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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.

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  3. 28 Drugs andhaemostasis SYNOPSIS (anticoagulants, thrombolytics, antiplatelet agents) are valuable in the management of pathological Occlusive vascular disease is a major cause of thrombus formation within blood vessels, or of morbidity and mortality.There is now better pathological bleeding. They are classified according understanding of the mechanisms by which the to which component of the system they affect. 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 Coagulation system prevent or reverse (lyse) pathological thrombosis. The blood coagulation system is shown in simplified • Coagulation system: the mode of action of form in Figure 28.1. It consists of glycoprotein drugs that promote coagulation and that components that circulate in (necessarily inactive) prevent it (anticoagulants) and their uses pro-enzyme or pro-cofactor (factors V and VIII) • Fibrinolytic system: the mode of action of form. The activated enzymes are serine proteases. drugs that promote fibrinolysis (fibrinolytics) Physiological coagulation (the 'extrinsic' pathway) and their uses to lyse arterial and venous begins when tissue factor (TF, tissue thromboplastin), thrombi (thrombolysis) exposed by vascular injury, activates and complexes • Platelets: the ways that drugs that inhibit with factor VII to activate factors IX and X which platelet activity are used to treat arterial complex with Villa and Va respectively on mem- disease brane 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 The haemostatic system is complex but can be accelerating coagulation and cross-linking fibrin separated into the following major components: (-F-F-F-). • Formation of fibrin (coagulation), which The 'intrinsic' pathway refers to coagulation in stabilises the platelet plug vitro. It is initiated when factor XII with the cofactor high molecular weight kininogen (HMWK) comes • Dissolution of fibrin (fibrinolysis) into contact with a foreign surface, e.g. glass, • Platelets, which form the haemostatic plug • Bloodvessels. kaolin. Thus it has no physiological role (and patients lacking factor XII do not have a bleeding Drugs that interfere with the haemostatic system disorder). 567
  4. 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 exoge- nous 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 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 Fig. 28.1 Blood coagulation system (see text) 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 The classical separation of the intrinsic and extrinsic liver by y-carboxylation of glutamic acid residues on pathways is a simplification but remains a useful the molecule. The y-carboxyglutamic acid residues in-vitro phenomenon for monitoring coagulation. permit calcium to bind to the molecule which in Both in vivo and in vitro the systems are dependent turn mediates binding to negatively charged phos- on the presence of Ca++ ions and key in-vivo steps pholipid surfaces. The vitamin K-dependent proteins involve the formation of macromolecular complexes are coagulation factors II (prothrombin), VII, IX and on membrane surfaces, usually those of platelets. X, and the anticoagulant (regulatory) proteins, Cascade reactions culminate in the generation of proteins C and S. During y-carboxylation of the fibrin and its polymerisation by factor XIII to form a proteins by the vitamin K dependent carboxylase, fibrin clot. the reduced form of vitamin K is converted to an 568
  5. COAGULATION SYSTEM 28 epoxide, an oxidation product, which is subsequently Menadiol sodium phosphate in moderate doses reduced again enzymatically to the active vitamin causes haemolytic anaemia and for this reason it K, i.e. there exists an interconversion cycle (the should not be given to neonates, especially those that vitamin K cycle) between vitamin K epoxide and are deficient in glucose-6-phosphate dehydrogenase; reduced and active vitamin K (KH2). When the their immature livers are unable to cope with the vitamin is deficient or where its action is inhibited heavy bilirubin load and there is danger of by drugs, coagulation proteins which cannot bind kernicterus. Ca++ result; their physiologically critical binding Fat-soluble analogues of vitamin K which are to membrane surfaces fails to occur, and this available in some countries include acetome- impairs the coagulation mechanism. This non- or- naphthone and menaphthone. descarboxylated protein is called 'protein induced in vitamin K absence' or PIVKA. Indications for vitamin K or its analogues Deficiency may arise from: • Haemorrhage or threatened bleeding due to the coumarin or indandione anticoagulants. • bile failing to enter the intestine, e.g. obstructive Phytomenadione is preferred for its more rapid jaundice or biliary fistula action; dosage regimens vary according to the • certain malabsorption syndromes, e.g. coeliac degree of urgency and the original indication for disease, or after extensive small intestinal anticoagulation, as described on page 576. resection • Haemorrhagic disease of the newborn which • reduced alimentary tract flora, e.g. in newborn develops during the first week of life, usually infants and rarely after broad-spectrum between days 2-7 (and also late haemorrhagic antimicrobials. disease which presents at 6-7 months). The following preparations of vitamin K are Prophylaxis is recommended1 during the period available: of vulnerability with vitamin K Phytomenadione (phytonadione, Konakion), the (phytomenadione, as Konakion) 1 mg by single naturally occurring fat-soluble vitamin K1 acts i.m. injection at birth. Alternatively, vitamin K within about 12 h and should correct the INK may be given by mouth as two doses of a within 24-48 h. The i.v. formulation is used in colloidal (mixed micelle) preparation of emergency and must be administered slowly as an phytomenadione in the first week. Breast-fed anaphylactoid reaction with facial flushing, sweating, babies should receive a further 2 mg at one fever, chest tightness, cyanosis and peripheral month of