Trevor Baglin
Synopsis
Occlusive vascular disease is a major cause of morbidity and mortality. There is now a better understanding of the mechanisms by which the haemostatic system maintains blood in a fluid state within vessels yet forms a solid plug when a vessel is breached, and of the ways in which these processes may be altered by drugs to prevent or reverse (lyse) thrombosis.
• Coagulation system: the mode of action of drugs that promote coagulation and that prevent it (anticoagulants) and their uses.
• Fibrinolytic system: the mode of action of drugs that promote fibrinolysis (fibrinolytics) and their uses to lyse arterial and venous thrombi (thrombolysis).
• Platelets: the ways that drugs that inhibit platelet activity benefit arterial disease.
Introduction
It is essential that blood remains fluid within the circulation but clots at sites of vascular injury. The haemostatic system maintains the integrity of the vascular tree through a complex network of cellular, ligand–receptor and enzymatic interactions. In normal circumstances there is an equilibrium between the natural coagulant–anticoagulant and fibrinolytic–antifibrinolytic systems. In response to endothelial damage, there is rapid molecular switching to thrombin generation and antifibrinolysis at the site of injury, and enhanced natural anticoagulant activity and fibrinolytic activity at areas of adjacent healthy intact endothelium. Regulation of the haemostatic network in such a way results in localised thrombus formation with minimal loss of vascular patency.
Pathological disruption of the network results in thrombosis or bleeding, or both; the extreme example of haemostatic pathology is a complete breakdown as occurs in disseminated intravascular coagulation (DIC). Drugs that modulate the haemostatic system are valuable in the management of bleeding and thrombotic disorders. Drugs are classified according to the component of the system they affect and their perceived primary mode of action.
The coagulation system
Coagulation initiates with tissue factor (TF), a cell membrane protein that binds activated factor VII (indicated by adding the letter ‘a’, i.e. factor VIIa). Although there is a small fraction of circulating factor VII in the activated state, it has little or no enzymatic activity until it is bound to TF. Most non-vascular cells express TF in a constitutive1 fashion, whereas de novo TF synthesis can be induced in monocytes and damaged endothelial cells. Injury to the arterial or venous wall exposes extravascular TF-expressing cells to blood. Lipid-laden macrophages in the core of atherosclerotic plaques are particularly rich in TF, thereby explaining the propensity for thrombus formation at sites of plaque disruption. Once bound to TF, factor VIIa activates factor IX and factor X (to IXa and Xa, respectively), leading to thrombin generation and clot formation (Fig. 29.1).
Fig. 29.1 The blood coagulation network (see text).
The classical view of blood coagulation with separate ‘extrinsic’ and ‘intrinsic’ pathways initiated by either TF or contact with an anionic surface does not reflect physiological coagulation. It is now evident that coagulation does not occur as linear sequential enzyme activation pathways but rather by a network of simultaneous interactions, which undergo regulation and modulation during the thrombin generation process itself.
In the current model, blood coagulation starts with a transient release of tissue factor by damaged endothelium, resulting in the formation of sub-nanomolar amounts of thrombin via TF/VIIa-driven Xa formation (extrinsic-tenase). The initial thrombin activity is necessary to prime the system for a full thrombin explosion. Tissue factor pathway inhibitor (TFPI) rapidly shuts down this priming pathway and the full thrombin explosion is then dependent on factor IXa-driven Xa formation. Factor IXa-driven Xa formation (intrinsic-tenase) is amplified by the thrombin explosion itself, as thrombin forms a positive feedback loop by activating factor XIa (not shown in Fig. 29.1), which converts more IX to IXa.
Thrombin converts soluble fibrinogen into insoluble fibrin monomers, which spontaneously polymerise to form the fibrin mesh that is then stabilised and cross-linked by activated factor XIII (factor XIIIa), a thrombin-activated transglutaminase. Thrombin amplifies its own generation by:
• feedback activation of factor V and factor VIII
• activating platelet-bound factor XI, thereby leading to further factor Xa generation
• activating cells that provide the phospholipid surface required for assembly of the macromolecular enzymatic complexes.
Procoagulant drugs
Vitamin K
Vitamin K (‘Koagulation’ vitamin) is essential for normal coagulation. It occurs naturally in two forms. Vitamin K1 (phylloquinone) is widely distributed in plants and K2 includes vitamin synthesised in the alimentary tract by bacteria, e.g. Escherichia coli (menaquinones). Leafy green vegetables are a good source of vitamin K1. Bile is required for the absorption of the natural forms of vitamin K, which are fat soluble. The storage pool of vitamin K is modest and can be exhausted in 1 week, although gut flora will maintain suboptimal production of vitamin K-dependent proteins. A synthetic analogue, menadione(K3), is water soluble.
Vitamin K is necessary for the final stage in the synthesis of coagulation proteins in the liver: the procoagulant factors II (prothrombin), VII, IX and X, and anticoagulant regulatory proteins, proteins C and S. The vitamin allows γ-carboxylation of glutamic acid residues in their structure; this permits calcium to bind to the molecule, mediating the conformational change required for enzymatic activity, and binding to negatively charged phospholipid surfaces, e.g. platelets. Membrane binding is required for full enzymatic potential.
During γ-carboxylation of the proteins, the reduced and active form of vitamin KH2 converts to an epoxide, an oxidation product. Subsequently vitamin K epoxide reductase converts oxidised vitamin K back to the active vitamin K, i.e. there exists an interconversion cycle between vitamin K epoxide and reduced vitamin K (Fig. 29.2).
Fig. 29.2 The vitamin K cycle.
When the vitamin is deficient or where drugs inhibit its action, the coagulation proteins produced are unable to associate with calcium in order to form the necessary three-dimensional configuration and associated membrane-binding properties that are required for full enzymatic activity. Their physiologically critical binding to membrane surfaces fails to occur, and this impairs the coagulation mechanism. These proteins are called ‘proteins induced in vitamin K absence’ or PIVKAs.
Oral vitamin K antagonists exert an anticoagulant effect by interrupting the vitamin K cycle. There are two classes of drugs: the coumarins, including warfarin and acenocoumarol, and the indanediones such as phenindione. The anticoagulant effect of oral vitamin K antagonists is expressed as the International Normalised Ratio (INR).
Vitamin K deficiency may arise from:
• dietary deficiency
• bile failing to enter the intestine, e.g. obstructive jaundice or biliary fistula
• malabsorption syndromes, e.g. coeliac disease, or after extensive small intestinal resection
• reduced alimentary tract flora, e.g. in newborn infants and rarely after broad-spectrum antibiotics.
The following preparations of vitamin K are available:
Phytomenadione
(Konakion), the naturally occurring fat-soluble vitamin K1, acts within about 12 h and should reduce the anticoagulant effect of warfarin within 24–48 h when given orally in a dose of 5–10 mg. The intravenous formulation will begin to reverse a vitamin K-deficient coagulopathy within 6 h in a patient with normal liver function. It should be administered slowly to reduce the risk of an anaphylactoid reaction with facial flushing, sweating, fever, chest tightness, cyanosis and peripheral vascular collapse. Phytomenadione may also be given orally using either tablet formulations or the preparation for intravenous use. Oral administration will result in a slower and often incomplete correction of coagulopathy. Otherwise phytomenadione may be given intramuscularly, subcutaneously or orally. The preferred route depends on the degree of coagulopathy and urgency of correcting the haemorrhagic tendency. The intramuscular route should not be used if the INR is increased, as local intramuscular haemorrhage may be induced; subcutaneous absorption is variable and, despite the risk of allergic reaction, the intravenous route ensures rapid delivery.
