SECTION BLOOD AND NEOPLASTIC DISEASE This page intentionally left blank 28 Drugs andhaemostasis SYNOPSIS Occlusive vascular disease is a major cause of morbidity and mortality.There is now better understanding of the mechanisms by which the haemostatic system ensures blood remains fluid within vessels, yet forms a solid plug when a vessel is breached, and of the ways in which haemostasis may be altered by drugs to prevent or reverse (lyse) pathological 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 are used to treat arterial disease The haemostatic system is complex but can be separated into the following major components: • Formation of fibrin (coagulation), which stabilises the platelet plug • Dissolution of fibrin (fibrinolysis) • Platelets, which form the haemostatic plug • Bloodvessels Drugs that interfere with the haemostatic system (anticoagulants, thrombolytics, antiplatelet agents) are valuable in the management of pathological thrombus formation within blood vessels, or of pathological bleeding They are classified according to which component of the system they affect Coagulation system The blood coagulation system is shown in simplified form in Figure 28.1 It consists of glycoprotein components that circulate in (necessarily inactive) pro-enzyme or pro-cofactor (factors V and VIII) form The activated enzymes are serine proteases Physiological coagulation (the 'extrinsic' pathway) begins when tissue factor (TF, tissue thromboplastin), exposed by vascular injury, activates and complexes with factor VII to activate factors IX and X which complex with Villa and Va respectively on membrane surfaces (which provide phospholipid, PL) The Xa/Va complex converts prothrombin to thrombin which converts fibrinogen to fibrin and also activates factors XI, VIII, V and XIII, both accelerating coagulation and cross-linking fibrin (-F-F-F-) The 'intrinsic' pathway refers to coagulation in vitro It is initiated when factor XII with the cofactor high molecular weight kininogen (HMWK) comes into contact with a foreign surface, e.g glass, kaolin Thus it has no physiological role (and patients lacking factor XII not have a bleeding disorder) 567 28 DRUGS AND HAEMOSTASIS The prothrombin time (FT), which is usually expressed as the International Normalised Ratio (INR) for control of oral anticoagulant therapy, primarily evaluates the extrinsic system The activated partial thromboplastin time (APTT), also known as the kaolin-cephalin clotting time (KCCT), primarily evaluates the intrinsic system In-vitro coagulation of plasma is initiated by the addition of negatively charged particles such as kaolin with phospholipid, and calcium and exogenous thromboplastin Each of these tests is also affected by the final common pathway, the endpoint of which is tested by the thrombin time This tests the formation of a fibrin clot by the addition of exogenous thrombin and calcium It is sensitive to the level of endogenous fibrinogen and to the presence of inhibitors of thrombin (heparin, FDPs) VITAMIN K:A CRITICAL CO-FACTOR Fig 28.1 Blood coagulation system (see text) The classical separation of the intrinsic and extrinsic pathways is a simplification but remains a useful in-vitro phenomenon for monitoring coagulation Both in vivo and in vitro the systems are dependent on the presence of Ca++ ions and key in-vivo steps involve the formation of macromolecular complexes on membrane surfaces, usually those of platelets Cascade reactions culminate in the generation of fibrin and its polymerisation by factor XIII to form a fibrin clot 568 Vitamin K (Koagulation vitamin) is essential to normal haemostatic and antithrombotic mechanisms This vitamin occurs naturally in two forms Vitamin Kj (phylloquinone) is widely distributed in plants and K2 includes vitamin synthesised in the alimentary tract by bacteria, e.g Escherichia coli (menaquinones) Bile is required for the absorption of the natural vitamins K, which are fat-soluble Leafy green vegetables are a good source of vitamin Kr The storage pool of vitamin K is modest and can be exhausted in one week, though gut flora will maintain suboptimal production of vitamin K dependent proteins A synthetic analogue, menadione, (K3) (below) of the natural vitamins also has biological activity in vivo; it is water-soluble Vitamin K is necessary for the final stage of the synthesis of six coagulation-related proteins in the liver by y-carboxylation of glutamic acid residues on the molecule The y-carboxyglutamic acid residues permit calcium to bind to the molecule which in turn mediates binding to negatively charged phospholipid surfaces The vitamin K-dependent proteins are coagulation factors II (prothrombin), VII, IX and X, and the anticoagulant (regulatory) proteins, proteins C and S During y-carboxylation of the proteins by the vitamin K dependent carboxylase, the reduced form of vitamin K is converted to an COAGULATION SYSTEM 28 epoxide, an oxidation product, which is subsequently reduced again enzymatically to the active vitamin K, i.e there exists an interconversion cycle (the vitamin K cycle) between vitamin K epoxide and reduced and active vitamin K (KH2) When the vitamin is deficient or where its action is inhibited by drugs, coagulation proteins which cannot bind Ca++ result; their physiologically critical binding to membrane surfaces fails to occur, and this impairs the coagulation mechanism This non- ordescarboxylated protein is called 'protein induced in vitamin K absence' or PIVKA Menadiol sodium phosphate in moderate doses causes haemolytic anaemia and for this reason it should not be given to neonates, 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 which are available in some countries include acetomenaphthone and menaphthone Deficiency may arise from: • Haemorrhage or threatened bleeding due to the coumarin or indandione anticoagulants Phytomenadione is preferred for its more rapid action; dosage regimens vary according to the degree of urgency and the original indication for anticoagulation, as described on page 576 • Haemorrhagic disease of the newborn which develops during the first week of life, usually between days 2-7 (and also late haemorrhagic disease which presents at 6-7 months) Prophylaxis is recommended1 during the period of vulnerability with vitamin K (phytomenadione, as Konakion) mg by single i.m injection at birth Alternatively, vitamin K may be given by mouth as two doses of a colloidal (mixed micelle) preparation of phytomenadione in the first week Breast-fed babies should receive a further mg at one month of age Formula-fed babies not need this last supplement as the formula contains vitamin K Fears that i.m vitamin K might cause childhood cancer have been allayed • Hypoprothrombinaemia due to intestinal malabsorption syndromes Menadiol sodium phosphate should be used as it is water-soluble • bile failing to enter the intestine, e.g obstructive jaundice or biliary fistula • certain 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 antimicrobials The following preparations of vitamin K are available: Phytomenadione (phytonadione, Konakion), the naturally occurring fat-soluble vitamin K1 acts within about 12 h and should correct the INK within 24-48 h The i.v formulation is used in emergency and must be administered slowly as an anaphylactoid reaction with facial flushing, sweating, fever, chest tightness, cyanosis and peripheral vascular collapse may occur Patients with chronic liver disease and those using histamine H2-receptor antagonists seem to be especially likely to react Otherwise phytomenadione may be given i.m., s.c or orally The preferred route depends on the urgency of correcting the haemorrhagic tendency The i.m route should be avoided if the INK is significantly prolonged as local intramuscular haemorrhage may be induced; s.c absorption is variable and despite the risk of allergic reaction, the intravenous route ensures rapid delivery Menadiol sodium phosphate (vitamin K3, Synkavit), the synthetic analogue of vitamin K, being watersoluble, is preferred in 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 Indications for vitamin K or its analogues DRUGSTHAT PREVENT COAGULATION: ANTICOAGULANTS There are two types of anticoagulant: Indirect-acting: coumarin2 and indandione drugs take about 72 h to become