age. Formula-fed babies do not need vascular collapse may occur. Patients with chronic this last supplement as the formula contains liver disease and those using histamine H2-receptor vitamin K. Fears that i.m. vitamin K might cause antagonists seem to be especially likely to react. childhood cancer have been allayed. Otherwise phytomenadione may be given i.m., s.c. • Hypoprothrombinaemia due to intestinal or orally. The preferred route depends on the malabsorption syndromes. Menadiol sodium urgency of correcting the haemorrhagic tendency. phosphate should be used as it is water-soluble. The i.m. route should be avoided if the INK is significantly prolonged as local intramuscular hae- DRUGSTHAT PREVENT morrhage may be induced; s.c. absorption is variable COAGULATION: ANTICOAGULANTS and despite the risk of allergic reaction, the intra- venous route ensures rapid delivery. There are two types of anticoagulant: Menadiol sodium phosphate (vitamin K3, Synkavit), Indirect-acting: coumarin2 and indandione drugs the synthetic analogue of vitamin K, being water- take about 72 h to become fully effective, act for soluble, is preferred in malabsorption or in states in several days, are given orally and can be antagonised which bile flow is deficient. The main disadvantage (see below) by vitamin K. is that it takes 24 h to act, but its effect lasts for 1 several days. The dose is 5-40 mg daily, orally. British National Formulary. 569
  6. 28 DRUGS AND HAEMOSTASIS Direct-acting: heparin, hirudin, bivalirudin and carboxylation sites (PIVKAs). This shift does not argatroban are rapidly effective, act for only a few take place until functional vitamin K-dependent hours and must be given parenterally. proteins made before the drug was administered are cleared from the circulation. The process occurs Indirect-acting anticoagulants at different rates for individual coagulation factors (VII tl/2 6 h, IX and X tl/2 24 h, prothrombin tl/2 72 h). Coumarins include warfarin and acenocoumarol Moreover, the anticoagulant proteins C and S have (nicoumalone). The vitamin K antagonists were a shorter tl/2 than the procoagulant proteins and discovered as a result of investigation of a haemor- their more rapid decline in concentration creates a rhagic disease of cattle that plagued farmers in the transient hypercoagulable state. This can be serious in Great Plains of the USA during the 1920s. The those who have inherited protein S and C disorder which was due to hypoprothrombinaemia deficiency who may develop skin necrosis and was caused by ingestion of spoiled sweet clover hay justifies initiating anticoagulation with heparin contaminated by specific toxins. The compound 3, 3'- until the effect of warfarin is well established. Thus methylene-bis-4-hydroxycoumarin was purified from the anticoagulant effect of warfarin is delayed and bacterial contaminants in the spoiled hay and was indeed the drug must be administered for 4-5 days found to produce a syndrome similar to vitamin K before the effect is properly therapeutic. Further- deficiency.3 Bishydroxycoumarin (dicoumarol) was more, the INR does not reliably reflect introduced into clinical practice as an anticoagulant in anticoagulant protection during this initial phase, the 1940s and other structurally related vitamin K because the vitamin K-dependent factors diminish antagonists followed; all share a common ring at different rates. structure with vitamin K. Warfarin is the most The great advantage of warfarin over heparin is widely used. that it can be given orally. Its chief disadvantage is the time lag before it exerts its effect, which is due to Warfarin its indirect mode of action. A similar time lag is found when the warfarin dose is altered or discontinued Mode of action. During the y-carboxylation of the as the tl/2 of the nonfunctioning proteins is coagulant factors II (prothrombin), VII, IX and X approximately that of functioning proteins. (and also the anticoagulant regulatory proteins C and S) in the liver, active vitamin K (KH2) is Pharmacokinetics. Warfarin is readily absorbed oxidised to an epoxide and must be reduced by the from the gastrointestinal tract and like all the oral enzymes vitamin K epoxide reductase and vitamin anticoagulants, is more than 90% bound to plasma K reductase to become active again (the vitamin K proteins. Its action is terminated by metabolism in cycle). Coumarins are structurally similar to vitamin the liver. Warfarin (t l / 2 36 h) is a racemic mixture of K and competitively inhibit vitamin K epoxide approximately equal amounts of two isomers S (tl/2 reductase and vitamin K reductase, so limiting 35 h) and R (tl/2 50 h) warfarin, i.e. it is in effect two availability of the active reduced form of the vitamin drugs. S warfarin is four times more potent than R to form coagulant (and anticoagulant) proteins. The warfarin. Drugs which interact with warfarin affect overall result is a shift in haemostatic balance in these isomers differently. favour of anticoagulation because of the accumulation of clotting proteins with absent or decreased y- 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 2 Coumarins are present in many plants and are important in prothrombin time. Usually the test is carried out the perfume industry; the smell of new mown hay and grass with a standardised thromboplastin and the result is due to coumarins. is expressed as the International Normalised Ratio 3 Campbell H A, Link K P 1941 Studies on the haemorrhagic sweet clover disease IV: the isolation and crystallisation of (INR), which is the ratio of the prothrombin time in the haemorrhagic agent. Journal of Biological Chemistry the patient to that in a normal (non-anticoagulated) 138: 21. person—taking account of the sensitivity of the 570
