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 formation of a network or clot of insoluble protein threads enmeshing blood cells. These threads are produced by polymerisation of molecules of fibrinogen (a soluble protein present in plasma) into threads of insoluble fibrin. The penultimate step in chain of reactions requires presence of an enzyme, thrombin, which is produced from its precursor prothrombin, already present in 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 anti-thrombin III. Platelets are also involved in coagulation process. Fibrinolysis is 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, .
Mode of action of anticoagulants
Anticoagulants may be divided into direct anticoagulants, which have an immediate effect, and indirect anticoagulants, which inhibit formation of coagulation factors, so have a delayed effect as they do not inactivate coagulation factors already formed. See table 1 below,, for a list.
The direct anticoagulants include heparin, which principally enhances effect of antithrombin III, thereby inhibiting 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 synthetic polysaccharide fondaparinux, which is an inhibitor of factor Xa. The other group of direct anticoagulants are thrombin inhibitors, which bind to 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 Megalatran and its oral prodrug ximelagatran act similarly,but have been withdrawn because of liver toxicity.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 indirect anticoagulants inhibit vitamin K-dependent synthesis of factors VII, IX, X and II (prothrombin) in liver, and may also be referred to as vitamin K antagonists. The most commonly used are coumarins, principally warfarin, but also acenocoumarol and phenprocoumon. The indanediones such as phenindione are now less frequently used. The indirect anticoagulants have 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 development of direct-acting oral anticoagulants, such as ximelegatran, which have different monitoring requirements and interactions.
During anticoagulant therapy aim is to give protection against intravascular clotting, without running risk of bleeding. To achieve this, doses of heparin and oral anticoagulants should be individually titrated until desired response is attained. With coumarin and indanedione oral anticoagulants, this procedure normally takes several days because they do not act directly on blood clotting factors already in circulation, but on rate of synthesis of new factors by liver. The successful titration is determined by one of a number of different but closely related laboratory tests,see table 2 below, 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 anticoagulant effect of fondaparinux or direct thrombin inhibitors, and these require no routine monitoring.
The prothrombin time test (PT, Pro-Time, tissue factor induced coagulation time) is most common method employed in clinical situations. It measures 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 International Normalised Ratio (INR).
International normalised ratio (INR). The INR was adopted by WHO in 1982 to standardise (using International Sensitivity Index) oral anticoagulant therapy to take into account sensitivities of different thromboplastins used in laboratories across world. The formula for calculating INR is as follows: INR = (patient’s prothrombin time in seconds/mean normal prothrombin time in seconds)(See reference number ISI)The PT values obtained from patient’s sample are compared to a control, and this gives INR. The higher INR, higher PT value so if patient’s ratio is 2, this means PT (and therefore clotting) is twice as long as normal plasma. The British Corrected Ratio is essentially same, but was calculated to a standard British thromboplastin.
Quick Value. The Quick Value is expressed as a percentage; lower value, longer blood takes to coagulate. Therefore as Quick Value increases, corresponding INR value gets smaller and vice versa.
The activated partial thromboplastin time (aPTT) is second most common method for monitoring anticoagulant therapy, measuring all clotting factors in intrinsic pathway as opposed to PT test, which measures extrinsic pathway.
Other tests used, which in some instances offer more sensitivity to specific aspects of therapy, include prothrombin-proconvertin ratio (PP), thrombotest, thrombin clotting time test (TCT, activated clotting time, activated coagulation time), platelet count and bleeding time test. The use of most appropriate test will depend on situation and desired result.
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 target range of 2 to 3, despite monitoring INR monthly and adjusting warfarin dose appropriately.(See reference number 1) A large number of factors can influence levels of coagulation, including diet, disease (fever, diarrhoea, heart failure, thyroid dysfunction), and 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 addition or withdrawal of drugs may upset balance in a patient already well stabilised on an anticoagulant. Some drugs are well known to increase activity of anticoagulants and can cause bleeding if dosage of anticoagulant is not reduced appropriately. Others reduce activity and return 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 more serious. The interaction mechanism may be pharmacodynamic or pharmacokinetic: pharmacokinetic mechanisms are particularly well established and important for coumarin anticoagulants.
(a) Metabolism of 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 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 cytochrome P450 isoenzyme CYP2C9, and to a much lesser extent, by CYP3A4. The metabolism of R-warfarin is more complex,but this enantiomer is primarily metabolised by CYP1A2, CYP3A4, and CYP2C19. S-warfarin is eliminated in bile and R-warfarin is excreted in urine as inactive metabolites. There is much more known about 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 (See reference number 2).