fully effective, act for several days, are given orally and can be antagonised (see below) by vitamin K British National Formulary 569 28 DRUGS AND HAEMOSTASIS Direct-acting: heparin, hirudin, bivalirudin and argatroban are rapidly effective, act for only a few hours and must be given parenterally Indirect-acting anticoagulants Coumarins include warfarin and acenocoumarol (nicoumalone) The vitamin K antagonists were discovered as a result of investigation of a haemorrhagic disease of cattle that plagued farmers in the Great Plains of the USA during the 1920s The disorder which was due to hypoprothrombinaemia was caused by ingestion of spoiled sweet clover hay contaminated by specific toxins The compound 3, 3'methylene-bis-4-hydroxycoumarin was purified from bacterial contaminants in the spoiled hay and was found to produce a syndrome similar to vitamin K deficiency.3 Bishydroxycoumarin (dicoumarol) was introduced into clinical practice as an anticoagulant in the 1940s and other structurally related vitamin K antagonists followed; all share a common ring structure with vitamin K Warfarin is the most widely used Warfarin Mode of action During the y-carboxylation of the coagulant factors II (prothrombin), VII, IX and X (and also the anticoagulant regulatory proteins C and S) in the liver, 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 (the vitamin K cycle) Coumarins 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 y2 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 Campbell H A, Link K P 1941 Studies on the haemorrhagic sweet clover disease IV: the isolation and crystallisation of the haemorrhagic agent Journal of Biological Chemistry 138: 21 570 carboxylation sites (PIVKAs) This shift does not take place until functional vitamin K-dependent proteins made before the drug was administered are cleared from the circulation The process occurs at different rates for individual coagulation factors (VII tl/2 h, IX and X tl/2 24 h, prothrombin tl/2 72 h) Moreover, the anticoagulant proteins C and S have a shorter tl/2 than the procoagulant proteins and their more rapid decline in concentration creates a transient hypercoagulable state This can be serious in those who have inherited protein S and C deficiency who may develop skin necrosis and justifies initiating anticoagulation with heparin until the effect of warfarin is well established Thus the anticoagulant effect of warfarin is delayed and indeed the drug must be administered for 4-5 days before the effect is properly therapeutic Furthermore, the INR does not reliably reflect anticoagulant protection during this initial phase, because the vitamin K-dependent factors diminish at different rates The great advantage of warfarin over heparin is that it can be given orally Its chief disadvantage is the time lag before it exerts its effect, which is due to its indirect mode of action A similar time lag is found when the warfarin dose is altered or discontinued as the tl/2 of the nonfunctioning proteins is approximately that of functioning proteins Pharmacokinetics Warfarin is readily absorbed from the gastrointestinal tract and like all the oral anticoagulants, is more than 90% bound to plasma proteins Its action is terminated by metabolism in the liver Warfarin (t l / 36 h) is a racemic mixture of approximately equal amounts of two isomers S (tl/2 35 h) and R (tl/2 50 h) warfarin, i.e it is in effect two drugs S warfarin is four times more potent than R warfarin Drugs which interact with warfarin affect these isomers differently Uses Warfarin is the oral anticoagulant of choice, for it is reliably effective and has the lowest incidence of adverse effects Monitoring of therapy is by the prothrombin time Usually the test is carried out with a standardised thromboplastin and the result is expressed as the International Normalised Ratio (INR), which is the ratio of the prothrombin time in the patient to that in a normal (non-anticoagulated) person—taking account of the sensitivity of the COAGULATION SYSTEM thromboplastin used Oral anticoagulation is commonly undertaken in patients who are already receiving heparin The INR reliably reflects the degree of prothrombin activity provided that the activated partial thromboplastin time (APTT, a measure of the anticoagulant effect of heparin, see below) is within the therapeutic range (1.5-2.5 times control) Warfarin therapy with an INR in the therapeutic range does not prolong the APTT Dose There is much inter-individual variation in dose requirements It is usual to initiate therapy with 10 mg daily for days, with the maintenance dose then adjusted according to the INR using an established protocol.4 The level of anticoagulation should be adjusted to match the perceived risk of thrombosis, by the following guidelines:5 • INR 2.0-2.5 Prophylaxis of deep vein thrombosis including surgery on high-risk patients (2.0-3.0 for hip surgery and fractured femur operations) • INR 2.0-3.0 Treatment of deep vein thrombosis; pulmonary embolism; systemic embolism; prevention of venous thromboembolism in myocardial infarction; mitral stenosis with embolism; transient ischaemic attacks; atrial fibrillation • INR 3.0-4.5 Recurrent deep vein thrombosis and pulmonary embolism; arterial disease including myocardial infarction; mechanical prosthetic heart valves Adverse effects Bleeding is the commonest complication of warfarin therapy The incidence of major haemorrhage is about 5% per year6 and an identifiable risk factor is often present, e.g thrombocytopenia, liver disease or vitamin K deficiency, an endogenous disturbance of coagulation, cancer or recent surgery Naturally, poor anticoagulant control or drug interaction with warfarin increase the risk Haemorrhage is most likely to occur in the alimentary and renal tracts, and in the brain in those with cerebrovascular disease 28 Cutaneous reactions, apart from purpura and ecchymoses in those who are excessively anticoagulated, include hypersensitivity, rash and alopecia Skin necrosis due to a mixture of haemorrhage and thrombosis occurs rarely where induction of warfarin therapy is over-abrupt and/or the patient has a genetically determined or acquired deficiency of the anticoagulant protein C or its cofactor protein S; it can be very serious Warfarin used in early pregnancy may injure the fetus (other than by bleeding) It causes skeletal disorders (5%) (bossed forehead, sunken nose, foci of calcification in the epiphyses) and absence of the spleen Women on long-term warfarin should be advised not to become pregnant while taking the drug Heparin should be substituted prior to conception and continued through the first trimester, after which warfarin should replace heparin, as continued exposure to heparin may cause osteoporosis Warfarin should be discontinued near term as it exacerbates neonatal hypoprothrombinaemia and its control is too imprecise to be safe in labour; heparin may be substituted at this stage for it can be discontinued just before labour and its anticoagulant effect wears off in about h CNS abnormalities (microcephaly, cranial nerve palsies) are reported with warfarin used at any stage of pregnancy and are presumed to be due to intracranial haemorrhage Management of bleeding or over-anticoagulation is guided by the clinical state and the INR:7 • Haemorrhage threatening life or major organs In addition to blood replacement, rapid reversal of anticoagulation is achieved with prothrombin complex concentrate (containing factors II, IX and X, and given i.v as 50 units per kg of factor IX) or fresh frozen plasma If full reversal of anticoagulation is judged necessary, phytomenadione mg is then given by slow i.v injection This renders the patient refractory to oral anticoagulant (but not to heparin) for about weeks The thrombotic risk so created must be assessed for each patient and may be judged Fennerty A et al 1988 British Medical Journal 297: 1285-1288 British Society for Haematology 1990 Guidelines on oral anticoagulants, 2nd edn Journal of Clinical Pathology 43: 177-183 (Reproduced with permission) A study of 261 patients who received warfarin for 221 patient-years reported major haemorrhage in 5.3% after year and 10.6% after years Gitter M J et al 1995 Mayo Clinic Proceedings 70: 725-733 571 28 DRUGS AND HAEMOSTASIS unacceptable in