  7. COAGULATION SYSTEM 28 thromboplastin used. Oral anticoagulation is Cutaneous reactions, apart from purpura and commonly undertaken in patients who are already ecchymoses in those who are excessively antico- receiving heparin. The INR reliably reflects the agulated, include hypersensitivity, rash and alopecia. degree of prothrombin activity provided that the Skin necrosis due to a mixture of haemorrhage and activated partial thromboplastin time (APTT, a thrombosis occurs rarely where induction of warfarin measure of the anticoagulant effect of heparin, see therapy is over-abrupt and/or the patient has a below) is within the therapeutic range (1.5-2.5 genetically determined or acquired deficiency of times control). Warfarin therapy with an INR in the the anticoagulant protein C or its cofactor protein S; therapeutic range does not prolong the APTT. it can be very serious. Warfarin used in early pregnancy may injure the Dose. There is much inter-individual variation in fetus (other than by bleeding). It causes skeletal dose requirements. It is usual to initiate therapy disorders (5%) (bossed forehead, sunken nose, foci with 10 mg daily for 2 days, with the maintenance of calcification in the epiphyses) and absence of the dose then adjusted according to the INR using an spleen. Women on long-term warfarin should be established protocol.4 advised not to become pregnant while taking the The level of anticoagulation should be adjusted drug. Heparin should be substituted prior to to match the perceived risk of thrombosis, by the conception and continued through the first trimester, following guidelines:5 after which warfarin should replace heparin, as continued exposure to heparin may cause osteo- • INR 2.0-2.5 Prophylaxis of deep vein thrombosis porosis. Warfarin should be discontinued near term including surgery on high-risk patients (2.0-3.0 as it exacerbates neonatal hypoprothrombinaemia for hip surgery and fractured femur operations). and its control is too imprecise to be safe in labour; • INR 2.0-3.0 Treatment of deep vein thrombosis; heparin may be substituted at this stage for it can be pulmonary embolism; systemic embolism; discontinued just before labour and its anticoagulant prevention of venous thromboembolism in effect wears off in about 6 h. myocardial infarction; mitral stenosis with CNS abnormalities (microcephaly, cranial nerve embolism; transient ischaemic attacks; atrial palsies) are reported with warfarin used at any fibrillation. stage of pregnancy and are presumed to be due to • INR 3.0-4.5 Recurrent deep vein thrombosis and intracranial haemorrhage. pulmonary embolism; arterial disease including Management of bleeding or over-anticoagulation myocardial infarction; mechanical prosthetic is guided by the clinical state and the INR:7 heart valves. • Haemorrhage threatening life or major organs. In Adverse effects. Bleeding is the commonest com- addition to blood replacement, rapid reversal of plication of warfarin therapy. The incidence of major anticoagulation is achieved with prothrombin haemorrhage is about 5% per year6 and an identifi- complex concentrate (containing factors II, IX able risk factor is often present, e.g. thrombo- and X, and given i.v. as 50 units per kg of factor cytopenia, liver disease or vitamin K deficiency, an IX) or fresh frozen plasma. If full reversal of endogenous disturbance of coagulation, cancer or anticoagulation is judged necessary, recent surgery. Naturally, poor anticoagulant control phytomenadione 5 mg is then given by slow i.v. or drug interaction with warfarin increase the risk. injection. This renders the patient refractory to Haemorrhage is most likely to occur in the alimentary oral anticoagulant (but not to heparin) for about and renal tracts, and in the brain in those with 2 weeks. The thrombotic risk so created must be cerebrovascular disease. assessed for each patient and may be judged 4 Fennerty A et al 1988 British Medical Journal 297: 6 1285-1288. A study of 261 patients who received warfarin for 221 5 British Society for Haematology 1990 Guidelines on oral patient-years reported major haemorrhage in 5.3% after 1 anticoagulants, 2nd edn. Journal of Clinical Pathology 43: year and 10.6% after 2 years. Gitter M J et al 1995 Mayo 177-183 (Reproduced with permission). Clinic Proceedings 70: 725-733. 571
  8. 28 DRUGS AND HAEMOSTASIS unacceptable in some, e.g. those with prosthetic • Antimicrobials. Aztreonam, cefamandole, heart valves. For less severe haemorrhage, chloramphenicol, ciprofloxacin, co-trimoxazole, warfarin should be withheld and erythromycin, fluconazole, itraconazole, phytomenadione 0.5-2 mg may be given by slow ketoconazole, metronidazole, miconazole, i.v. injection if rapid correction of the INR is ofloxacin and sulphonamides (including co- necessary. trimoxazole) increase anticoagulant effect by • INR > 7 but without bleeding. Correct by mechanisms that include interference with withholding warfarin, and giving warfarin or vitamin K metabolism. Rifampicin phytomenadione 0.5 mg by slow i.v. injection if and griseofulvin accelerate warfarin metabolism judged appropriate. (enzyme induction) and reduce its effect. • INR 4.5-7.0. Manage by withholding warfarin Intensive broad-spectrum antimicrobials, e.g. for 1-2 days and then reviewing the INR. eradication regimens for Helicobacter pylori (see • INR 2.0-4.5 (the therapeutic range). Bleeding, p. 630), may increase sensitivity to warfarin by e.g. from the nose, alimentary or renal tract, reducing the intestinal flora that produce should be fully investigated as a local cause vitamin K. frequently exists. • Anticonvulsants. Carbamazepine, phenobarbital and primidone accelerate warfarin metabolism Withdrawal of oral anticoagulant. The balance of (enzyme induction); the effect of phenytoin is evidence is that abrupt, as opposed to gradual variable. Clonazepam and sodium valproate are withdrawal of therapy does not of itself add to the safe. risk of thromboembolism, for renewed synthesis of • Cardiac antiarrhythmics. Amiodarone, functional vitamin K dependent clotting factors propafenone and possibly quinidine potentiate takes several days. the effect of warfarin and dose adjustment is required, but atropine, disopyramide and Interactions. Oral anticoagulant control must be lignocaine do not interfere. precise both for safety and efficacy. If a drug that • Antidepressants. Serotonin reuptake inhibitors alters the action of warfarin must be used, the INR may enhance the effect of warfarin but tricyclics should be monitored frequently and the dose of may be