Menadiol
sodium phosphate (vitamin K3), the synthetic analogue of vitamin K, being water soluble, is preferred in intestinal malabsorption or in states in which bile flow is deficient. The main disadvantage is that it takes 24 h to act, but its effect lasts for several days. The dose is 5–40 mg daily, orally. Menadiol sodium phosphate in moderate doses causes haemolytic anaemia and, for this reason, neonates should not receive it, especially those that are deficient in glucose 6-phosphate dehydrogenase; their immature livers are unable to cope with the heavy bilirubin load and there is danger of kernicterus.
Fat-soluble analogues of vitamin K that are available in some countries include acetomenaphthone and menaphthone.
Vitamin K is used to treat the following:
• Haemorrhage or threatened bleeding due to the coumarin or indanedione anticoagulants. Phytomenadione is preferred for its more rapid action; dosage regimens vary according to the degree of urgency and the original indication for anticoagulation.
• Haemorrhagic disease of the newborn, which develops usually between 2 and 7 days, and late haemorrhagic disease that presents at 6–7 months. Prophylaxis is recommended during the period of vulnerability with vitamin K (phytomenadione, as Konakion) 1 mg by single i.m. injection at birth. Alternatively, give vitamin K by mouth as two doses of a colloidal (mixed micelle) preparation of phytomenadione in the first week. Breast-fed babies should receive a further 2 mg at 1 month of age. Formula-fed babies do not need this last supplement as the formula contains vitamin K. Fears that intramuscular vitamin K might cause childhood cancer have been dispelled.
• Intestinal malabsorption syndromes; menadiol sodium phosphate should be used as it is water soluble.
Coagulation factor concentrates
Bleeding due to deficiency of specific coagulation factors is treated by either elevating the deficient factor, e.g. treatment of mild factor VIII deficiency with desmopressin (see below), or replacement of the missing factor. Recombinant factor VIII and IX are now available in some countries for patients with congenital deficiency of these factors. For patients with rare coagulation factor deficiencies or multiple acquired deficiencies (liver disease, massive blood loss with dilutional coagulopathy or DIC), replacement therapy requires human-derived fresh frozen plasma (FFP) or factor concentrates containing factors II, VII, IX and X (Beriplex, Octaplex).
Solvent–detergent virally inactivated FFP (Octaplas) is currently given to selected patients in the UK, for example those with rare bleeding disorders and patients with thrombotic thrombocytopenic purpura who require repeated exposure to FFP. Methylene blue-treated single donor unit FFP is also available as a virally inactivated product.
Use of coagulation factor concentrates
Management of haemophilia A and haemophilia B (deficiency of factor VIII and IX, respectively) requires special expertise but the following points are notable:
• Superficial haemorrhage sometimes responds to local pressure.
• Minor bleeding can arrest with plasma factor concentrations of 0.25–0.30 units/mL, but severe bleeding requires at least 0.50 units/mL and surgical procedures or life-threatening haemorrhage require 0.75–1.00 units/mL by infusion of factor concentrate.
• In haemophilia A, factor VIII concentrate (t½ 8–12 h) is used for bleeding that is more than minor. Repeat dosing is necessary to maintain haemostatic levels.
• Factor IX (t½ 18–24 h) is used for bleeding that is more than minor in haemophilia B (Christmas disease).
• The speed of recovery of the affected joint or resolution of a haematoma determines the duration of therapy. After surgery, 7–14 days of replacement therapy is required to ensure adequate wound healing and to prevent secondary haemorrhage.
• Primary prophylaxis with factor concentrates two or three times weekly at doses sufficient to keep the factor above 0.01–0.02 units/mL reduces bleeding and hence the severity of chronic haemophilic arthropathy.
FEIBA is a human donor-derived factor concentrate for patients with inhibitory antibodies to factor VIII or IX. It contains a mixture of coagulation factors and produces thrombin generation even in the presence of inhibitors to factor VIII or IX.
Recombinant factor VIIa (NovoSeven) is effective for patients with inhibitory antibodies to factor VIII or IX or deficiency of factor VII. A pure synthetic activated coagulation factor, it generates thrombin even in the presence of inhibitors to factor VIII or IX. Owing to its short duration of action, three doses (90 μg/kg) are usually necessary at 2-h intervals. Alternatively a single large dose can be used (270 μg/kg).
Desmopressin (DDAVP)
Desmopressin is a vasopressin analogue that increases the plasma concentrations of factor VIII and von Willebrand factor, and directly activates platelets. DDAVP is usually given subcutaneously or intravenously, but unwanted effects (headache, flushing and tachycardia) are less severe after subcutaneous use. A concentrated form is available for intranasal use.
DDAVP is useful for treating patients with mild haemophilia A and von Willebrand's disease, especially for short-term therapy. For dental extraction, a single injection of 0.3 micrograms/kg 1–2 h before surgery, combined with the oral antifibrinolytic drug, tranexamic acid, for 5–7 days after the procedure (see Antifibrinolytic drugs, p. 492), will produce normal haemostasis and prevent secondary haemorrhage.
Patients with Type 3 (severe) or some forms of Type 2 von Willebrand's disease (VWD) and some with Type 1 with severe haemorrhage, or patients who require major surgery, need replacement therapy with human-derived intermediate-purity factor VIII concentrate known to contain high molecular weight von Willebrand factor (vWF) multimers. The larger multimers are required for normal haemostatic function. Cryoprecipitate that is rich in factor VIII and vWF is not virally inactivated and should not be used for patients with VWD or mild to moderate factor VIII deficiency.
DDAVP shortens the bleeding time in patients with renal or liver failure.
Adverse effects
Water retention and hyponatraemia may complicate therapy and very young children (< 1 year) should not receive DDAVP. Fluid intake should not exceed 1 L in the 8 h following treatment and with repeated doses the plasma sodium should be monitored. Tachyphylaxis (progressively diminishing response to the same dose) can occur.
Other agents
Adrenaline/epinephrine
is effective as a topical agent for epistaxis, applied in ribbon gauze that is packed into the nostril, haemorrhage being arrested by local vasoconstriction.
Fibrin glue
consists of fibrinogen and thrombin contained in two syringes, the tips of which form a common port that allows delivery of the two components to a bleeding point where fibrinogen converts to fibrin at a rate determined by the concentration of thrombin. Fibrin glue can be used to secure surgical haemostasis, e.g. on a large raw surface, and to prevent external oozing of blood in patients with haemophilia (see also above).
Sclerosing agents
produce inflammation and thrombosis in veins to induce permanent obliteration, e.g. ethanolamine oleate injection, sodium tetradecyl sulphate (given intravenously for varicose veins) and oily phenol injection (given submucosally for haemorrhoids). Local reactions and tissue necrosis may occur.
Anticoagulant drugs
Anticoagulant drugs act principally to reduce the activity of thrombin, the enzyme that is mainly responsible for blood clotting. The following discussion will show that drugs do so by:
• limiting thrombin generation, either as a result of inhibiting other proteases (clotting factors) involved in its generation or by reducing the activity of zymogens (the precursor inactive forms of the enzymes); or
• inhibiting (neutralising) thrombin activity, either directly or indirectly, depending on whether or not they activate the natural serpin-dependent anticoagulant pathway.2
Oral vitamin K antagonists (VKA)
Warfarin and other oral vitamin K antagonists (VKA) reduce the activity of zymogens.
Pharmacokinetics
Warfarin is readily absorbed from the gastrointestinal tract and, like all the current oral anticoagulants, is more than 90% bound to plasma proteins. Metabolism in the liver terminates its action. Warfarin (t½ 36 h) is a racemic mixture of approximately equal amounts of two isomers, S (t½ 27 h) and R (t½ 40 h) warfarin, i.e. it is in effect two drugs. S warfarin is four times more potent than R warfarin. The isomers respond differently to drugs that interact with warfarin.