some, e.g those with prosthetic heart valves For less severe haemorrhage, warfarin should be withheld and phytomenadione 0.5-2 mg may be given by slow i.v injection if rapid correction of the INR is necessary • INR > but without bleeding Correct by withholding warfarin, and giving phytomenadione 0.5 mg by slow i.v injection if judged appropriate • INR 4.5-7.0 Manage by withholding warfarin for 1-2 days and then reviewing the INR • INR 2.0-4.5 (the therapeutic range) Bleeding, e.g from the nose, alimentary or renal tract, should be fully investigated as a local cause frequently exists Withdrawal of oral anticoagulant The balance of evidence is that abrupt, as opposed to gradual withdrawal of therapy does not of itself add to the risk of thromboembolism, for renewed synthesis of functional vitamin K dependent clotting factors takes several days Interactions Oral anticoagulant control must be precise both for safety and efficacy If a drug that alters the action of warfarin must be used, the INR should be monitored frequently and the dose of warfarin adjusted during the period of institution of the new drug until a new stable therapeutic dose of warfarin is identified; careful monitoring is also needed on withdrawal of the interacting drug The following list, although not comprehensive, identifies medicines that should be avoided and those which may safely be used with warfarin • Analgesics Avoid if possible, all NSAIDs including aspirin (but see p 576, myocardial infarction)because of their irritant effect on gastric mucosa and action on platelets Paracetamol is acceptable but doses over 1.5 g/d 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 Based on recommendations of the British Society for Haematology 572 • Antimicrobials Aztreonam, cefamandole, chloramphenicol, ciprofloxacin, co-trimoxazole, erythromycin, fluconazole, itraconazole, ketoconazole, metronidazole, miconazole, ofloxacin and sulphonamides (including cotrimoxazole) increase anticoagulant effect by mechanisms that include interference with warfarin or vitamin K metabolism Rifampicin and griseofulvin accelerate warfarin metabolism (enzyme induction) and reduce its effect Intensive broad-spectrum antimicrobials, e.g eradication regimens for Helicobacter pylori (see p 630), may increase sensitivity to warfarin by reducing the intestinal flora that produce vitamin K • Anticonvulsants Carbamazepine, phenobarbital and primidone accelerate warfarin metabolism (enzyme induction); the effect of phenytoin is variable Clonazepam and sodium valproate are safe • Cardiac antiarrhythmics Amiodarone, propafenone and possibly quinidine potentiate the effect of warfarin and dose adjustment is required, but atropine, disopyramide and lignocaine 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 but INR should be checked if the dose is high Most antacids are safe • Lipid-lowering drugs Fibrates, and some statins, enhance anticoagulant effect Colestyramine is best avoided for it may impair the absorption of both warfarin and vitamin K • Sex hormones and hormone antagonists Oestrogens increase the synthesis of some vitamin K dependent clotting factors and progestogen-only contraceptives are preferred The hormone antagonists danazol, flutamide and tamoxifen enhance the effect of warfarin • Sedatives and anxiolytics Benzodiazepines may be used Other vitamin K antagonists Acenocoumarol (nicoumalone) is similar to warfarin but seldom COAGULATION SYSTEM used; it is eliminated in the urine mainly in unchanged form (t l / 24 h) Indandione anticoagulants are practically obsolete because of allergic adverse reactions unrelated to coagulation; phenindione (tl/2 h) is still available but also seldom used Direct-acting anticoagulants: heparin Heparin was discovered by a medical student, J McLean, working at Johns Hopkins Medical School in 1916 Seeking to devote one 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 which he had kept longest not only failed to accelerate but actually retarded clotting His personal account proceeds: 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.]8 Heparin is a sulphated mucopolysaccharide which occurs in the secretory granules of mast cells and is prepared commercially from a variety of animal tissues (generally porcine intestinal mucosa or bovine lung) to give preparations that vary in molecular weight from 3000 to 30000 (average 15 000) It is the strongest organic acid in the body and in solution carries an electronegative charge The low molecular weight (LMW) heparins (mean MW 4000-6500) are prepared from standard heparin by a variety of chemical techniques and commercial preparations (dalteparin, enoxaprin, tinzaparin) contain different fractions and display different pharmacokinetics Mode of action Heparin depends for its anticoagulant action on the presence in plasma of a single chain glycoprotein, antithrombin (formerly antithrombin III), a naturally-occurring inhibitor of 28 activated coagulation factors of the intrinsic and common pathways including thrombin, factor Xa and factor IXa (Fig 28.1) Antithrombin is homologous to members of the a-antitrypsin family of serine protease inhibitors (serpins) On intravenous administration heparin binds to antithrombin and this leads to rapid inhibition of the proteases of the coagulation pathway In the presence of heparin antithrombin becomes vastly more active (approximately 1000-fold) and inhibition is essentially instantaneous Heparin binding to antithrombin induces a conformational change in antithrombin that locks the heparin in place and is followed by rapid reaction with a target protease This reaction in turn reduces the affinity of antithrombin for heparin, allowing the heparin to dissociate from the antithrombin/protease complex and to catalyse further antithrombin/protease interactions The importance of inhibition of factor Xa is that this factor is a critical step in both the intrinsic and extrinsic coagulation systems and heparin is effective in small quantities This provides the rationale for giving low dose subcutaneous heparin to prevent thrombus formation At a molecular level the capacity of heparin to inhibit factor Xa has been found to depend on a specific pentasaccharide sequence which can be isolated in fragments of average MW 5000 (LMW heparins) LMW heparins inhibit factor Xa at a dose similar to standard heparin but have much less antithrombin activity These fragments are too short to inhibit thrombin which is the principal action of conventional heparin (average MW 15 000) Fibrin formed in the circulation binds to thrombin and protects it from inactivation by the heparin-antithrombin complex, which may provide a further explanation for the higher doses of heparin needed to stop extension of a thrombus than to prevent its formation Heparin also inhibits thrombin through other inhibitors and, at higher concentrations, accelerates plasminogen activation and inhibits platelet aggregation Apart from its anticoagulant properties, heparin inhibits the proliferation of vascular smooth muscle cells and is involved in angiogenesis Heparin also 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: 75 573 28 DRUGS AND HAEMOSTASIS inhibits certain aspects of the inflammatory response; this is evident in the rapid resolution of inflammation that accompanies deep vein thrombosis when heparin is given Pharmacokinetics Heparin is poorly absorbed from the gastrointestinal tract and is given i.v or s.c.; once in the blood its effect is immediate Heparin binds to several plasma proteins and to sites on endothelial cells; it is also taken up by cells of the reticuloendothelial system and some is cleared by the kidney Due to these factors, elimination of heparin from the plasma appears to involve a combination of zero-order and first-order processes, the effect of which is that the plasma biological effect tl/2 alters disproportionately with dose, being 60 after 75 units per kg and 150 after 400 units per kg LMW heparins are less protein bound and have a predictable dose-response profile when administered s.c or i.v They also have a longer tl/2 than standard heparin preparations Monitoring heparin therapy Control of standard heparin therapy is by the activated partial thromboplastin time (APTT), the optimum therapeutic range being 1.5-2.5 times the