used. warfarin adjusted during the period of institution • Gastrointestinal drugs. Avoid cimetidine and of the new drug until a new stable therapeutic dose omeprazole which inhibit the clearance of R of warfarin is identified; careful monitoring is also warfarin, and sucralfate which may impair its needed on withdrawal of the interacting drug. absorption. Ranitidine may be used but INR The following list, although not comprehensive, should be checked if the dose is high. Most identifies medicines that should be avoided and antacids are safe. those which may safely be used with warfarin. • Lipid-lowering drugs. Fibrates, and some statins, enhance anticoagulant effect. Colestyramine is • Analgesics. Avoid if possible, all NSAIDs best avoided for it may impair the absorption of including aspirin (but see p. 576, myocardial both warfarin and vitamin K. infarction)because of their irritant effect on • Sex hormones and hormone antagonists. Oestrogens gastric mucosa and action on platelets. increase the synthesis of some vitamin K Paracetamol is acceptable but doses over 1.5 g/d dependent clotting factors and progestogen-only may raise the INR. Dextropropoxyphene inhibits contraceptives are preferred. The hormone warfarin metabolism and compounds that antagonists danazol, flutamide and tamoxifen contain it, e.g. co-proxamol, should be avoided. enhance the effect of warfarin. Codeine, dihydrocodeine and combinations with • Sedatives and anxiolytics. Benzodiazepines may paracetamol, e.g. co-dydramol, are preferred. be used. 7 Based on recommendations of the British Society for Other vitamin K antagonists. Acenocoumarol Haematology. (nicoumalone) is similar to warfarin but seldom 572
  9. COAGULATION SYSTEM 28 used; it is eliminated in the urine mainly in un- activated coagulation factors of the intrinsic and changed form (t l / 2 24 h). Indandione anticoagulants common pathways including thrombin, factor Xa are practically obsolete because of allergic adverse and factor IXa (Fig. 28.1). Antithrombin is reactions unrelated to coagulation; phenindione (tl/2 homologous to members of the a-antitrypsin 5 h) is still available but also seldom used. family of serine protease inhibitors (serpins). On intravenous administration heparin binds to antithrombin and this leads to rapid inhibition of Direct-acting anticoagulants: heparin the proteases of the coagulation pathway. In the Heparin was discovered by a medical student, J. presence of heparin antithrombin becomes vastly McLean, working at Johns Hopkins Medical School more active (approximately 1000-fold) and in 1916. Seeking to devote one year to physiological inhibition is essentially instantaneous. Heparin research he was set to study 'the thromboplastic binding to antithrombin induces a conformational (clotting) substance in the body'. He found that change in antithrombin that locks the heparin in extracts of brain, heart and liver accelerated clotting place and is followed by rapid reaction with a target but that activity deteriorated during storage. To his protease. This reaction in turn reduces the affinity surprise, the extract of liver which he had kept of antithrombin for heparin, allowing the heparin to longest not only failed to accelerate but actually dissociate from the antithrombin/protease complex retarded clotting. His personal account proceeds: and to catalyse further antithrombin/protease interactions. After more tests and the preparation of other The importance of inhibition of factor Xa is that batches of heparophosphatide, I went one morning this factor is a critical step in both the intrinsic and to the door of Dr. Howell's office, and standing extrinsic coagulation systems and heparin is effective there (he was seated at his desk), I said 'Dr. in small quantities. This provides the rationale for Howell, I have discovered antithrombin'. He was giving low dose subcutaneous heparin to prevent most skeptical. So I had the Deiner, John thrombus formation. At a molecular level the capacity Schweinhant, bleed a cat. Into a small beaker full of of heparin to inhibit factor Xa has been found to its blood, I stirred all of a proven batch of depend on a specific pentasaccharide sequence heparophosphatides, and I placed this on Dr. which can be isolated in fragments of average MW Howell's laboratory table and asked him to call me 5000 (LMW heparins). LMW heparins inhibit factor when it clotted. It never did clot. [It was heparin.]8 Xa at a dose similar to standard heparin but have Heparin is a sulphated mucopolysaccharide much less antithrombin activity. These fragments which occurs in the secretory granules of mast cells are too short to inhibit thrombin which is the and is prepared commercially from a variety of principal action of conventional heparin (average animal tissues (generally porcine intestinal mucosa MW 15 000). Fibrin formed in the circulation binds or bovine lung) to give preparations that vary in to thrombin and protects it from inactivation by the molecular weight from 3000 to 30000 (average heparin-antithrombin complex, which may provide 15 000). It is the strongest organic acid in the body a further explanation for the higher doses of and in solution carries an electronegative charge. heparin needed to stop extension of a thrombus The low molecular weight (LMW) heparins (mean than to prevent its formation. Heparin also inhibits MW 4000-6500) are prepared from standard heparin thrombin through other inhibitors and, at higher by a variety of chemical techniques and commercial concentrations, accelerates plasminogen activation preparations (dalteparin, enoxaprin, tinzaparin) and inhibits platelet aggregation. contain different fractions and display different Apart from its anticoagulant properties, heparin pharmacokinetics. inhibits the proliferation of vascular smooth muscle cells and is involved in angiogenesis. Heparin also Mode of action. Heparin depends for its anti- coagulant action on the presence in plasma of a 8 McLean gives a fascinating account of his struggles to pay single chain glycoprotein, antithrombin (formerly his way through medical school, as well as his discovery of antithrombin III), a naturally-occurring inhibitor of heparin in: McLean J 1959 Circulation XIX: 75. 573