Pharmacodynamics
During the γ-carboxylation of factors II (prothrombin), VII, IX and X (and also the natural anticoagulant proteins C and S), active vitamin K (KH2) is oxidised to an epoxide and must be reduced by the enzymes vitamin K epoxide reductase and vitamin K reductase to become active again (see the vitamin K cycle, p. 483). Coumarins3 are structurally similar to vitamin K and competitively inhibit vitamin K epoxide reductase and vitamin K reductase, so limiting availability of the active reduced form of the vitamin to form coagulant (and anticoagulant) proteins. The overall result is a shift in haemostatic balance in favour of anticoagulation because of the accumulation of clotting proteins with absent or decreased γ-carboxylation sites (PIVKAs).4
This shift does not take place until functioning vitamin K-dependent proteins, made before the drug was administered, have been cleared from the circulation. The process occurs at different rates for individual coagulation factors (VII t½ 6 h, IX and X t½ 18–24 h, prothrombin t½ 72 h). The anticoagulant proteins C and S have a shorter t½ than the pro-coagulant proteins and their more rapid decline in concentration may create a transient hypercoagulable state. This can be dangerous in individuals with inherited protein C or S deficiency who may develop thrombotic skin necrosis during initiation of oral anticoagulant therapy with vitamin K antagonists. Anticoagulation with heparin until the effect of warfarin is well established reduces the risk of skin necrosis when rapid induction of anticoagulation is required.
The therapeutic anticoagulant effect of warfarin develops only after 4–5 days. Furthermore, the INR does not reliably reflect anticoagulant protection during this initial phase, as the vitamin K-dependent factors diminish at different rates and the INR is particularly sensitive to the level of factor VII, which is not a principal determinant of thrombotic or bleeding risk.
Warfarin is the oral anticoagulant of choice, for it is reliably effective and has the lowest incidence of adverse effects. Because of the delay in onset of anticoagulant effect with oral vitamin K antagonists (VKAs) there is a need for an immediate-acting anticoagulant, such as a heparin, in the first few days of therapy if rapid anticoagulation is required.
The response to warfarin, and other coumarins, varies within and between individuals and therefore regular monitoring of dose is essential. The pharmacokinetics (absorption and metabolism) and pharmocodynamics (haemostatic effect) are influenced by vitamin K intake and absorption, by heritable functional polymorphisms affecting metabolism such as P450 CYP 2 C9 polymorphisms, by rates of synthesis and clearance of coagulation proteins, and by drugs. The effectiveness of anticoagulant therapy with oral VKAs is determined by the INR, a standardised method derived from the prothrombin time that permits comparison between different laboratories.
Dose
There is much inter-individual variation in dose requirements. It is usual to initiate therapy with 10-mg doses, depending on the daily INR, with the maintenance dose then adjusted according to the INR using an established protocol.
The level of anticoagulation matches the perceived risk of thrombosis (see below). The target INR for deep vein thrombosis (DVT) is 2.5 (typical range 2.0–3.0).
Adverse effects
The major complication of treatment with warfarin is bleeding. As well as a risk of haemorrhage after trauma or surgery, spontaneous bleeding may occur. Each year a patient is on treatment there is a 1 in 20 (5%) risk of minor haemorrhage. The annual risk of major bleeding is 1 in 100, of which one-quarter are fatal. The risk of bleeding relates to the INR, not the dose of warfarin: the higher the INR, the greater the chance of bleeding. The risk of over-anticoagulation increases with intercurrent illness and interaction with other drugs, and is more likely in patients whose anticoagulant control is unstable. Therefore, it is essential to:
• maintain as stable a level of anticoagulation as possible
• adopt the lowest effective target INR
• educate patients about risk, particularly that associated with additional drug use.
Warfarin is a small molecule that crosses the placenta and can produce harmful effects in the developing fetus.
Warfarin embryopathy develops only after exposure to oral anticoagulant during the first trimester of pregnancy. The most common feature is chondrodysplasia punctata, characterised by abnormal cartilage and bone formation (with stippling of epiphyses visible on radiography) in vertebrae and femur, and the bones of the hands and feet during infancy and early childhood; these disappear with age (warfarin is not the only cause of this abnormality). Other less common skeletal abnormalities include nasal hypoplasia and hypertelorism (wide-set eyes).
Bleeding into the central nervous system is a danger throughout pregnancy but particularly at the time of delivery.
As a consequence of the above, warfarin is contraindicated in the first 6–12 weeks of pregnancy and should be replaced by heparin before the anticipated date of delivery, as the action of the latter drug can be terminated rapidly prior to the birth.
Withdrawal of oral anticoagulant therapy
The balance of evidence is that abrupt, as opposed to gradual, withdrawal of oral anticoagulant therapy does not of itself add to the risk of thromboembolism, for renewed synthesis of functional vitamin K-dependent clotting factors takes several days.
Reversal of anticoagulation
can be gradual or rapid depending on the circumstances, i.e. from undue prolongation of INR to frank bleeding. Vitamin K 5–10 mg is usually adequate for complete reversal, oral administration being less rapid than intravenous. Immediate reversal is more readily achieved with a factor concentrate than fresh frozen plasma. Detailed guidance on corrective therapy in relation to the degree of over-anticoagulation is available, e.g. from the British National Formulary.
Drug interactions
Oral anticoagulant control must be precise for safety and efficacy. If a drug that alters the action of warfarin is essential, monitor the INR frequently and adjust the dose of warfarin during the period of institution of the new drug until a new stable therapeutic dose of warfarin results; careful monitoring is also needed on withdrawal of the interacting drug.
Analgesics. Avoid, if possible, non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin because of their irritant effect on gastric mucosa and action on platelets. Paracetamol is acceptable but doses above 1.5 g/day may raise the INR. Dextropropoxyphene inhibits warfarin metabolism, and compounds that contain it, e.g. co-proxamol, should be avoided. Codeine, dihydrocodeine and combinations with paracetamol, e.g. co-dydramol, are preferred. Concomitant use of misoprostol with a NSAID may reduce the risk of gastric bleeding and a selective cyclo-oxygenase (COX)-2 inhibitor may be associated with a lower bleeding risk in patients taking oral anticoagulants.
Antimicrobials. Aztreonam, cefamandole, chloramphenicol, ciprofloxacin, co-trimoxazole, erythromycin, fluconazole, itraconazole, ketoconazole, metronidazole, miconazole, ofloxacin and sulphonamides (including co-trimoxazole) increase anticoagulant effect by mechanisms that include interference with warfarin or vitamin K metabolism. Rifampicin and griseofulvin induce relevant hepatic enzymes and accelerate warfarin metabolism, reducing its effect. Intensive broad-spectrum antibiotics, e.g. eradication regimens for Helicobacter pylori, may increase sensitivity to warfarin by reducing the intestinal flora that provide vitamin K.
Anticonvulsants. Carbamazepine, phenobarbital and primidone accelerate warfarin metabolism (by enzyme induction); the effect of phenytoin is variable. Clonazepam and sodium valproate are safe.
Antiarrhythmics. Amiodarone, propafenone and possibly quinidine potentiate the effect of warfarin and dose adjustment is required, but atropine, disopyramide and lidocaine do not interfere.
Antidepressants. Serotonin-reuptake inhibitors may enhance the effect of warfarin, but tricyclics may be used.
Gastrointestinal drugs. Avoid cimetidine and omeprazole, which inhibit the clearance of R warfarin, and sucralfate, which may impair its absorption. Ranitidine may be used. Most antacids are safe.
Lipid-lowering drugs. Fibrates, and some statins, enhance anticoagulant effect. Avoid colestyramine as it may impair the absorption of both warfarin and vitamin K.
Sex hormones and hormone antagonists. The hormone antagonists danazol, flutamide and tamoxifen enhance the effect of warfarin.
Sedatives and anxiolytics. Benzodiazepines may be used.