control (which is preferably the patient's own pretreatment APTT) An alternative method is to measure the plasma concentration of heparin using an anti-Xa assay aiming for a therapeutic concentration of 0.1-1.0 U/ml Therapeutic doses of LMW heparin not prolong the APTT and, having predictable pharmacokinetics, they can be administered using a bodyweight adjusted algorithm without laboratory monitoring If necessary an anti-Xa assay can be used to measure the heparin level Dose Treatment of established thrombosis The traditional intravenous regimen of standard unfractionated heparin is a bolus i.v injection of 5000 units (or 10 000 units in severe pulmonary embolism) followed by a constant rate i.v infusion of 1000-2000 units per hour Alternatively 15 000 units may be given s.c every 12 h but control is less even The APTT should be measured h after starting therapy and the administration rate adjusted to keep it in the optimum therapeutic ratio of 1.5-2.5; this usually requires daily measurements of APTT preferably 574 between 0900 h and 1200 h (noon) as the anticoagulant effect of heparin exhibits circadian changes The convenience (and cost-effectiveness) of LMW heparin therapy has resulted in widespread changes in practice Patients with acute venous thromboembolism can be treated safely and effectively with LMW heparin as outpatients Large-scale studies have demonstrated that outpatient treatment of acute deep vein thrombosis (DVT) with unmonitored body-weight adjusted LMW heparin is as safe and effective as inpatient treatment with adjusted dose intravenous standard heparin.9, 10, 11 Further trials have confirmed the safety and efficacy of LMW heparin therapy in acute pulmonary embolism12 and that 80% of unselected patients with acute thromboembolism can be safely treated as outpatients.13 Prevention of thrombosis Postoperatively or after myocardial infarction 5000 units of unfractionated heparin should be given s.c every or 12 h without monitoring (this dose does not prolong the APPT), or in pregnancy 5000-10 000 units s.c every 12 h with monitoring (except for pregnant women with prosthetic heart valves for whom specialist monitoring is needed) LMW heparins have become the preferred drugs for perioperative prophylaxis because of their convenience They are as effective and safe as unfractionated heparin at preventing venous thrombosis (see above) Once-daily s.c administration suffices, as their duration of action is longer than that of conventional heparin and no laboratory monitoring is required LMW heparins are at least as effective as standard heparin for unstable angina, in combination with aspirin Adverse effects Bleeding is the principal acute complication of heparin therapy It is uncommon, Levine M et al 1996 New England Journal of Medicine 334: 677-681 10 Koopman M M W et al 1996 New England Journal of Medicine 334: 682-687 11 The Columbus Investigators 1997 New England Journal of Medicine 337: 657-662 12 Simonneau G et al 1997 New England Journal of Medicine 337: 663-669 13 Lindmarker P, Holmstrom M 1996 Journal of Internal Medicine 240: 395-401 COAGULATION SYSTEM but patients with impaired hepatic or renal function, with carcinoma, and those over 60 years appear to be most at risk An APPT ratio > is associated with an 8-fold increased chance of bleeding Heparin-induced thrombocytopenia (HIT), characterised by arterial thromboemboli and haemorrhage, occurs in about 2-3% of patients who receive standard heparin for a week or more (less in patients on LMW heparins) It is due to an autoantibody directed against heparin in association with platelet factor 4, causing platelet activation, and occurs most commonly with heparin derived from bovine lung HIT should be suspected in any patient in whom the platelet count falls by 50% or more after starting heparin, and usually occurs or more days after starting therapy (or sooner if the patient has previously been exposed to heparin) Up to 30% of patients may require amputation or may die In patients with HIT and evidence of thrombosis, danaparoid sodium, hirudin or argatroban (see p 577) should be substituted Warfarin should not be started until adequate anticoagulation has been achieved with one of these agents and the platelet count has returned to normal as skin necrosis or worsening thromboembolism may result LMW heparins are unsuitable as the antibody may be cross-reactive Osteoporosis may occur, it is dose-related and may be expected with 15 000-30 000 units/day for about months It is most frequently seen in pregnancy The relative risk with LMW heparin is not yet established Hypersensitivity reactions and skin necrosis (similar to that seen with warfarin) occur but are rare Transient alopecia has been ascribed to heparin but in fact may be due to the severity of the thromboembolic disease for which the drug was given Heparin antagonism Heparin effects wear off so rapidly that an antagonist is seldom required except after extracorporeal perfusion for heart surgery Protamine, a protein obtained from fish sperm, reverses the anticoagulant action of heparin, when antagonism is needed It is as strongly basic as heparin is acidic, which explains its immediate action Protamine sulphate, mg by slow i.v injection, neutralises about 100 units of heparin derived from mucosa (mucous) or 80 units of heparin from lung; 28 but if the heparin was given more than 15 previously, the dose must be scaled down Protamine itself has some anticoagulant effect and overdosage must be avoided The maximum dose must not exceed 50 mg Its effectiveness in patients treated with LMW heparins is unknown Heparinoids Danaparinoid sodium is a mixture of several types of non-heparin glycosaminoglycans extracted from pig intestinal mucosa (84% heparan sulphate) It is an effective anticoagulant for the treatment of deep vein thrombosis (DVT) prophylaxis in high-risk patients and treatment of patients with heparin-associated thrombocytopenia USES OF ANTICOAGULANTS Venous disease Established venous thromboembolism An anticoagulant is used to prevent extension of an existing thrombus while its size is reduced by natural thrombolytic activity Effective anticoagulation prevents formation of fresh thrombus, which is more likely to detach and embolise, particularly if it is in large proximal veins; it also helps to recanalise veins and to clear vein valves of thrombus and should thus prevent long-term consequences such as swelling of the leg and stasis ulceration The site and extent of thrombosis should be established by venous ultrasound The majority of patients with proximal vein thrombosis or calf vein thrombosis can be treated with outpatient low molecular weight heparin, weight-adjusted and administered once or twice daily according to manufacturer's recommendations It should be continued for a total of 4-7 days and until the signs of thrombosis (heat, swelling of the limb) have settled Warfarin should be started at the same time as the heparin Patients with a symptomatic pulmonary embolism should be treated in hospital with LMW heparin or highdose intravenous unfractionated heparin (above) In patients with an uncomplicated DVT following a precipitating event (e.g orthopaedic surgery), warfarin may be necessary for only weeks if the patient has returned to normal mobility and the precipitating factor(s) have been eliminated The patient should wear a well-fitting compression 575 28 DRUGS AND HAEMOSTASIS stocking to increase flow in deep veins, should exercise the leg and should be encouraged to mobilise as soon as the discomfort has settled The risk of recurrence reduces with passage of time after the initial event In cases of DVT uncomplicated by pulmonary embolus, months of anticoagulant therapy appears adequate Where there is evidence of pulmonary embolus it is common practice to continue therapy for to 12 months Thrombolytic therapy with streptokinase or urokinase i.v may be used for life-threatening thrombosis, e.g major pulmonary embolism with compromised haemodynamics (see p 580) Anticoagulant therapy may be life-saving in thromboembolic pulmonary hypertension Long-term anticoagulation with warfarin to prevent arterial thromboembolism should be considered for any patient who has a large left atrium or a low cardiac output or paroxysmal or established atrial