) is twice as long as the normal plasma. The British Corrected Ratio is essentially the same, but was calculated to a standard British thromboplastin.
2. Quick Value. The Quick Value is expressed as a percentage; the lower the value, the longer the blood takes to coagulate. Therefore as the Quick Value increases, the corresponding INR value gets smaller and vice versa.
1. International normalised ratio (INR). The INR was adopted by the WHO in 1982 to standardise (using the International Sensitivity Index) oral anticoagulant therapy to take into account the sensitivities of the different thromboplastins used in laboratories across the world. The formula for calculating the INR is as follows:
INR = (patient’s prothrombin time in seconds/mean normal prothrombin time in seconds)ISI
The PT values obtained from the patient’s sample are compared to a control, and this gives the INR. The higher the INR, the higher the PT value so if the patient’s ratio is 2, this means the PT (and therefore clotting) is twice as long as the normal plasma. The British Corrected Ratio is essentially the same, but was calculated to a standard British thromboplastin.
2. Quick Value. The Quick Value is expressed as a percentage; the lower the value, the longer the blood takes to coagulate. Therefore as the Quick Value increases, the corresponding INR value gets smaller and vice versa.
(b) Activated partial thromboplastin time
The activated partial thromboplastin time (aPTT) is the second most common method for monitoring anticoagulant therapy, measuring all the clotting factors in the intrinsic pathway as opposed to the PT test, which measures the extrinsic pathway.
(c) Other methods of assessing clottingOther tests used, which in some instances offer more sensitivity to specific aspects of therapy, include the prothrombin-proconvertin ratio (PP), the thrombotest, the thrombin clotting time test (TCT, activated clotting time, activated coagulation time), the platelet count and the bleeding time test.
The use of the most appropriate test will depend on the situation and the desired result.
Anticoagulant interactions
Stable oral anticoagulant therapy is difficult to achieve even during close monitoring. For example, in one controlled study in patients with atrial fibrillation, only 61% of INR values were within the target range of 2 to 3, despite monitoring the INR monthly and adjusting the warfarin dose appropriately.
1 A large number of factors can influence levels of coagulation, including diet, disease (fever, diarrhoea, heart failure, thyroid dysfunction), and the use of other drugs. It must therefore be remembered that it is particularly difficult to ascribe a change in INR specifically to a drug interaction in a single case report, and single case reports or a few isolated reports for widely used drugs do not prove that an interaction occurs.
Nevertheless, either the addition or the withdrawal of drugs may upset the balance in a patient already well stabilised on an anticoagulant. Some drugs are well known to increase the activity of the anticoagulants and can cause bleeding if the dosage of the anticoagulant is not reduced appropriately.
Others reduce the activity and return the prothrombin time to normal.
Both situations are serious and may be fatal, although excessive hypoprothrombinaemia manifests itself more obviously and immediately as bleeding and is usually regarded as the more serious. The interaction mechanism may be pharmacodynamic or pharmacokinetic: pharmacokinetic mechanisms are particularly well established and important for coumarin anticoagulants.
Stable oral anticoagulant therapy is difficult to achieve even during close monitoring. For example, in one controlled study in patients with atrial fibrillation, only 61% of INR values were within the target range of 2 to 3, despite monitoring the INR monthly and adjusting the warfarin dose appropriately.
1 A large number of factors can influence levels of coagulation, including diet, disease (fever, diarrhoea, heart failure, thyroid dysfunction), and the use of other drugs. It must therefore be remembered that it is particularly difficult to ascribe a change in INR specifically to a drug interaction in a single case report, and single case reports or a few isolated reports for widely used drugs do not prove that an interaction occurs.
Nevertheless, either the addition or the withdrawal of drugs may upset the balance in a patient already well stabilised on an anticoagulant. Some drugs are well known to increase the activity of the anticoagulants and can cause bleeding if the dosage of the anticoagulant is not reduced appropriately.
Others reduce the activity and return the prothrombin time to normal.
Both situations are serious and may be fatal, although excessive hypoprothrombinaemia manifests itself more obviously and immediately as bleeding and is usually regarded as the more serious. The interaction mechanism may be pharmacodynamic or pharmacokinetic: pharmacokinetic mechanisms are particularly well established and important for coumarin anticoagulants.
(a) Metabolism of the coumarins
The coumarins, warfarin, phenprocoumon and acenocoumarol, are racemic mixtures of S- and R-enantiomers. The S-enantiomers of these coumarins have several times more anticoagulant activity than the R-enantiomers.