  10. 28 DRUGS AND HAEMOSTASIS inhibits certain aspects of the inflammatory response; between 0900 h and 1200 h (noon) as the anti- this is evident in the rapid resolution of inflam- coagulant effect of heparin exhibits circadian mation that accompanies deep vein thrombosis changes. when heparin is given. The convenience (and cost-effectiveness) of LMW heparin therapy has resulted in widespread changes Pharmacokinetics. Heparin is poorly absorbed in practice. Patients with acute venous thrombo- from the gastrointestinal tract and is given i.v. or embolism can be treated safely and effectively with s.c.; once in the blood its effect is immediate. LMW heparin as outpatients. Large-scale studies Heparin binds to several plasma proteins and to have demonstrated that outpatient treatment of sites on endothelial cells; it is also taken up by cells acute deep vein thrombosis (DVT) with unmonitored of the reticuloendothelial system and some is body-weight adjusted LMW heparin is as safe and cleared by the kidney. Due to these factors, effective as inpatient treatment with adjusted dose elimination of heparin from the plasma appears to intravenous standard heparin.9, 10, 11 Further trials involve a combination of zero-order and first-order have confirmed the safety and efficacy of LMW processes, the effect of which is that the plasma heparin therapy in acute pulmonary embolism12 biological effect tl/2 alters disproportionately with and that 80% of unselected patients with acute dose, being 60 min after 75 units per kg and 150 min thromboembolism can be safely treated as after 400 units per kg. outpatients.13 LMW heparins are less protein bound and have Prevention of thrombosis. Postoperatively or after a predictable dose-response profile when admin- myocardial infarction 5000 units of unfractionated istered s.c. or i.v. They also have a longer tl/2 than heparin should be given s.c. every 8 or 12 h without standard heparin preparations. monitoring (this dose does not prolong the APPT), or in pregnancy 5000-10 000 units s.c. every 12 h Monitoring heparin therapy. Control of standard with monitoring (except for pregnant women with heparin therapy is by the activated partial thrombo- prosthetic heart valves for whom specialist mon- plastin time (APTT), the optimum therapeutic itoring is needed). range being 1.5-2.5 times the control (which is LMW heparins have become the preferred drugs preferably the patient's own pretreatment APTT). for perioperative prophylaxis because of their con- An alternative method is to measure the plasma venience. They are as effective and safe as un- concentration of heparin using an anti-Xa assay fractionated heparin at preventing venous thrombosis aiming for a therapeutic concentration of 0.1-1.0 (see above). Once-daily s.c. administration suffices, U/ml. Therapeutic doses of LMW heparin do not as their duration of action is longer than that of prolong the APTT and, having predictable pharma- conventional heparin and no laboratory monitoring cokinetics, they can be administered using a body- is required. LMW heparins are at least as effective weight adjusted algorithm without laboratory as standard heparin for unstable angina, in monitoring. If necessary an anti-Xa assay can be combination with aspirin. used to measure the heparin level. Adverse effects Bleeding is the principal acute Dose Treatment of established thrombosis. The complication of heparin therapy. It is uncommon, traditional intravenous regimen of standard un- fractionated heparin is a bolus i.v. injection of 5000 9 Levine M et al 1996 New England Journal of Medicine 334: units (or 10 000 units in severe pulmonary embolism) 677-681. followed by a constant rate i.v. infusion of 1000-2000 10 Koopman M M W et al 1996 New England Journal of units per hour. Alternatively 15 000 units may be Medicine 334: 682-687. 11 given s.c. every 12 h but control is less even. The The Columbus Investigators 1997 New England Journal of APTT should be measured 6 h after starting therapy Medicine 337: 657-662. 12 Simonneau G et al 1997 New England Journal of Medicine and the administration rate adjusted to keep it in 337: 663-669. the optimum therapeutic ratio of 1.5-2.5; this usually 13 Lindmarker P, Holmstrom M 1996 Journal of Internal requires daily measurements of APTT preferably Medicine 240: 395-401. 574
  11. COAGULATION SYSTEM 28 but patients with impaired hepatic or renal function, but if the heparin was given more than 15 min with carcinoma, and those over 60 years appear to previously, the dose must be scaled down. Protamine be most at risk. An APPT ratio > 3 is associated with itself has some anticoagulant effect and overdosage an 8-fold increased chance of bleeding. must be avoided. The maximum dose must not Heparin-induced thrombocytopenia (HIT), charac- exceed 50 mg. Its effectiveness in patients treated terised by arterial thromboemboli and haemorrhage, with LMW heparins is unknown. occurs in about 2-3% of patients who receive standard heparin for a week or more (less in patients on Heparinoids. Danaparinoid sodium is a mixture of LMW heparins). It is due to an autoantibody several types of non-heparin glycosaminoglycans directed against heparin in association with platelet extracted from pig intestinal mucosa (84% heparan factor 4, causing platelet activation, and occurs sulphate). It is an effective anticoagulant for the most commonly with heparin derived from bovine treatment of deep vein thrombosis (DVT) prophylaxis lung. HIT should be suspected in any patient in in high-risk patients and treatment of patients with whom the platelet count falls by 50% or more after heparin-associated thrombocytopenia. starting heparin, and usually occurs 5 or more days after starting therapy (or sooner if the patient has previously been exposed to heparin). Up to 30% of USES OF ANTICOAGULANTS patients may require amputation or may die. In patients with HIT and evidence of thrombosis, Venous disease danaparoid sodium, hirudin or argatroban (see p. 577) should be substituted. Warfarin should not be Established venous thromboembolism. An