Uses of oral VKA
Oral vitamin K antagonist drugs are used to prevent and treat venous thrombosis and pulmonary embolus, and to prevent arterial thromboemboli in patients with atrial fibrillation or cardiac disease, including mechanical heart valves. The British Society for Haematology publishes recommended target INRs and duration of therapy for different thrombotic disorders, available at http://www.bcshguidelines.com. The following are general indications:
• Target INR 2.5 is appropriate for treatment of DVT; pulmonary embolism (PE); systemic embolism; prevention of venous thromboembolism in myocardial infarction; mitral stenosis with embolism; transient ischaemic attacks; atrial fibrillation; mechanical prosthetic aortic valves.
• Target INR 3.5 is preferred for recurrent DVT and PE when already on warfarin with target of 2.5, arterial disease and some mechanical prosthetic mitral valves.
• At least 6 weeks’ anticoagulation is recommended after calf vein thrombosis and at least 3 months after proximal DVT or PE. For patients with temporary risk factors and a low risk of recurrence, 3 months of treatment may be sufficient. For patients with idiopathic venous thromboembolism or permanent risk factors, at least 6 months’ anticoagulation is usual.
Surgery in patients receiving oral VKA
Elective surgery
Warfarin is withdrawn 5 days before the operation and recommenced when the patient resumes oral intake; heparin (low molecular weight heparin (LMWH) or unfractionated heparin (UFH); see below) provides cover in the intervening period. In patients with mechanical mitral prosthetic valves, LMWH or UFH is added when the INR is subtherapeutic.
Emergency surgery
Proceed as for bleeding (above).
Dental extractions
Anticoagulation may continue for patients whose INR is less than 4.0. The INR is measured no more than 72 h before the procedure to ensure that the INR will be less than 4.0 on the day of the extraction.
Other vitamin K antagonists
Acenocoumarol (nicoumalone) is similar to warfarin but seldom used; the kidney eliminates it mainly in unchanged form.
Indanedione anticoagulants are rarely used because of allergic reactions unrelated to coagulation; phenindione is still available.
Oral direct thrombin and factor Xa inhibitors
Dabigatran
Dabigatran is a small molecule (mol. wt. 471) direct thrombin inhibitor (DTI). Dabigatran etexilate is an oral prodrug of the active compound dabigatran. Dabigatran is a direct specific competitive inhibitor of free and fibrin-bound thrombin. It binds to the active site of thrombin with high affinity (Kd 7 × 10-10 M). Absorption of the prodrug is rapid (C max < 4 h) and the half life of dabigatran is 12–14 h in healthy volunteers and 14–17 h in patients undergoing major orthopaedic surgery. The active compound is not metabolised and is eliminated by renal excretion with 85% of an administered dose detectable in urine. Clearance is significantly prolonged when the glomerular filtration rate is less than 50 mL/min. There is no antidote. There is a significant potentiating drug interaction with amiodarone and other drugs. The drug is approved in many countries for prevention of venous thrombosis in patients undergoing hip or knee replacement.
Rivaroxaban
Rivaroxaban is a small molecule (mol. wt. 436) direct competitive inhibitor of factor Xa and limits thrombin generation in a dose dependent manner. It binds to the active site of factor Xa with high affinity (Kd 3 × 10-10 M). Absorption of drug is rapid (C max < 4 hours) with a half-life of 7–11 h. Rivaroxaban is metabolised in the liver but can be used in patients with liver disease if there is no coagulopathy. Renal excretion is minimal and there is no accumulation of drug when the glomerular filtration rate is above 15 mL/min. There is no antidote. There are significant potentiating drug interactions with protease inhibitors used to treat HIV infection and with antifungals. The drug is approved in many countries for prevention of venous thrombosis in patients undergoing hip or knee replacement.
Parenteral anticoagulants
Heparin
A medical student, J McLean, working at Johns Hopkins Medical School in 1916, discovered heparin. Seeking to devote 1 year to physiological research, he was set to study ‘the thromboplastic (clotting) substance in the body’. He found that extracts of brain, heart and liver accelerated clotting but that activity deteriorated during storage. To his surprise, the extract of liver that he had kept longest not only failed to accelerate but actually retarded clotting. His personal account states:
After more tests and the preparation of other batches of heparophosphatide, I went one morning to the door of Dr. Howell's office, and standing there (he was seated at his desk), I said ‘Dr. Howell, I have discovered antithrombin’. He was most skeptical. So I had the Deiner, John Schweinhant, bleed a cat. Into a small beaker full of its blood, I stirred all of a proven batch of heparophosphatides, and I placed this on Dr. Howell's laboratory table and asked him to call me when it clotted. It never did clot. [It was heparin]5
Heparin is a sulphated mucopolysaccharide that is found in the secretory granules of mast cells and is prepared commercially from porcine intestinal mucosa to give preparations that vary in molecular weight from 3000 to 30 000 Da (average 15 000 Da). It is the strongest organic acid in the body and in solution carries an electronegative charge. The low molecular weight heparins (LMWH, mean mol. wt. 4000–6500 Da) are prepared from standard unfractionated (UF) heparin by a variety of chemical techniques. Commercial preparations contain different fractions and display different pharmacokinetics. Some currently available in the UK include bemiparin, dalteparin, enoxaparin, reviparin and tinzaparin.
Pharmacokinetics
Heparin is poorly absorbed from the gastrointestinal tract and is given intravenously or subcutaneously; once in the blood its effect is immediate. Heparin binds to several plasma proteins, to endothelial cells, and is taken up by reticuloendothelial cells; the kidney excretes a proportion. Because of these different mechanisms, elimination of heparin from the plasma involves a combination of zero- and first-order processes. The result is that the plasma biological effect t½ alters disproportionately with dose, being 60 min after 75 units/kg and increasing to 150 min after 400 units/kg.
LMW heparins are less protein bound and have a predictable dose–response profile when administered subcutaneously or intravenously. They also have a longer t½ than standard heparin preparations.
Pharmacodynamics
Heparin depends for its anticoagulant action on the presence in plasma of a single-chain glycoprotein called antithrombin (formerly antithrombin III), a naturally occurring inhibitor of activated coagulation proteases (factors) that include thrombin, factor Xa and factor IXa. Heparin binds to antithrombin, inducing a conformational change that leads to rapid inhibition of the proteases of the coagulation pathway. In the presence of heparin, antithrombin becomes approximately 1000-fold more active and inhibition is essentially instantaneous. Following destruction of the proteases, the affinity of antithrombin for heparin falls; heparin then dissociates from the antithrombin–protease complex and catalyses further antithrombin–protease interactions.
Factor Xa is critical to thrombin generation (see Fig. 29.1) and heparin has the capacity to inhibit factor Xa in small quantities by virtue of a specific pentasaccharide sequence. This provides the rationale for using low-dose subcutaneous heparin to prevent thrombus formation.
LMWHs inhibit factor Xa at a dose similar to that for UFH, but have much less antithrombin activity, the principal action of conventional heparin. Fibrin formed in the circulation binds to thrombin and protects it from inactivation by the heparin–antithrombin complex; this may provide a further explanation for the higher doses of heparin needed to stop extension of a thrombus than to prevent it.
Fondaparinux is a synthetic pentasaccharide that inhibits factor Xa by an antithrombin-dependent mechanism. Fondaparinux, has a molecular weight of 1728. Its specific anti-Xa activity is higher than that of LMWH and its half-life after subcutaneous injection is longer than that of LMWH. Based on its almost complete bioavailability after subcutaneous injection, lack of variability in anticoagulant response and long half-life, fondaparinux can be administered subcutaneously once daily in fixed doses without coagulation monitoring. Fondaparinux is contraindicated in patients with renal insufficiency (CrCl < 30 mL/min). It is used used for prevention and treatment of venous thromboembolism in the same way as traditional LMWHs. The risk of HIT(T) (see below) is lower, but the risk of bleeding may be greater than that associated with LMWHs.
Monitoring heparin therapy
Control of standard heparin therapy is by the activated partial thromboplastin time (APTT), the target therapeutic range being 1.5–2.5 times the control. An alternative method is to measure the plasma concentration of heparin by anti-Xa assay. Therapeutic amounts of LMWH do not prolong the APTT and, because the pharmacokinetics are predictable, a safe and effective dose can be calculated without laboratory monitoring, using an algorithm that is adjusted for body-weight.