fibrillation (with or without cardiac valvular disease) Where warfarin is considered unsuitable, aspirin may be substituted, for it prevents stroke in patients with atrial fibrillation, though less effectively The combination of warfarin and aspirin, once regarded as contraindicated, may yet be most effective in patients at high risk of embolism Heparin is given for h to patients after undergoing angioplasty Heparin, aspirin or both are used to prevent myocardial infarction in the acute phase of unstable angina Prevention of venous thrombosis Oral anticoagulant reduces the risk of thromboembolism in conditions in which there is special hazard, e.g after surgery Partly because of the danger of bleeding and partly because of the effort of maintaining control, oral anticoagulants have not been widely adopted Numerous trials, however, have shown the protective effect of low doses of unfractionated heparin (5000 units every 8-12 h s.c.) and more recently LMW heparin (dose adjusted for bodyweight and/or risk) against deep leg vein thrombosis The significant fact is that it takes a lot less heparin to prevent thrombosis than it does to treat established thrombosis, because heparin acts in low concentration at an early stage in the cascade of coagulation factors which leads to fibrin formation (see above) Low-dose unfractionated heparin or LMW heparin can be used to prevent venous thromboembolism in other high-risk patients, e.g those confined to bed and immobilised with strokes, cardiac failure or malignant disease Spontaneous bleeding has not been a problem with this form of anticoagulant treatment Low MW dextrans (see later) Peripheral arterial occlusion Heparin may prevent extension of a thrombus and hasten its recanalisation; it is commonly used in the acute phase following thrombosis or embolism There is no case for treating ischaemic peripheral vascular disease with an oral anticoagulant (for prevention, see Antiplatelet drugs) Cardiovascular disease Acute myocardial infarction Anticoagulation with heparin is used to reduce the risk of venous thromboembolism, and the risk and size of emboli from mural thrombi following acute myocardial infarction 576 Long-term anticoagulant prophylaxis The decision to use warfarin long-term must take into account nondrug factors The patient should be told of the risks of haemorrhage, including those introduced by taking other drugs, and of the signs of bleeding into the alimentary or urinary tracts All patients should carry a card stating that they are receiving an oral anticoagulant Such therapy should be withheld from a patient who is considered to be unlikely or unable to comply with the requirements of regular medication and blood testing The incidence of haemorrhagic complications is directly related to the level of anticoagulation; safety and good results can be obtained only by close attention to detail The INR should be monitored at a maximum interval of weeks in patients on a stable maintenance dose and more frequently in patients with an unstable INR Surgery in patients receiving anticoagulant therapy For elective surgery warfarin may be withdrawn about days before the operation and resumed about days later if conditions seem appropriate; heparin may be used in the intervening period In COAGULATION SYSTEM patients with mechanical prosthetic valves, heparin is substituted at full dosage days before surgery, and restarted 12-24 h after the operation Warfarin is restarted when the patient resumes oral intake Emergency surgery: proceed as for bleeding (p 571) For dental extractions: omission of warfarin for 1-2 days to adjust the INR to the lower limit of the therapeutic range is adequate (INR should be tested just prior to the procedure) The usual dose of warfarin can be resumed the day after extraction Aspirin, taken prophylactically for thromboembolic disorders (see below), is commonly discontinued weeks before elective procedures and restarted when oral intake permits Contraindications to anticoagulant therapy Contraindications relate mostly to conditions in which there is a tendency to bleed, and are relative rather than absolute, the dangers being balanced against the possible benefits They include: • Behavioural: inability or unwillingness to cooperate, dependency on alcohol • Neurological: stroke within weeks, or surgery to the brain or eye • Alimentary: active peptic ulcer, active inflammatory bowel disease, oesophageal varices, uncompensated hepatic cirrhosis • Cardiovascular: severe uncontrolled hypertension • Renal: if function is severely impaired • Pregnancy: in early pregnancy the fetal warfarin syndrome is a hazard and bleeding may cause fetal death in late pregnancy • Haematological: pre-existing bleeding disorder Emerging anticoagulant drugs Recent strategies have sought to develop substances that act at different sites in the coagulation cascade and agents that inhibit thrombin, or prevent thrombin generation, or block initiation of the coagulation process or enhance endogenous anticoagulation have reached the clinical arena Novel delivery systems, using synthetic amino acids (e.g SNAC) to facilitate absorption, allow the oral administration of unfractionated or LMW heparins sufficient to prolong the APTT These are being evaluated 28 Direct inhibitors of thrombin inactivate fibrinbound thrombin which may promote thrombus extension (as opposed to heparin which acts indirectly through antithrombin) as follows: Hirudin, a polypeptide originally isolated from the salivary glands of the medicinal leech Hirudo medicalis, is now produced by recombinant technology It is a potent and specific inhibitor of thrombin with which it forms an almost irreversible complex It is cleared predominantly by the kidneys and has a t l / of 40 minutes after i.v administration No antidote is available for a bleeding patient It has been used successfully in patients with heparininduced thrombocytopenia (HIT), thromboprophylaxis in elective hip arthroplasty, unstable angina and myocardial infarction Bivalirudin is a semisynthetic bivalent thrombin inhibitor which contains an analogue of the Cterminal of hirudin; this binds to thrombin but having a lower affinity, produces only transient inhibition and hence may be safer It has been used in patients undergoing coronary angioplasty Argatroban, a carboxylic acid derivative, binds noncovalently to the active site of thrombin and is an effective alternative to heparin in patients with HIT Other highly selective agents in clinical development include blockers of: factor IXa, an essential factor for amplification of the coagulation cascade (by active-site-blocked factor IXa or monoclonal antibodies against the factor), the factor Vila/tissue factor pathway, the initiating step of coagulation [with recombinant tissue factor pathway inhibitor (TFPI) the analogue of the natural inhibitor], and factor X or factor Xa and inhibition of factor VIIa within the factor Vila/tissue factor complex (by NAPc2, a recombinant nematode anticoagulant peptide) Fibrinolytic (thrombolytic) system The preservation of an intact vascular system requires not only that blood be capable of coagulating but 577 28 DRUGS AND HAEMOSTASIS also that there should be a mechanism for removing the products of coagulation when they have served their purpose of stopping a vascular leak This is the function of the fibrinolytic system, the essential features of which are shown in Figure 28.2 The system depends on the formation of the fibrinolytic enzyme plasmin from its precursor protein, plasminogen, in the blood During the coagulation process, plasminogen binds to specific sites on fibrin Simultaneously the natural activators of plasminogen, i.e tissue plasminogen activator (tPA) and urokinase, are released from endothelial and other tissue cells and act on plasminogen to form plasmin The result is that plasmin formation only takes place locally on the fibrin surface but not generally within the circulation where widespread defibrination would occur and the whole coagulation mechanism would be compromised Since fibrin is the framework of the thrombus, its dissolution clears the clot away Fibrinolytics (thrombolytics) can remove established thrombi and emboli Inhibitors of the fibrinolytic system (antifibrinolytics) can be of value in certain