Reports suggest for example, that S-warfarin is three to five times more potent a vitamin K antagonist than R-warfarin. The S-enantiomer of warfarin is metabolised primarily by the cytochrome P450 isoenzyme CYP2C9, and to a much lesser extent, by CYP3A4. The metabolism of Rwarfarin is more complex, but this enantiomer is primarily metabolised by CYP1A2, CYP3A4, and CYP2C19. S-warfarin is eliminated in the bile and R-warfarin is excreted in the urine as inactive metabolites. There is much more known about the metabolism of warfarin compared with other anticoagulants, but it is established that S-phenprocoumon and S-acenocoumarol are also substrates for CYP2C9 and that they differ from warfarin in their hepatic metabolism, and stereospecific potency.2
It makes sense to assume therefore, that an inhibitor of CYP2C9 (e.g. ‘fluconazole’, (p.387)) is likely to increase the concentration of the coumarin and enhance the anticoagulant effect. Drugs that induce CYP2C9 (e.g. ‘rifampicin’, (p.375)) reduce plasma levels of the coumarins by increasing the clearance.
‘Genetic differences’, (p.4), in the genes for these cytochrome P450 isoenzymes may have an important influence on drug metabolism of the coumarins. For example, different versions of the gene encoding CYP2C9 exist and the enzymatic activity of the most clinically important CYP2C9 variants, CYP2C9*2 and CYP2C9*3, is significantly reduced. Studies have suggested an association between patients possessing one or more of these variants and a low-dose requirement of warfarin. Similar observations have been seen with the CYP2C9*3 variant and acenocoumarol.
While the metabolism of the coumarins, especially warfarin, are well known, the numerous interaction pathways and the variability in patient responses, makes the clinical consequences difficult to predict.
The coumarins, warfarin, phenprocoumon and acenocoumarol, are racemic mixtures of S- and R-enantiomers. The S-enantiomers of these coumarins have several times more anticoagulant activity than the R-enantiomers.
Reports suggest for example, that S-warfarin is three to five times more potent a vitamin K antagonist than R-warfarin. The S-enantiomer of warfarin is metabolised primarily by the cytochrome P450 isoenzyme CYP2C9, and to a much lesser extent, by CYP3A4. The metabolism of Rwarfarin is more complex, but this enantiomer is primarily metabolised by CYP1A2, CYP3A4, and CYP2C19. S-warfarin is eliminated in the bile and R-warfarin is excreted in the urine as inactive metabolites. There is much more known about the metabolism of warfarin compared with other anticoagulants, but it is established that S-phenprocoumon and S-acenocoumarol are also substrates for CYP2C9 and that they differ from warfarin in their hepatic metabolism, and stereospecific potency.2
It makes sense to assume therefore, that an inhibitor of CYP2C9 (e.g. ‘fluconazole’, (p.387)) is likely to increase the concentration of the coumarin and enhance the anticoagulant effect. Drugs that induce CYP2C9 (e.g. ‘rifampicin’, (p.375)) reduce plasma levels of the coumarins by increasing the clearance.
‘Genetic differences’, (p.4), in the genes for these cytochrome P450 isoenzymes may have an important influence on drug metabolism of the coumarins. For example, different versions of the gene encoding CYP2C9 exist and the enzymatic activity of the most clinically important CYP2C9 variants, CYP2C9*2 and CYP2C9*3, is significantly reduced. Studies have suggested an association between patients possessing one or more of these variants and a low-dose requirement of warfarin. Similar observations have been seen with the CYP2C9*3 variant and acenocoumarol.
While the metabolism of the coumarins, especially warfarin, are well known, the numerous interaction pathways and the variability in patient responses, makes the clinical consequences difficult to predict.
(b) Other mechanisms for anticoagulant interactions
Some drugs, such as ‘colestyramine’, (p.393), may also prevent the absorption of the coumarins and reduce their bioavailability. See also ‘Drug absorption interactions’, (p.3). Additive anticoagulant effects can occur if anticoagulants are given with other drugs that also impair coagulation by other mechanisms such as ‘antiplatelets’, (p.700). Coumarins and indanediones act as vitamin K antagonists, and so dietary intake of ‘vitamin K’, (p.409) can also ‘reduce or abolish’, (p.9) their effects. ‘Protein-binding displacement’, (p.3) is another possible drug interaction mechanism but this usually plays a minor role compared with other mechanisms.3
Bleeding and its treatment
When prothrombin times become excessive, bleeding can occur. In order of decreasing frequency the bleeding shows itself as ecchymoses, blood in the urine, uterine bleeding, black faeces, bruising, nose-bleeding, haematoma, gum bleeding, coughing and vomiting blood.
Vitamin K is an antagonist of the coumarin and indanedione oral anticoagulants.
The British Society for Haematology has given advice on the appropriate course of action if bleeding occurs in patients taking warfarin, and this is readily available in summarised form in the British National Formulary.
If the effects of heparin are excessive it is usually sufficient just to stop the heparin, but protamine sulfate is a specific antidote if a rapid effect is required. Protamine sulfate only partially reverses the effect of low molecular weight heparins.
There is currently no known specific antidote for fondaparinux, or for the direct thrombin inhibitors.
1. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet (1996) 348, 633–8.
2. Ufer M. Comparative pharmacokinetics of vitamin-K antagonists. Warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet (2005) 44, 1227–46.
3. Sands CD, Chan ES, Welty TE. Revisiting the significance of warfarin protein-binding displacement interactions. Ann Pharmacother (2002) 36, 1642–4.
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