Adverse effects
Bleeding is the main acute complication of heparin therapy. Patients with impaired hepatic or renal function, with carcinoma, and those aged over 60 years are most at risk. An APTT ratio greater than 3 is associated with an increased risk of bleeding.
Heparin-induced thrombocytopenia (HIT), some times accompanied by thrombosis (HIT/T), is due to an autoantibody against heparin in association with platelet factor 4, which activates platelets. It occurs most commonly with heparin derived from bovine lung and is more common with UFHs than with LMWHs. Suspect HIT in any patient in whom the platelet count falls by 50% or more after starting heparin. It usually occurs after 5 days or more of heparin exposure (or sooner if the patient has previously been exposed to heparin). Thrombosis occurs in less than 1% of patients treated with LMWHs but is associated with a mortality and limb amputation rate in excess of 30%. Patients with HIT/T should discontinue all heparin (UF and LMW) and receive an alternative thrombin inhibitor, such as danaparoid or lepirudin. Warfarin should not be commenced until there is adequate anticoagulation with one of these agents and the platelet count has returned to normal.
Osteoporosis may complicate long-term heparin exposure. It is dose related and most frequently observed during pregnancy. The relative risk between LMWHs is not yet established but it appears to be less than with UFHs.
Hypersensitivity reactions and skin necrosis (similar to that seen with warfarin) occur but are rare. Transient alopecia may occur.
Heparin reversal
Protamine, a protein obtained from fish sperm, immediately reverses the anticoagulant action of heparin. It is as strongly basic as heparin is acidic, which explains its rapid action. The effect of UFH is short lived, and reversal with protamine sulphate is seldom required except after extracorporeal perfusion for heart surgery. Protamine sulphate, 1 mg by slow intravenous injection, neutralises 80–100 units UFH. The quantity of heparin given and its expected t½determine the amount required but the maximum must not exceed 50 mg. Protamine itself has some anticoagulant effect and overdosage is to be avoided. Its effectiveness in patients treated with LMWH is unknown.
Use of heparin
Treatment of established venous thromboembolism
Patients with acute venous thromboembolism are treated safely and effectively with LMWH as outpatients. Large-scale studies demonstrate that outpatient treatment of acute DVT with unmonitored, body-weight-adjusted LMWH is as safe and effective as inpatient treatment with adjusted-dose i.v. UFH. Further trials confirm the safety and efficacy of LMWH therapy in acute PE.
The traditional regimen for standard UFH is a bolus i.v. injection of 5000 units (or 10 000 units in major PE) followed by a constant rate i.v. infusion of 1000–2000 units/h. The APTT should be measured 6 h after starting therapy and the administration rate adjusted to keep it in the optimal therapeutic range of 1.5–2.5; this usually requires daily measurement of APTT.
Coincident with commencing heparin, patients usually start taking an oral vitamin K antagonist, typically warfarin in the UK. The INR is monitored and loading doses of VKA are given according to a validated loading protocol in order to minimise the risk of over-anticoagulation and bleeding. Ideally the INR should be measured daily during the first 4 days of loading with a VKA; guidance is available at http://www.bcshguidelines.com.
Prevention of venous thromboembolism
LMWHs are preferred for perioperative prophylaxis because of their convenience. They are as effective and safe as UFH at preventing venous thrombosis. Once-daily subcutaneous administration suffices, as their duration of action is longer than that of UFH and no laboratory monitoring is required.
If UFH is used, 5000 units should be given subcutaneously every 8 or 12 h without monitoring (this dose does not prolong the APTT), or in pregnancy 5000–10 000 units subcutaneously every 12 h with monitoring (except for pregnant women with prosthetic heart valves, for whom specialist monitoring is needed).
Cardiac disease
LMWHs are at least as effective as standard heparin for unstable angina. Patients undergoing angioplasty may also receive LMWHs.
Heparin is used to reduce the risk of venous thromboembolism, and the size of emboli from mural thrombi following acute myocardial infarction.
Peripheral arterial occlusion
In the acute phase following thrombosis or arterial embolism, heparin may prevent extension of a thrombus and hasten its recanalisation. Long-term antithrombotic therapy for patients with ischaemic peripheral vascular disease generally requires specific antiplatelet therapy (see p. 494).
Other anticoagulant drugs
Danaparinoid sodium is a mixture of several types of non-heparin glycosaminoglycans extracted from pig intestinal mucosa (84% heparan sulphate). It is an indirect thrombin inhibitor and effective for the treatment of DVT, prophylaxis in high-risk patients and treatment of patients with heparin-associated thrombocytopenia (HIT/T).
Hirudin, a polypeptide originally isolated from the salivary glands of the medicinal leech Hirudo medicalis, is now produced by recombinant technology. It forms an almost irreversible complex with thrombin, causing a potent and specific inhibition of its action. The kidneys are principally responsible for clearing hirudin and the t½ is 60 min after intravenous administration. No antidote is available for a bleeding patient. It has been used in patients with HIT, thromboprophylaxis in elective hip arthroplasty, unstable angina and myocardial infarction.
Bivalirudin is a bivalent direct thrombin inhibitor produced as a 20-amino-acid recombinant polypeptide. It is a relatively low-affinity inhibitor of thrombin and may thus present a lower bleeding risk, but clinical advantage remains to be shown.
Argatroban, a carboxylic acid derivative, binds non-covalently to the active site of thrombin and is an effective alternative to heparin in patients with HIT.
Anticoagulant drugs under development
Dabigatran and rivaroxaban are likely to soon be approved for treatment of venous thrombosis, prevention of stroke in patients with atrial fibrillation and treatment of acute coronary syndrome. Other direct inhinbitors are currently being evaluated. Apixaban is a direct Xa inhibitor that has completed phase III studies and is likely to soon be approved for prevention of venous thrombosis in patients undergoing hip and knee replacement and thereafter treatment of venous thrombosis, prevention of stroke in patients with atrial fibrillation and treatment of acute coronary syndrome.
Idraparinux is a hypersulphated derivative of fondaparinux with an elimination half-life about five to six times longer (an increase from fondaparinux's 17 h to approximately 80 h), which means that the drug should only need to be injected once a week. A biotinylated form which can be rapidly removed from the circulation by injection of avidin is currently being investigated in clinical trials.
Other highly selective agents in clinical development include a variety of blockers of: (1) factor IXa (by active site-blocked factor IXa or monoclonal antibodies); (2) the factor VIIa/tissue factor pathway (with recombinant tissue factor pathway inhibitor, TFPI, the analogue of the natural inhibitor).
Novel delivery systems, using synthetic amino acids (e.g. SNAC) to facilitate absorption, may allow the oral administration of unfractionated or LMW heparins.
Fibrinolytic (thrombolytic) system
The system acts to remove intravascular fibrin, thereby restoring blood flow.
Plasminogen activators
that convert plasminogen to plasmin initiate the process. A trypsin-like protease, plasmin, then degrades fibrin into soluble fibrin degradation products (Fig. 29.3).
Fig. 29.3 The blood fibrinolytic system. tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator.
Two immunologically distinct plasminogen activators are found in blood, namely tissue-type (tPA) and urokinase-type (uPA), both of which are synthesised and released from endothelial cells. Intravascular plasminogen activation is initiated by tPA. In this process, plasminogen and tPA bind to fibrin and the enzymatic activity of tPA is enhanced by fibrin. The result is that plasmin formation takes place only on the fibrin surface and not generally in the circulation, where widespread defibrination would occur and compromise the whole coagulation mechanism. tPA is the plasminogen activator used for the treatment of coronary occlusion.