It makes sense to assume therefore,that an inhibitor of CYP2C9 (e.g. fluconazole, ) is likely to increase concentration of coumarin and enhance anticoagulant effect. Drugs that induce CYP2C9
(e.g. rifampicin, ) reduce plasma levels of coumarins by increasing clearance.
Genetic differences, , in genes for these cytochrome P450 isoenzymes may have an important influence on drug metabolism of coumarins. For example, different versions of gene encoding CYP2C9 exist and enzymatic activity of 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 CYP2C9*3 variant and acenocoumarol.
While metabolism of coumarins, especially warfarin, are well known, numerous interaction pathways and variability in patient responses, makes clinical consequences difficult to predict.
Some drugs, such as colestyramine, , may also prevent absorption of coumarins and reduce their bioavailability. See also Drug absorption interactions,. Additive anticoagulant effects can occur if anticoagulants are given with other drugs that also impair coagulation by other mechanisms such as antiplatelets,. Coumarins and indanediones act as vitamin K antagonists,and so dietary intake of vitamin K,
can also reduce or abolish, their effects. Protein-binding displacement, is another possible drug interaction mechanism but this usually plays a minor role compared with other mechanisms (See reference number 3).
When prothrombin times become excessive,bleeding can occur. In order of decreasing frequency bleeding shows itself as ecchymoses, blood in urine, uterine bleeding, black faeces, bruising, nose-bleeding, haematoma, gum bleeding, coughing and vomiting blood.
Vitamin K is an antagonist of coumarin and indanedione oral anticoagulants. The British Society for Haematology has given advice on appropriate course of action if bleeding occurs in patients taking warfarin, and this is readily available in summarised form in British National Formulary.
If effects of heparin are excessive it is usually sufficient just to stop heparin, but protamine sulfate is a specific antidote if a rapid effect is required. Protamine sulfate only partially reverses effect of low molecular weight heparins.
There is currently no known specific antidote for fondaparinux, or for direct thrombin inhibitors.
Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity,fixed dose warfarin plus aspirin for high-risk patients with atrial fibrillation: StrokePrevention in Atrial Fibrillation III randomised clinical trial. Lancet (1996) 348, 633–8.
Ufer M. Comparative pharmacokinetics of vitamin-K antagonists. Warfarin,phenprocoumonand acenocoumarol. Clin Pharmacokinet (2005) 44, 1227–46.
Sands CD,Chan ES, Welty TE. Revisiting the significance of warfarin protein-binding displacement interactions. Ann Pharmacother (2002) 36, 1642–4.
| Table 1 Anticoagulants | |
| Direct anticoagulants | Indirect anticoagulants |
| Fondaparinux sodium | Coumarins |
| Heparin | Acenocoumarol |
| Heparin calcium | Dicoumarol |
| Heparin sodium | Ethyl biscoumacetate |
| Heparinoids | Phenprocoumon |
| Danaparoid | Warfarin |
| Dermatan sulfate | Indanediones |
| Pentosan polysulfate | Fluindione |
| Suleparoid | Phenindione |
| Sulodexide | |
| Low-molecular-weight heparins | |
| Bemiparin | |
| Certoparin | |
| Dalteparin | |
| Enoxaparin | |
| Nadroparin | |
| Parnoparin | |
| Reviparin | |
| Tinzaparin | |
| Thrombin inhibitors | |
| Argotroban | |
| Bivalirudin | |
| Desirudin | |
| Hirudin | |
| Lepirudin | |
| Melagatran | |
| Ximelagatran |
| Table 2 Coagulation tests | ||
|---|---|---|
| Test | Normal range | Therapeutic/diagnostic range |
| Activated partial thromboplastin time | 20 to 39 seconds after reagents added | 1.5 to 2.5 x control |
| Bleeding time | 1 to 9 minutes depending on method used | Critical value greater than 15 minutes |
| International normalised ratio | 0.9 to 1.2 | 2 to 4 depending on indication for anticoagulation |
| Plasma thrombin time test | 10 to 15 seconds | Greater than 15 seconds |
| Prothrombin-proconvertin ratio | 70 to 130 % | 10 to 30 % |
| Prothrombin time | 10 to 15 seconds | 1 to 2 x control |
| Quick value | 70 to 130 % | 10 to 20 % |
| Thrombin clotting time | 70 to 120 seconds | 150 to 600 seconds depending on indication for anticoagulation |
| Thrombotest | 100% | 10 to 20 % |