haemorrhagic states notably those characterised by excessive fibrinolysis DRUGSTHAT PROMOTE FIBRINOLYSIS An important application of fibrinolytic drugs has been to dissolve thrombi in acutely occluded coronary arteries, thereby to restore blood supply to ischaemic myocardium, to limit necrosis and to improve prognosis The approach is to give a plasminogen activator intravenously by infusion or by bolus injection in order to increase the formation of the fibrinolytic enzyme plasmin Those currently available include: Streptokinase is a protein derived from (3-haemolytic streptococci: it forms a complex with plasminogen (bound loosely to fibrin) where it converts plasminogen to plasmin Too rapid administration causes abrupt fall in blood pressure The t l / is 20 Anistreplase (anisoylated plasminogen Streptokinase activator complex, APSAC), is the plasminogenstreptokinase complex (above) in which the enzyme centre that converts plasminogen to plasmin is protected from deactivation, so prolonging its action 578 Fig 28.2 Blood fibrinolytic system The tl/2 is 70 It is not available in some countries Urokinase made from human fetal kidney cells in tissue culture, is a direct activator of plasminogen The tl/2 is 15 Streptokinase, anistreplase and urokinase are not well absorbed by fibrin thrombi and are called nonfibrin-selective They convert plasminogen to plasmin in the circulation, which depletes plasma fibrinogen and induces a general hypocoagulant state This does not reduce their local thrombolytic potential but increases the risk of bleeding Recombinant prourokinase, as the name suggests, is produced by recombinant DNA technology; on binding to fibrin it converts to urokinase The tl/2 is Alteplase (rt-PA) (tl/2 min) is tissue type plasminogen activator produced by recombinant F I BRI N O L Y T I C ( T H R O M B O LY T I C ) S Y S T E M DNA technology Reteplase (tl/2 15 min) is another recombinant human protein Recombinant prourokinase and alteplase are termed fibrin-selective, for they bind strongly to fibrin, and are capable of dissolving aging or lysisresistant thrombi better than nonfibrin-selective agents These drugs are less likely to produce a coagulation disturbance in the plasma, i.e they are selective for thrombi USES OFTHROMBOLYTIC DRUGS Coronary artery thrombolysis (See also Ch 23) Timing of administration The earlier thrombolysis is given the better the outcome Treatment commencing within the first h of onset is a realistic aim but thrombolysis up to 12 h is still worthwhile Benefit is most striking in patients with anterior myocardial infarction treated within h of onset Anistreplase can be given i.v over 4-5 (and so more easily out of hospital); its effect persists for 6-9 h Other agents are normally infused i.v over 1-3 h with most of the dose being given early in that period Retelpase is given as a double bolus 30 apart Reduction in mortality (see also Myocardial infarction, p 485) There is now compelling evidence that streptokinase, anistreplase, alteplase and retelpase reduce mortality with an acceptable frequency of adverse effects.14 Comparisons between these drugs show no apparent survival advantage of one over the others in respect of survival.15,16 Both streptokinase and t-PA decrease mortality by about 25% when used alone but by 40-50% when either agent is used with aspirin17 which reduces the incidence of reinfarction Those under 75 years appeared to gain most from thrombus dispersal but 'physiological' age is more important than chronological age Stroke may complicate myocardial infarction and is considered usually to be embolic, for its incidence correlates with the extent of myocardial infarction Evidence18 indicates that the combination of thrombolysis plus aspirin lowers the overall risk of stroke, possibly by limiting the size of the infarct, 28 or by reducing thromboembolic episodes, or by both Thrombolysis may also be valuable in persistent unstable angina and especially where arteriography demonstrates substantial thrombus in coronary arteries Adverse effects Bleeding is the most important complication and usually occurs at a vascular lesion, e.g the site of injection, for fibrinolytic therapy does not distinguish between an undesired thrombus and a useful haemostatic plug If the contraindications are followed, the incidence of bleeding severe enough to require transfusion is < 1% Nausea and vomiting may occur Multiple microemboli from disintegration of preexisting thrombus anywhere in the vascular system may endanger life; these commonly originate in an enlarged left atrium, or a ventricular or aortic aneurysm Cardiac arrhythmias result from reperfusion of ischaemic tissue These vary in type and are often transient, a factor which may influence the decision whether or not to treat Allergy Streptokinase and anistreplase are antigenie and anaphylactic reactions with rash, urticaria and hypotension may occur for most people have circulating antibodies to streptococci Antibodies persist after exposure to these drugs and their reuse should be avoided between days and 12 months as the recommended dose may not overcome immune resistance to plasminogen activation Contraindications to thrombolytic drug use (see Myocardial infarction, p 485) Noncoronary thrombolysis Pulmonary embolism Thrombolysis is superior to heparin at relieving obstructed veins demonstrated radiologically While a reduction in mortality is thus implied, the numbers of cases reported in clinical trials of thrombolytics have been insufficient to 14 Carins J A et al 1992 Chest 102 (Suppl): 482S-507S The International Study Group 1990 Lancet 336: 71-75 16 ISIS-3 Collaborative Group 1992 Lancet 339: 753-770 17 Carins J A et al 1998 Chest 114: 634S-657S 18 ISIS-2 Collaborative Group 1988 Lancet 2: 349-360 15 579 28 DRUGS AND HAEMOSTASIS provide conclusive statistical proof There is, nevertheless, a strong impression that thrombolysis is beneficial where pulmonary embolism is accompanied by signs of haemodynamic decompensation (raised jugular venous pressure, pulse rate > 100 beats/min, systolic pressure < 100 mmHg, arterial oxygen desaturation) Alteplase 100 mg may be infused over h, followed by an i.v infusion of heparin Deep vein thrombosis Thrombolysis may be justified where the affected vessels are proximal and the risk of pulmonary embolism is high Complete lysis may be achieved in 50% of cases treated within days of onset Arterial occlusion Systemic or local thrombolysis may be considered for arterial occlusions distal to the popliteal artery (thrombectomy being the usual therapeutic approach for occlusion of < 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 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 considered for ocular thrombosis (urokinase) and for thrombosed arteriovenous shunts (streptokinase) DRUGSTHAT PREVENT FIBRINOLYSIS Antifibrinolytics are useful in a number of bleeding disorders Tranexamic acid competitively inhibits the binding of plasminogen and t-PA to fibrin and effectively blocks conversion of plasminogen to plasmin (which causes dissolution of fibrin); fibrinolysis is thus retarded After an i.v bolus injection it is excreted largely unchanged in the urine; the tl/2 is 1.5 h It may also be administered orally or topically The principal indication for tranexamic acid is to prevent the hyperplasminaemic bleeding state that results from damage to certain tissues rich in plasminogen activator, e.g after prostatic surgery, tonsillectomy, uterine cervical conisation, and 580 menorrhagia, whether primary or induced by an intrauterine contraceptive device Tranexamic acid may also reduce bleeding after ocular trauma and in haemophiliacs after dental extraction where it is normally used in combination with desmopressin The drug benefits some patients with hereditary angioedema presumably by preventing the plasmininduced uncontrolled activation of the complement system which characterises that condition Tranexamic acid may be of value in thrombocytopenia (idiopathic or following cytotoxic chemotherapy) to reduce the risk of haemorrhage by inhibiting natural fibrinolytic destabilisation of small platelet plugs; the requirement for platelet transfusion is thereby reduced It may also be used for overdose with thrombolytic agents Adverse effects are rare but include