Plasminogen activator inhibitors
The most important is endothelial cell-derived type 1 plasminogen activator inhibitor (PAI-1), which blocks the action of tPA. Another inhibitor, α2-antiplasmin, rapidly complexes with and inactivates freeplasmin. Fibrin-bound plasmin is relatively protected from inactivation so that fibrinolysis can occur despite physiological plasma concentrations of this inhibitor.
An enzyme, known as thrombin-activatable fibrinolysis inhibitor (TAFI), attenuates fibrinolysis by cleaving carboxyl-terminal lysine residues from fibrin, the removal of which decreases plasminogen and plasmin binding to fibrin, retarding the lytic process. TAFI thus serves as a link between coagulation and fibrinolysis.
Drugs that promote fibrinolysis
An important application of fibrinolytic drugs has been to dissolve thrombi in acutely occluded coronary arteries, thereby restoring blood flow to ischaemic myocardium and improving prognosis. The approach is to give a plasminogen activator by intravenous infusion or bolus injection in order to increase the formation of the fibrinolytic enzyme plasmin.
Recombinant thrombolytic proteins can be re-engineered to prolong t½ and possibly reduce the induced systemic fibrinolytic state. Current drugs possess a broadly equivalent risk of inducing bleeding. Recombinant drugs of human origin are non-antigenic, whereas those with a bacterial origin, whether purified from bacteria or produced by recombinant technology, can result in antibody formation and produce allergic reactions that preclude repeated treatment. The t½ determines whether a drug is suitable for bolus i.v. injection or continuous i.v. infusion. Reteplase and tenecteplase are most appropriate for bolus injection.
Alteplase (t½ 2–6 min) is a single-chain recombinant tissue-type plasminogen activator (rtPA) that is usually given by continuous i.v. infusion over 30–180 min, according to the indication, i.e. for acute myocardial infarction and acute ischaemic stroke. A bolus dose is recommended for pulmonary embolus.
Reteplase is a deletion mutant of tPA lacking a growth factor and the kringle-binding domain; it possesses a longer t½ (1.6 h) than alteplase. This permits a double bolus regimen, with completion of treatment in 30 min, rather than the need for administration by infusion. It is licensed for acute myocardial infarction.
Tenecteplase is a tPA variant with amino acid substitutions that confer a longer t½ (2 h), greater enzymatic efficiency and a more fibrin-specific profile. It is administered as a single i.v. injection over 5–10 s and is licensed for treatment of acute myocardial infarction.
Streptokinase, derived from culture filtrates of Streptococcus haemolyticus, is not an enzyme. It binds human plasminogen to produce a plasminogen activator that undergoes a time-dependent change of conformation to create an active site that auto-catalytically converts plasminogen to plasmin. The plasmin-complexed streptokinase then decays by proteolytic degradation.
Streptokinase (t½ 20 min) is given by i.v. infusion, e.g. for up to 72 h when treating patients with venous thromboembolism. It finds use for acute myocardial infarction, deep vein thrombosis and pulmonary embolism, acute arterial thromboembolism, and central retinal venous or arterial thrombosis. The rate of infusion may be limited by tachycardia, fever and muscle aches. Nausea and vomiting may also occur.
Uses of thrombolytic drugs
Coronary artery thrombolysis
The earlier thrombolysis starts, the better the outcome. Benefit is most striking in patients with anterior myocardial infarction treated within 4 h of onset. Contraindications to thrombolytic drug use are those that predispose to intracranial haemorrhage (haemorrhagic stroke, intracranial tumour, recent neurosurgery or brain trauma within the previous 10 days and uncontrolled hypertension) or massive haemorrhage (major surgery of thorax or abdomen within the previous 10 days, current major bleeding such as from the gastrointestinal tract or prolonged cardiopulmonary resuscitation).
Adverse effects
If bleeding occurs, thrombolytic therapy must cease. Depending on the timing of bleeding in relation to therapy, consider antifibrinolytic therapy with aprotonin (for longer-acting drugs) and raising the fibrinogen concentration with fresh frozen plasma or cryoprecipitate (more likely required after streptokinase therapy). Platelet transfusion may be given to correct the platelet function defect induced by plasmin proteolysis of platelet membrane receptors.
Following thrombolytic therapy intramuscular injections are contraindicated, any venepuncture requires at least 10 min of local compression, and arterial puncture must be avoided.
Hypotension can follow treatment with any thrombolytic drug but febrile allergic reactions are about six times more likely with use of a thrombolytic of bacterial origin. Some milder reactions can be managed with paracetamol, an H1-receptor antihistamine and corticosteroid.
Non-coronary thrombolysis
Pulmonary embolism
Thrombolysis is used in patients with massive pulmonary emboli with cardiovascular compromise; its value in patients with submassive pulmonary embolus is uncertain.
Deep vein thrombosis
Thrombolysis is often not effective in patients with DVT but may be justified when the affected vessels are proximal and risk of pulmonary embolism is high.
Arterial occlusion
Systemic or local thrombolysis may be an option for arterial occlusions distal to the popliteal artery (thrombectomy is the usual therapeutic approach for occlusion of less than 24 h duration proximal to this site). Intravenous streptokinase will lyse 80% of occlusions if infusion begins within 12 h, and 60% if it is delayed for up to 3 days.
Ischaemic stroke
There is little evidence of benefit and most trials have shown increased short-term mortality in patients treated with thrombolysis.
Thrombolysis may also be effective for occluded arteriovenous shunts and for blocked, e.g. central venous, catheters.
Drugs that prevent fibrinolysis
Antifibrinolytics are useful in a number of bleeding disorders.
Tranexamic acid
competitively inhibits the binding of plasminogen and tPA to fibrin and effectively blocks conversion of plasminogen to plasmin; fibrinolysis is thus retarded. An intravenous bolus passes largely unchanged in the urine with a t½ of 1.5 h. Oral and topical formulations are available.
Tranexamic acid is used principally to prevent the hyperplasminaemic bleeding state that results from damage to tissues rich in plasminogen activator, e.g. after prostatic surgery, tonsillectomy, uterine cervical cone biopsy and menorrhagia, whether primary or induced by an intrauterine contraceptive device. Tranexamic acid may also reduce bleeding after ocular trauma, and in von Willebrand's disease and haemophilia after dental extraction (normally combined with DDAVP or factor VIII, respectively).
Some patients with hereditary angioedema may benefit, presumably by prevention of plasmin-induced activation of the complement system.
Tranexamic acid may be of value in thrombocytopenia (idiopathic or following cytotoxic chemotherapy). The natural fibrinolytic destabilisation of small platelet plugs is inhibited, reducing the risk of haemorrhage and requirement for platelet transfusion.
Adverse effects are rare but include nausea, diarrhoea and sometimes orthostatic hypotension. Tranexamic acid is contraindicated for patients with haematuria because clot lysis in the urinary tract is prevented and clot colic results.
Aprotinin
is a naturally occurring inhibitor of plasmin and other proteolytic enzymes that has been used in the past to limit perioperative bleeding during cardiac bypass and liver transplantation surgery. However, a recently recognised association between aprotonin use and serious end-organ damage has resulted in its withdrawal.
Platelet function
Platelets have a key role in maintaining vascular integrity. They aggregate at and adhere to exposed collagen to form a physical barrier at the site of vessel injury; they accelerate the activation of coagulation proteins; they release stored granules that promote vasoconstriction and wound healing.
Platelets have rightly been termed ‘pharmacological packages’. To deliver the above functions, they must first undergo a process of activation that involves multiple agonists through numerous intracellular second-messenger pathways and complex networks (Fig. 29.3). These pathways converge on and activate the fibrinogen receptor, glycoprotein IIbIIIa (integrin αIIbβ3), inducing a conformational change that results in fibrinogen/fibrin binding. When fibrinogen occupies the receptor, outside-in signalling consolidates platelet activation by up-regulating second-messenger pathways, so providing a positive feedback loop.