anti- started until adequate anticoagulation has been coagulant is used to prevent extension of an achieved with one of these agents and the platelet existing thrombus while its size is reduced by count has returned to normal as skin necrosis or natural thrombolytic activity. Effective anticoagulation worsening thromboembolism may result. LMW prevents formation of fresh thrombus, which is heparins are unsuitable as the antibody may be more likely to detach and embolise, particularly if it cross-reactive. is in large proximal veins; it also helps to recanalise Osteoporosis may occur, it is dose-related and veins and to clear vein valves of thrombus and may be expected with 15 000-30 000 units/day for should thus prevent long-term consequences such about 6 months. It is most frequently seen in as swelling of the leg and stasis ulceration. The site pregnancy. The relative risk with LMW heparin is and extent of thrombosis should be established by not yet established. venous ultrasound. The majority of patients with Hypersensitivity reactions and skin necrosis proximal vein thrombosis or calf vein thrombosis (similar to that seen with warfarin) occur but are can be treated with outpatient low molecular rare. Transient alopecia has been ascribed to heparin weight heparin, weight-adjusted and administered but in fact may be due to the severity of the once or twice daily according to manufacturer's thromboembolic disease for which the drug was recommendations. It should be continued for a total given. of 4-7 days and until the signs of thrombosis (heat, swelling of the limb) have settled. Warfarin should Heparin antagonism. Heparin effects wear off so be started at the same time as the heparin. Patients rapidly that an antagonist is seldom required except with a symptomatic pulmonary embolism should after extracorporeal perfusion for heart surgery. be treated in hospital with LMW heparin or high- Protamine, a protein obtained from fish sperm, dose intravenous unfractionated heparin (above). reverses the anticoagulant action of heparin, when In patients with an uncomplicated DVT following antagonism is needed. It is as strongly basic as a precipitating event (e.g. orthopaedic surgery), heparin is acidic, which explains its immediate warfarin may be necessary for only 6 weeks if the action. Protamine sulphate, 1 mg by slow i.v. injection, patient has returned to normal mobility and the neutralises about 100 units of heparin derived from precipitating factor(s) have been eliminated. The mucosa (mucous) or 80 units of heparin from lung; patient should wear a well-fitting compression 575
  12. 28 DRUGS AND HAEMOSTASIS stocking to increase flow in deep veins, should Long-term anticoagulation with warfarin to prevent exercise the leg and should be encouraged to arterial thromboembolism should be considered for mobilise as soon as the discomfort has settled. The any patient who has a large left atrium or a low risk of recurrence reduces with passage of time after cardiac output or paroxysmal or established atrial the initial event. In cases of DVT uncomplicated by fibrillation (with or without cardiac valvular disease). pulmonary embolus, 3 months of anticoagulant Where warfarin is considered unsuitable, aspirin therapy appears adequate. Where there is evidence may be substituted, for it prevents stroke in patients of pulmonary embolus it is common practice to with atrial fibrillation, though less effectively. The continue therapy for 6 to 12 months. combination of warfarin and aspirin, once regarded Thrombolytic therapy with streptokinase or as contraindicated, may yet be most effective in urokinase i.v. may be used for life-threatening patients at high risk of embolism. Heparin is given thrombosis, e.g. major pulmonary embolism with for 2 h to patients after undergoing angioplasty. compromised haemodynamics (see p. 580). Heparin, aspirin or both are used to prevent Anticoagulant therapy may be life-saving in myocardial infarction in the acute phase of unstable thromboembolic pulmonary hypertension. angina. Prevention of venous thrombosis. Oral anti- Peripheral arterial occlusion. Heparin may prevent coagulant reduces the risk of thromboembolism in extension of a thrombus and hasten its recanalisation; conditions in which there is special hazard, e.g. it is commonly used in the acute phase following after surgery. Partly because of the danger of bleeding thrombosis or embolism. There is no case for treating and partly because of the effort of maintaining ischaemic peripheral vascular disease with an oral control, oral anticoagulants have not been widely anticoagulant (for prevention, see Antiplatelet drugs). adopted. Numerous trials, however, have shown the protective effect of low doses of unfractionated Long-term anticoagulant prophylaxis heparin (5000 units every 8-12 h s.c.) and more The decision to use warfarin long-term must take recently LMW heparin (dose adjusted for body- into account nondrug factors. The patient should be weight and/or risk) against deep leg vein thrombosis. told of the risks of haemorrhage, including those The significant fact is that it takes a lot less heparin introduced by taking other drugs, and of the signs to prevent thrombosis than it does to treat of bleeding into the alimentary or urinary tracts. All established thrombosis, because heparin acts in low patients should carry a card stating that they are concentration at an early stage in the cascade of receiving an oral anticoagulant. Such therapy should coagulation factors which leads to fibrin formation be withheld from a patient who is considered to be (see above). unlikely or unable to comply with the requirements Low-dose unfractionated heparin or LMW heparin of regular medication and blood testing. The can be used to prevent venous thromboembolism in incidence of haemorrhagic complications is directly other high-risk patients, e.g. those confined to bed related to the level of anticoagulation; safety and and immobilised with strokes, cardiac failure or good results can be obtained only by close attention malignant disease. Spontaneous bleeding has not to detail. The INR should be monitored at a been a problem with this form of anticoagulant maximum interval of 8 weeks in patients on a stable treatment. maintenance dose and more frequently in patients Low MW dextrans (see later). with an unstable INR. Cardiovascular disease Surgery in patients receiving anticoagulant therapy Acute myocardial infarction. Anticoagulation with heparin is used to reduce the risk of venous For elective surgery warfarin may be withdrawn thromboembolism, and the risk and size of emboli about 5 days before the operation and resumed from mural thrombi following acute myocardial about 3 days later if conditions seem appropriate; infarction. heparin may be used in the intervening period. In 576