nausea, diarrhoea and sometimes orthostatic hypotension It is contraindicated in patients with haematuria as it will prevent clot lysis in the urinary tract and result in 'clot colic' Aprotinin is a naturally-occurring inhibitor of plasmin and other proteolytic enzymes which has been used to limit bleeding following open heart surgery with extracorporeal circulation, and for the treatment of life-threatening haemorrhage due to hyperplasminaemia complicating surgery of malignant tumours or thrombolytic therapy or in Jehovah's witnesses.19 It must be administered intravenously or topically Platelets Platelets support haemostasis in three ways: first by sticking to exposed collagen to form a physical barrier at the site of vessel injury; second by accelerating the activation of coagulation proteins and finally by release of storage granule contents promotes vasoconstriction and wound healing SOME PHYSIOLOGY Circulating 'resting' platelets not stick to healthy endothelium or each other but if a vessel wall is 19 A religious sect that is opposed to blood transfusion on a scriptural basis PLATE LETS breached they react at the site by four steps: attachment, spreading, secretion and aggregation Exposure of constituents of the subendothelial matrix most notably collagen initiates platelet attachment which is stabilised by von Willebrand factor Shape change of the attached platelets, spreading along the fibrils permits multiple tight contacts with the matrix and there is simultaneous release of thromboxane-A2 (TXA2) and adenosine diphosphate (ADP) which recruit additional platelets Agonists in the microenvironment also trigger secretion of the contents of intracellular storage granules which activate circulating platelets and vasoconstriction (including proteins, enzymes, enzyme inhibitors, vasoactive and other peptides and agents that participate in the coagulation process) and translocation of negatively charged phospholipids to the outer surface of the plasma membrane providing a binding site for coagulation proteins (an activity known as 'platelet factor 3') These platelets interact with each other and aggregate through binding of fibrinogen or fibrin to the surface through glycoprotein (GP) Ilb/IIIa (integrin aIIb B3) to form an effective plug to seal the injured vessel which is stabilised by cross linked fibrin 28 release of active substances (see above), and low concentrations of cyclic AMP have the opposite effect The quantity of cyclic AMP within platelets is under enzymatic control, for it is formed by the action of adenylate cyclase and degraded by phosphodiesterase Platelet adenylate cyclase formation in turn is stimulated by prostacyclin (from the endothelium, also called PGI2) and inhibited by thromboxaneA2 (from within platelets, also called TXA2) Hence the action of thromboxane-A2 lowers cyclic AMP concentration and promotes platelet adhesion; prostacyclin raises cyclic AMP concentration and prevents platelet adhesion Prostacyclin and thromboxane-A2 are derived from arachidonic acid which is a constituent of cell walls, both platelet and endothelial Cyclooxygenase (COX, PGH synthase), an enzyme present in cells at both sites, converts arachidonic acid to cyclic endoperoxides which are further metabolised by prostacyclin synthase to prostacyclin in the endothelium and by thromboxane synthase to thromboxane-A2 in platelets Thus prostacyclin is principally The system that enables platelets to distinguish between healthy and damaged endothelium is shown in simplified form in Figure 28.3 It is a continuation of, and should be studied in conjunction with, the general diagram for eicosanoids on page 281 Platelet mechanisms The mechanism which transforms a freely circulating resting platelet (surrounded by fibrinogen and buffeted in the circulation) into an adherent platelet has been a frequent target for drug development Platelet aggregation does not occur as long as the resting conformation of GP IIb/IIIa is maintained and several external and internal factors dampen activation signals Cyclic AMP plays a key role High concentrations of intraplatelet cyclic AMP inhibit platelet adhesion, aggregation and the cyclic AMP 581 28 DRUGS AND HAEMOSTASIS formed in the endothelium whereas thromboxane-A2 is formed mainly in platelets These differences in the prostaglandins synthesised in endothelium and platelets are important Intact vascular endothelium does not activate platelets because of the high concentration of prostacyclin in the intima Subintimal tissues contain little prostacyclin and platelets, under the influence of thromboxaneA2/ immediately adhere and aggregate at any breach in the intima Atheromatous plaques not generate prostacyclin—which explains platelet adhesion and thrombosis at these sites Endothelial cells also produce nitric oxide which raises cyclic GMP levels in platelets to inhibit activation and have on their surface ectoADPase (CD39) that metabolises secreted ADP before it can cause platelet activation Inhibitors or activators of platelet aggregation act directly or indirectly by altering the rate of formation or degradation of platelet cyclic AMP Local concentrations of these substances determine whether the platelet adhesion/aggregation process will occur DRUGSTHAT INHIBIT PLATELET ACTIVITY (ANTIPLATELET DRUGS) (See also Myocardial infarction Ch 23) Aspirin (acetylsalicylic acid) acetylates and thus inactivates COX, the enzyme responsible for the first step in the formation of prostaglandins, the conversion of arachidonic acid to prostaglandin H2 It follows from the diagram on page 281 (Fig 15.1) that aspirin can prevent formation of both thromboxane-A2 (TXA2) and prostacyclin (PGI2) Acylation of COX is irreversible and, as the platelet is unable to synthesise new enzyme, COX activity is irreversibly lost for its lifetime (8-10 d) Therapeutic interest in the antithrombotic effect of aspirin has centred on separating its actions on thromboxaneA2 and prostacyclin formation, and this can be achieved by using a low dose Thus 75-100 mg/d by mouth is sufficient to abolish synthesis of thromboxane-A2 without significant impairment of prostacyclin formation, i.e amounts substantially below the 2.4 g/d used to control pain and inflammation Low-dose aspirin is yet not without risk: 582 some 13% of episodes of peptic ulcer bleeds in people over 60 years can be attributed to prophylactic asprin (use in the community about 8%).20 Dipyridamole reversibly inhibits platelet phosphodiesterase (see Fig 28.3) and in consequence cyclic AMP concentration is increased and platelet (thrombotic) reactivity reduced; evidence also suggests that its antithrombotic effect may derive from release of prostaglandin precursors by vascular endothelium Dipyridamole is extensively bound to plasma proteins and has a tl/2 of 12 h Ticlopidine is a thienopyridine derivative that inhibits ADP-dependent platelet aggregation It is converted to its active form by metabolism by the liver and the tl/2 of the parent drug is 40 h Ticlopidine is more effective than aspirin in reducing stroke in patients with transient ischaemic attacks (TIA) but aspirin is safer and less expensive It is also effective in reducing the risk of the combined outcome of stroke, myocardial infarction (MI) or vascular death in patients with thromboembolic stroke, decreasing vascular death and MI in patients with unstable angina, reducing acute occlusion of coronary bypass grafts and improving walking distance and decreasing vascular complications in patients with peripheral vascular disease It may be used to prevent stroke in patients who are intolerant of aspirin Neutropenia is the most serious adverse effect (risk 2.4%) and is greatest in the first 12 weeks of therapy; leucocyte counts should be checked every weeks during this period Diarrhoea and other gastrointestinal symptoms may be induced in a third of patients Clopidogrel is also a thienopyridine derivative which is also more effective than aspirin for the prevention of ischaemic stroke, MI or vascular death in patients at high risk but it is not associated with neutropenia It is more expensive than aspirin though safer than ticlodipine Epoprostenol (prostacyclin) may be given to prevent platelet loss during renal dialysis, with or without heparin; it is infused i.v