In the coagulation process, platelets provide an anionic phospholipid surface for assembly of the macromolecular enzymatic complexes required for thrombin generation. Phospholipids in the bilayer membrane of resting platelets are distributed asymmetrically, with anionic phospholipid held in the internal leaflet. Full platelet activation results in scrambling of the membrane with exposure of negatively charged phospholipid on the external leaflet. This lipid cooperates in the assembly of the thrombin-generating enzymatic complexes.
Receptors on the platelet membrane that are known to result in platelet activation through intracellular second messengers include those for thrombin, adenosine diphosphate (ADP), collagen, thromboxane and adrenaline/epinephrine.
Activation is enhanced by occupancy of glycoprotein IIbIIIa (the fibrinogen receptor) and glycoprotein Ib (a component of the Ib/IX/V receptor for von Willebrand protein). The process is mediated primarily through G-coupled second messengers in response to occupancy of the thrombin, ADP and collagen receptors (at high collagen concentration), and through phospholipases and consequent thromboxane generation in response to occupancy of the thromboxane, adrenaline/epinephrine and collagen receptors (at low collagen concentration).
Both thromboxane and ADP are produced in response to platelet activation, and recruit further platelets to activation sites, so providing a positive feedback loop to their respective receptors. There are several ADP receptors on the platelet membrane. Multiple second-messenger pathways are probably involved in their mechanism of activation, not just G-protein-coupled systems. Collagen-induced platelet activation involves at least three receptors with both thromboxane-dependent and thromboxane-independent second-messenger pathways.
High ‘shear forces’ also activate platelets but the mechanisms are unclear: fibrinogen and its receptor, GPIIbIIIa, are required at low shear rates, and von Willebrand factor and its receptor, GPIb, at high shear rates. ADP and adrenaline/epinephrine are synergistic at high shear and result in larger thrombi for a given rate of shear.
Drugs that inhibit platelet activity (antiplatelet drugs)
(See also Myocardial infarction, p. 411.)
Aspirin
(acetylsalicylic acid) acetylates and thus inactivates cyclo-oxygenase (COX), the enzyme responsible for the first step in the formation of prostaglandins, the conversion of arachidonic acid to prostaglandin H2. As acetylation of COX is irreversible and the platelet is unable to synthesise new enzyme, COX activity is lost for the platelet lifetime (8–10 days).
Aspirin prevents formation of both thromboxane A2 (TXA2) and prostacyclin (PGI2) (see Fig.16.1, p. 241). Therapeutic interest in the antithrombotic effect of aspirin has centred on separating these actions by using a low dose. In general, 75–100 mg/day by mouth will abolish synthesis of TXA2 without significant impairment of prostacyclin formation, i.e. amounts substantially below the 2.4 g/day used to control pain and inflammation. Laboratory testing of TXA2 production or TXA2-dependent platelet function can provide an assessment of the adequacy of aspirin dose. Among several causes of resistance to aspirin are genetic polymorphisms of COX-1 and other genes involved in thromboxane biosynthesis.6
Low-dose aspirin is not without risk: a proportion of peptic ulcer bleeds in people aged over 60 years occur from prophylactic low-dose aspirin.
Dipyridamole
reversibly inhibits platelet phosphodiesterase, and consequently cyclic AMP concentration is increased and platelet activity reduced; evidence also suggests that its antithrombotic effect may derive from release of prostaglandin precursors by vascular endothelium. Dipyridamole is bound extensively to plasma proteins and has a t½ of 12 h.
Clopidogrel
is a thienopyridine derivative that inhibits ADP-dependent platelet aggregation. The t½ of the parent drug is 40 h and metabolism by the liver converts it to its active form. Clopidogrel reduces the risk of the combined outcome of stroke, myocardial infarction (MI) or vascular death in patients with thromboembolic stroke. It decreases vascular death and MI in patients with unstable angina, reduces acute occlusion of coronary bypass grafts, and improves walking distance and decreases vascular complications in patients with peripheral vascular disease. Clopidogrel also finds use in the prevention of stroke in patients who are intolerant of aspirin. An initial dose of 300 mg is followed by a daily dose of 75 mg.
Prasugrel
is a thienopyridine derivative like clopidogrel. It inhibits ADP-induced platelet aggregation more rapidly, more consistently, and to a greater extent than standard dose clopidogrel. A 60-mg loading dose results in at least 50% inhibition of platelet aggregation by 1 h in 90% of patients. The subsequent daily dose is 10 mg.
Epoprostenol
(prostacyclin) may be given as an anticoagulant during renal dialysis, with or without heparin; it is infused i.v. and s.c (t½ 3 min). It is a potent vasodilator.
Glycoprotein (GP) IIb–IIIa antagonists
The platelet glycoprotein IIb–IIIa complex is the predominant platelet integrin, a molecule restricted to megakaryocytes and platelets that mediates platelet aggregation by the binding of proteins such as fibrinogen and von Willebrand factor (vWF) (see Fig. 29.4). Hereditary absence of the GPIIb–IIIa complex (Glanzmann's thrombasthenia) results in platelets that are incapable of aggregation by physiological agonists.
Fig. 29.4 Mechanisms for the activation of platelets. ADP, adenosine diphosphate; GP, glycoprotein.
GPIIb–IIIa antagonists have been developed as antiplatelet agents. As blockers of the final common pathway of platelet aggregation (the binding of fibrinogen or vWF to the GPIIb–IIIa complex) they are more complete inhibitors of platelets than either aspirin or clopidogrel which act only on the cyclo-oxygenase or ADP pathway respectively. GPIIb–IIIa antagonists also have an anticoagulant effect by reducing availability of platelet membrane anionic phospholipid. Inhibition of platelet aggregation is dose dependent.
Abciximab
is a human–murinechimeric monoclonal antibody Fab fragment that binds to the GPIIb–IIIa complex with a high affinity and slow dissociation rate. Given intravenously, it is cleared rapidly from plasma (t½ 20 min). Abciximab (0.25 mg/kg bolus then 0.125 micrograms/kg/min infusion for 12 h) produces immediate and profound inhibition of platelet activity that lasts for 12–36 h after termination of the infusion. The dose causes and maintains blockade of more than 80% of receptors, with a greater than 80% reduction in aggregation. Patients may also receive heparin and an antiplatelet drug, e.g. aspirin. Abciximab is effective in acute coronary syndromes.
Eptifibatide
is a cyclic heptapeptide based upon the Lys-Gly-Asp sequence. Tirofiban and lamifiban are non-peptide mimetics. All three are competitive inhibitors of the GPIIb–IIIa complex, with lower affinities and higher dissociation rates than abciximab and relatively short plasma t½ values (2–2.5 h). Platelet aggregation returns to normal from 30 min to 4 h after discontinuation. Eptifibatide and tirofiban are effective in acute coronary syndromes.
Adverse effects
Platelet transfusion after cessation of abciximab is necessary for refractory or life-threatening bleeding. After transfusion, the antibody redistributes to the transfused platelets, reducing the mean level of receptor blockade and improving platelet function. Thrombocytopenia may occur from 1 h to days after commencing treatment in up to 1% of patients. This necessitates platelet counts 2–4 h after commencement and then daily; if severe, therapy must be stopped and, if necessary, platelets transfused. EDTA-induced pseudothrombocytopenia has been reported and a low platelet count should prompt examination of a blood film for agglutination before therapy is stopped.
Other drugs
Dextrans, particularly of mol. wt. 70 000 Da (dextran 70), alter platelet function and prolong the bleeding time. Dextrans differ from the other antiplatelet drugs, which tend to be used for arterial thrombosis; dextran 70 reduces the incidence of postoperative venous thromboembolism if it is given during or just after surgery. The dose should not exceed 10% of the estimated blood volume. Dextrans are rarely used.