  13. COAGULATION SYSTEM 28 patients with mechanical prosthetic valves, heparin Direct inhibitors of thrombin inactivate fibrin- is substituted at full dosage 4 days before surgery, bound thrombin which may promote thrombus and restarted 12-24 h after the operation. Warfarin extension (as opposed to heparin which acts is restarted when the patient resumes oral intake. indirectly through antithrombin) as follows: Emergency surgery: proceed as for bleeding (p. 571). Hirudin, a polypeptide originally isolated from For dental extractions: omission of warfarin for 1-2 the salivary glands of the medicinal leech Hirudo days to adjust the INR to the lower limit of the medicalis, is now produced by recombinant techno- therapeutic range is adequate (INR should be tested logy. It is a potent and specific inhibitor of thrombin just prior to the procedure). The usual dose of with which it forms an almost irreversible complex. warfarin can be resumed the day after extraction. It is cleared predominantly by the kidneys and has Aspirin, taken prophylactically for thromboem- a t l / 2 of 40 minutes after i.v. administration. No bolic disorders (see below), is commonly discontinued antidote is available for a bleeding patient. It has 2 weeks before elective procedures and restarted been used successfully in patients with heparin- when oral intake permits. induced thrombocytopenia (HIT), thrombopro- phylaxis in elective hip arthroplasty, unstable Contraindications to anticoagulant angina and myocardial infarction. therapy Bivalirudin is a semisynthetic bivalent thrombin inhibitor which contains an analogue of the C- Contraindications relate mostly to conditions in terminal of hirudin; this binds to thrombin but having which there is a tendency to bleed, and are relative a lower affinity, produces only transient inhibition rather than absolute, the dangers being balanced and hence may be safer. It has been used in patients against the possible benefits. They include: undergoing coronary angioplasty. • Behavioural: inability or unwillingness to Argatroban, a carboxylic acid derivative, binds cooperate, dependency on alcohol noncovalently to the active site of thrombin and is an • Neurological: stroke within 3 weeks, or surgery to effective alternative to heparin in patients with HIT. the brain or eye • Alimentary: active peptic ulcer, active Other highly selective agents in clinical devel- inflammatory bowel disease, oesophageal opment include blockers of: varices, uncompensated hepatic cirrhosis factor IXa, an essential factor for amplification of • Cardiovascular: severe uncontrolled hypertension the coagulation cascade (by active-site-blocked • Renal: if function is severely impaired factor IXa or monoclonal antibodies against the • Pregnancy: in early pregnancy the fetal warfarin factor), syndrome is a hazard and bleeding may cause the factor Vila/tissue factor pathway, the initiating fetal death in late pregnancy step of coagulation [with recombinant tissue factor • Haematological: pre-existing bleeding disorder. pathway inhibitor (TFPI) the analogue of the natural inhibitor], and Emerging anticoagulant drugs factor X or factor Xa and inhibition of factor VIIa Recent strategies have sought to develop substances within the factor Vila/tissue factor complex (by that act at different sites in the coagulation cascade NAPc2, a recombinant nematode anticoagulant and agents that inhibit thrombin, or prevent thrombin peptide). generation, or block initiation of the coagulation process or enhance endogenous anticoagulation have reached the clinical arena. Fibrinolytic Novel delivery systems, using synthetic amino acids (e.g. SNAC) to facilitate absorption, allow the (thrombolytic) system oral administration of unfractionated or LMW heparins sufficient to prolong the APTT. These are The preservation of an intact vascular system requires being evaluated. not only that blood be capable of coagulating but 577
  14. 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 estab- lished 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 Fig. 28.2 Blood fibrinolytic system An important application of fibrinolytic drugs has been to dissolve thrombi in acutely occluded The tl/2 is 70 min. It is not available in some coronary arteries, thereby to restore blood supply to countries. ischaemic myocardium, to limit necrosis and to improve prognosis. The approach is to give a Urokinase made from human fetal kidney cells in plasminogen activator intravenously by infusion or tissue culture, is a direct activator of plasminogen. by bolus injection in order to increase the formation The tl/2 is 15 min. of the fibrinolytic enzyme plasmin. Those currently Streptokinase, anistreplase and urokinase are not available include: well absorbed by fibrin thrombi and are called non- fibrin-selective. They convert plasminogen to plasmin Streptokinase is a protein derived from (3-haemolytic in the circulation, which depletes plasma fibrinogen streptococci: it forms a complex with plasminogen and induces a general hypocoagulant state. This (bound loosely to fibrin) where it converts plas- does not reduce their local thrombolytic potential minogen to plasmin. Too rapid administration but increases the risk of bleeding. causes abrupt fall in blood pressure. The t l / 2 is 20 min. Recombinant prourokinase, as the name suggests, is produced by recombinant DNA technology; on Anistreplase (anisoylated plasminogen Streptokinase binding to fibrin it converts to urokinase. The tl/2 is activator complex, APSAC), is the plasminogen- 7 min. streptokinase complex (above) in which the enzyme centre that converts plasminogen to plasmin is Alteplase (rt-PA) (tl/2 5 min) is tissue type protected from deactivation, so prolonging its action. plasminogen activator produced by recombinant 578