and s.c (tl/2 min) It is a potent vasodilator 20 Weil J et al 1995 Prophylactic aspirin and risk of peptic ulcer bleeding British Medical Journal 310: 827-830 PLATE LETS Glycoprotein (GP) IIb-IIIa antagonists The platelet glycoprotein Ilb-IIIa complex is the predominant platelet integrin,21 a molecule restricted to megakaryocytes and platelets which mediates platelet aggregation via the binding of adhesive proteins such as fibrinogen and von Willebrand factor (vWF) Where there is hereditary absence of the GP Ilb-IIIa complex (Glanzmann's thrombasthenia) platelets are incapable of aggregation by all physiological agonists GP Ilb-IIIa antagonists have been developed as antiplatelet agents and administered intravenously, they inhibit the final common pathway of platelet aggregation: binding of fibrinogen or vWF to the GP IIb-IIIa complex They are more complete inhibitors than either aspirin or clopidogrel which inhibit only the cyclo-oxygenase or ADP pathway respectively GP IIb-IIIa antagonists also have an anticoagulant effect through inhibition of prothrombin binding to the complex and inhibition of procoagulant platelet-derived microparticle formation Platelet aggregation is inhibited in a dose-dependent manner Abciximab is a human-murine chimeric monoclonal antibody Fab fragment that binds to the GP IIb-IIIa complex with high affinity and slow dissociation rate After i.v administration it is cleared rapidly from plasma (tl/2 20 min) Abciximab (0.25 mg/kg bolus then 0.125 microgram/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 This reduces the risk of death, MI or need for urgent coronary artery bypass grafting after percutaneous coronary angioplasty and benefit is maintained up to years The dose causes and maintains blockade of > 80% receptors, causing > 80% reduction in aggregation Patients also receive aspirin and heparin and if a coronary stent has been inserted, either clopidogrel or ticlodipine Abciximab is also effective in refractory unstable angina prior to percutaneous coronary intervention It has a potential role in combination with low dose thrombolysis in acute myocardial infarction and as a single agent in stroke 28 Eptifibatide is a cyclic heptapeptide based upon the Lys-Gly-Asp sequence Tirofiban and lamifiban are nonpeptide mimetics All three are competitive inhibitors of the GPIIb-IIIa complex with lower affinities and higher dissociation rates than abciximab and short plasma tl/2 (2-2.5 h) Platelet aggregation returns to normal 30 to h after discontinuation Eptifibatide and tirofiban are effective in acute coronary syndromes Lamifiban is undergoing clinical development Adverse effects Haemorrhage occurs but is less of a problem with low doses of heparin; it remains a particular risk in patients treated after failed fibrinolytic therapy for acute myocardial infarction Platelet transfusion after cessation of abciximab is necessary for refractory or life threatening bleeding After transfusion, the antibody redistributes to the transfused platelets, reduces the mean level of receptor blockade and improves platelet function Thrombocytopenia may occur from hour to days after commencing treatment in up to 1% of patients This necessitates platelet counts at 2-4 hours 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 Dazoxiben, an inhibitor of thromboxane-A2 but not of prostacyclin synthesis, is being evaluated in cardiovascular disease Dextrans, particularly of MW 70 000 (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 They are rarely used USES OF ANTIPLATELET DRUGS 21 Integrins are cell surface adhesion receptors consisting of non-covalently associated alpha- and beta- subunits, now redesignated integrin aIIb B3 Antiplatelet therapy protects 'at risk' patients against stroke, myocardial infarction or death A meta-analysis of 145 clinical trials of prolonged 583 28 DRUGS AND HAEMOSTASIS antiplatelet therapy versus control and 29 trials between antiplatelet regimens found that the chance of nonfatal myocardial infarction and nonfatal stroke were reduced by one-third, and that there was a one-sixth reduction in the risk of death from any vascular cause.22 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 patients for every 100 treated Aspirin is by far the most commonly used antiplatelet agent The optimum dose is not certain but one not exceeding aspirin 325 mg is acceptable, and 75-100 mg/d 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 was studied systematically.23 Many patients who take aspirin for vascular disease may also require an NSAID for, e.g joint disease, and it may be argued that the NSAID renders aspirin unnecessary as both act by inhibition of prostaglandin G/H synthase As inhibition by aspirin is irreversible and that by NSAIDs may not be, continued use of aspirin in such circumstances seems prudent, especially if NSAID use is intermittent Haemostatics Etamsylate (Dicynene) is given systemically to reduce capillary bleeding, e.g in menorrhagia Adrenaline (epinephrine) may be useful for epistaxis, stopping haemorrhage by local vasoconstriction when applied by packing the nostril with ribbon gauze soaked in adrenaline solution Fibrin glue consists of fibrinogen and thrombin contained in two syringes, the tips of which form a common port The two components are thus delivered in equal volumes to a bleeding point where fibrinogen is converted 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 below) 22 Antiplatelet Trialists' Collaboration 1994 British Medical Journal 308: 81 23 Antiplatelet Trialists' Collaboration 1994 British Medical Journal 308:159 584 • Myocardial infarction.Aspirin should be given indefinitely to patients who have survived myocardial infarction.There is as yet no case for using aspirin to prevent myocardial infarction in those without important risk factors for the disease • Transient ischaemic attacks (TIAs) or minor ischaemic stroke.There is grave risk of progression to completed stroke and patients should receive aspirin indefinitely Before starting treatment it is important to exclude intracerebral haemorrhage (by computed tomography) and other conditions that mimic TIAs, e.g cardiac arrhythmia, migraine, focal epilepsy and hypoglycaemia • Unstable angina.The chance of myocardial infarction is high and aspirin should be used with other drugs, i.e a (3adrenoceptor antagonists nitrate, a calcium channel blocker and possibly heparin i.v as is judged appropriate • Arterial grafts, peripheral vascular disease.Aspirin (possibly combined with dipyridamole for grafts) should be given to prevent occlusion.These drugs may also be used to protect against thrombotic occlusion following percutaneous transluminal coronary angioplasty • Inhibitors of ADP-dependent platelet aggregation, e.g ticlopidine.clopidorgrel.and glycoprotein llb-llla antagomists, e.g abciximab, can be expected to form part of regimens for cardiovascular disease, as evidence accumulates Sderosing agents Chemicals may be used to cause inflammation and thrombosis in veins so as to induce permanent obliteration, e.g ethanolamine oleate injection, sodium tetradecyl sulphate (given i.v for varicose veins) and oily phenol injection (given submucously for haemorrhoids) Local reactions, tissue necrosis and embolus can occur Haemophilia Management of the haemophilia A and haemophilia B (genetic deficiencies of factor VIII or IX) is a matter for those with special expertise but the following points are of general interest • Haemorrhage can sometimes be stopped by pressure; edges of superficial wounds should be strapped, not stitched • Minor bleeding can be stopped with plasma factor levels of 25-30% but severe bleeding requires a level of at least 50% and surgical ... syndrome similar to vitamin K deficiency.3 Bishydroxycoumarin (dicoumarol) was introduced into clinical practice as an anticoagulant in the 1940s and other structurally related vitamin K antagonists... due to intracranial haemorrhage Management of bleeding or over-anticoagulation is guided by the clinical state and the INR:7 • Haemorrhage threatening life or major organs In addition to blood... 1285-1288 British Society for Haematology 1990 Guidelines on oral anticoagulants, 2nd edn Journal of Clinical Pathology 43: 177-183 (Reproduced with permission) A study of 261 patients who received