Uses of antiplatelet drugs
Antiplatelet therapy protects at-risk patients against stroke, myocardial infarction or death. A meta-analysis of 145 clinical trials of prolonged (> 1 month) antiplatelet therapy versus control, and trials between antiplatelet regimens, found that the chance of non-fatal myocardial infarction and non-fatal stroke fell by one-third, and that there was a one-sixth reduction in the risk of death from any vascular cause.7 Expressed in another way, in the first month after an acute myocardial infarction (a vulnerable period) aspirin prevents death, stroke or a further heart attack in about 4 of every 100 patients treated. Continuing treatment from the end of year 1 to year 3 conferred further benefit.
Aspirin is by far the most commonly used anti-platelet agent. The optimal dose is not certain, but one not exceeding aspirin 325 mg/day is acceptable, and 75–100 mg/day may be as effective and preferred where there is gastric intolerance. Aspirin alone (mainly) or aspirin plus dipyridamole greatly reduced the risk of occlusion where vascular grafts or arterial patency were studied systematically.8
Many patients who take aspirin for vascular disease may also require a NSAID, e.g. for joint disease. Given their common mode of action by inhibiting prostaglandin synthesis, this raises the issue that NSAIDs may block access of aspirin to active sites on platelets, with loss of cardioprotection. Retrospective cohort9 and case-control10 studies suggest no adverse interaction with ibuprofen, but the issue remains unresolved and in the meantime it seems prudent to take aspirin 2 h before a NSAID, e.g. at bedtime.
Summary
• Coagulation does not occur as a consequence of linear sequential enzyme activation pathways but by a network of simultaneous interactions, with regulation and modulation of these interactions during the thrombin generation process itself.
• Vitamin K is necessary for the final stage in the synthesis of coagulant factors II (prothrombin), VII, IX and X, and anticoagulant regulatory proteins, proteins C and S.
• Vitamin K is used to treat haemorrhage or threatened bleeding due to the coumarin or indanedione anticoagulants, haemorrhagic disease of the newborn and hypoprothrombinaemia due to intestinal malabsorption syndromes.
• Desmopressin increases the plasma concentration of factor VIII and von Willebrand factor, directly activates platelets, and is useful in patients with mild haemophilia A and von Willebrand's disease.
• The predominant effect of anticoagulant drugs is to limit thrombin generation, or to neutralise thrombin.
• Warfarin and other oral vitamin K antagonists act by reducing the activity of vitamin K-dependent clotting factors (see above); they take 4–5 days to produce a therapeutic effect. Warfarin is the oral anticoagulant of choice, for it is reliably effective and has the lowest incidence of adverse effects.
• Oral VKA have a delayed pharmacodynamic effect relative to their pharmacokinetic profiles with both a slow on and off effect but the anticoagulant effect can be reversed with factor concentrate (II, VII, IX & X) and vitamin K.
• Oral direct thrombin and anti-Xa inhibitors have a fast pharmacodynamic effect in parallel with their pharmacokinetic profile. The anticoagulant effect cannot be reversed.
• Oral anticoagulant drugs are used to prevent and treat venous thrombosis and pulmonary embolus, and to prevent arterial thromboemboli in patients with atrial fibrillation or cardiac disease, including mechanical heart valves.
• Heparin depends for its anticoagulant action on the presence in plasma of antithrombin, a naturally occurring inhibitor of activated coagulation proteases that include thrombin, factor Xa and factor IXa.
• Patients with acute venous thromboembolism can be treated safely and effectively with low molecular weight heparin as outpatients.
• LMWHs and direct thrombin and Xa inhibitors are the preferred drugs for perioperative prophylaxis and are at least as effective as standard heparin for unstable angina.
• Fibrinolytic drugs dissolve thrombi in acutely occluded coronary arteries, thereby restoring blood flow to ischaemic myocardium and improving prognosis. The earlier thrombolysis is given the better the outcome. Thrombolysis is also effective for massive pulmonary emboli with cardiovascular compromise.
• Aspirin acetylates and thus inactivates cyclo-oxygenase (COX), the enzyme responsible for the first step in the formation of prostaglandins, and in low dose reduces platelet activity by preventing the formation of thromboxane.
• Clopidogrel inhibits ADP-dependent platelet aggregation; it reduces the risk of stroke, myocardial infarction or vascular death.
• GPIIb–IIIa antagonists block the final common pathway of platelet aggregation (the binding of fibrinogen or vWF to the GPIIb–IIIa complex) and are more complete inhibitors of platelets than either aspirin or clopidogrel.
• Antiplatelet therapy protects at-risk patients against stroke, myocardial infarction or death.
Guide to further reading
Baglin T., Barrowcliffe T.W., Cohen A., Greaves M. Guidelines on the use and monitoring of heparin. Br. J. Haematol.. 2006;133:19–34.
Baglin T.P., Keeling D.M., Watson H.G. Guidelines on oral anticoagulation (warfarin): third edition-2005 update. Br. J. Haematol.. 2006;132:277–285.
CRASH-2 trial collaborators, Shakur H., Roberts I., Bautista R., et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32.
De Meyer S.F., Vanhoorelbeke K., Broos K., et al. Antiplatelet drugs. Br. J. Haematol.. 2008;142:515–528.
Di Nisio M., Middeldorp S., Büller H.R., et al. Direct thrombin inhibitors. N. Engl. J. Med.. 2005;353:1028–1040.
Huntington J.A., Baglin T.P. Targeting thrombin: rational drug design from natural mechanisms. Trends Pharmacol. Sci.. 2003;24:589–595.
Patrono C., Garcia Rodriguez L.A., Landolfi R., Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N. Engl. J. Med.. 2005;353:2373–2383.
Weitz J.I., Hirsh J., Samama M.M. New antithrombotic drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133:234S–256S.
1 Genetically controlled by an active promoter and constantly produced rather than depending on the presence of an inducer.
2 Serpin: serine protease inhibitors. Antithrombin is the principal serpin involved in regulating coagulation.
3 Coumarins are present in many plants and are important in the perfume industry; the smell of new mown hay and grass is due to coumarins. Yellow sweet clover (King's clover) is rich in coumarins and was used as a herbal medicine to reduce inflammation. It was a constituent of an ointment to ‘cool and dry and comfort the Membre’ of King Henry VIII of England, who enjoyed a particularly active sexual life (Cutler T 2003 College Commentary, May/June. Royal College of Physicians, London, p. 23). The discovery of coumarins as anticoagulants dates from investigation of an unexplained haemorrhagic disease of cattle that had eaten mouldy sweet clover. Subsequent research at the University of Wisconsin, USA, culminated in the isolation of the causative agent, dicoumarol (Stahmann M A, Huebner C F, Link K P 1941 Journal of Biological Chemistry 138:513–527).
4 Warfarin is 10 times more potent than dicoumarol and was originally used as a rodenticide. Its name is derived from the patent holder, Wisconsin Alumni Research Foundation, and the suffix comes from ‘coumarin’.
5 McLean gives a fascinating account of his struggles to pay his way through medical school, as well as his discovery of heparin in: McLean J 1959 Circulation XIX:75.
6 Hankey G J, Eikelboom J W 2006 Aspirin resistance. Lancet 367:606–617.
7 Antiplatelet Trialists’ Collaboration 1994 Collaborative overview of randomised trials of antiplatelet therapy – I: Prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy and various categories of patients. British Medical Journal 308:81–106.
8 Antiplatelet Trialists’ Collaboration 1994 Collaborative overview of randomised trials of antiplatelet therapy – II: Maintenance of vascular grafts or arterial patency by antiplatelet therapy. British Medical Journal 308:159–168.
9 García Rodríguez L A, Varas-Lorenzo C, Maguire A, González-Pérez A 2004 Nonsteroidal anti-inflammatory drugs and the risk of myocardial infarction in the general population. Circulation 109:3000–3006.
10 Patel T N, Goldberg K C 2004 Use of aspirin and ibuprofen compared with aspirin alone and the risk of myocardial infarction. Archives of Internal Medicine 164:852–856.