  15. 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 28 DNA technology. Reteplase (tl/2 15 min) is another or by reducing thromboembolic episodes, or by recombinant human protein. both. Recombinant prourokinase and alteplase are Thrombolysis may also be valuable in persistent termed fibrin-selective, for they bind strongly to unstable angina and especially where arteriography fibrin, and are capable of dissolving aging or lysis- demonstrates substantial thrombus in coronary resistant thrombi better than nonfibrin-selective arteries. agents. These drugs are less likely to produce a coagulation disturbance in the plasma, i.e. they are Adverse effects. Bleeding is the most important selective for thrombi. complication and usually occurs at a vascular lesion, e.g. the site of injection, for fibrinolytic therapy does not distinguish between an undesired thrombus USES OFTHROMBOLYTIC DRUGS and a useful haemostatic plug. If the contraindications are followed, the incidence of bleeding severe Coronary artery thrombolysis enough to require transfusion is < 1%. Nausea and vomiting may occur. (See also Ch. 23) Multiple microemboli from disintegration of pre- existing thrombus anywhere in the vascular system Timing of administration. The earlier thrombolysis may endanger life; these commonly originate in an is given the better the outcome. Treatment com- enlarged left atrium, or a ventricular or aortic mencing within the first 3 h of onset is a realistic aneurysm. aim but thrombolysis up to 12 h is still worthwhile. Cardiac arrhythmias result from reperfusion of Benefit is most striking in patients with anterior ischaemic tissue. These vary in type and are often myocardial infarction treated within 4 h of onset. transient, a factor which may influence the decision Anistreplase can be given i.v. over 4-5 min (and whether or not to treat. so more easily out of hospital); its effect persists for Allergy. Streptokinase and anistreplase are anti- 6-9 h. Other agents are normally infused i.v. over genie and anaphylactic reactions with rash, urticaria 1-3 h with most of the dose being given early in that and hypotension may occur for most people have period. Retelpase is given as a double bolus 30 min circulating antibodies to streptococci. Antibodies apart. persist after exposure to these drugs and their re- use should be avoided between 5 days and 12 Reduction in mortality (see also Myocardial infarction, months as the recommended dose may not overcome p. 485). There is now compelling evidence that immune resistance to plasminogen activation. streptokinase, anistreplase, alteplase and retelpase reduce mortality with an acceptable frequency of Contraindications to thrombolytic drug use (see adverse effects.14 Comparisons between these drugs Myocardial infarction, p. 485). show no apparent survival advantage of one over the others in respect of survival.15,16 Both streptokinase Noncoronary thrombolysis and t-PA decrease mortality by about 25% when used alone but by 40-50% when either agent is used Pulmonary embolism. Thrombolysis is superior to with aspirin17 which reduces the incidence of re- heparin at relieving obstructed veins demonstrated infarction. Those under 75 years appeared to gain radiologically. While a reduction in mortality is thus most from thrombus dispersal but 'physiological' implied, the numbers of cases reported in clinical age is more important than chronological age. trials of thrombolytics have been insufficient to Stroke may complicate myocardial infarction and is considered usually to be embolic, for its 14 incidence correlates with the extent of myocardial Carins J A et al 1992 Chest 102 (Suppl): 482S-507S. 15 The International Study Group 1990 Lancet 336: 71-75. infarction. Evidence18 indicates that the combination 16 ISIS-3 Collaborative Group 1992 Lancet 339: 753-770. of thrombolysis plus aspirin lowers the overall risk 17 Carins J A et al 1998 Chest 114: 634S-657S 18 of stroke, possibly by limiting the size of the infarct, ISIS-2 Collaborative Group 1988 Lancet 2: 349-360. 579
  16. 28 DRUGS AND HAEMOSTASIS provide conclusive statistical proof. There is, menorrhagia, whether primary or induced by an nevertheless, a strong impression that thrombolysis intrauterine contraceptive device. Tranexamic acid is beneficial where pulmonary embolism is ac- may also reduce bleeding after ocular trauma and companied by signs of haemodynamic decom- in haemophiliacs after dental extraction where it is pensation (raised jugular venous pressure, pulse normally used in combination with desmopressin. rate > 100 beats/min, systolic pressure < 100 mmHg, The drug benefits some patients with hereditary arterial oxygen desaturation). Alteplase 100 mg may angioedema presumably by preventing the plasmin- be infused over 2 h, followed by an i.v. infusion of induced uncontrolled activation of the complement heparin. system which characterises that condition. Tranex- amic acid may be of value in thrombocytopenia Deep vein thrombosis. Thrombolysis may be (idiopathic or following cytotoxic chemotherapy) to justified where the affected vessels are proximal reduce the risk of haemorrhage by inhibiting and the risk of pulmonary embolism is high. natural fibrinolytic destabilisation of small platelet Complete lysis may be achieved in 50% of cases plugs; the requirement for platelet transfusion is treated within 7 days of onset. thereby reduced. It may also be used for overdose with thrombolytic agents. Arterial occlusion Systemic or local thrombolysis Adverse effects are rare but include nausea, may be considered for arterial occlusions distal to diarrhoea and sometimes orthostatic hypotension. the popliteal artery (thrombectomy being the usual It is contraindicated in patients with haematuria as therapeutic approach for occlusion of < 24 h duration it will prevent clot lysis in the urinary tract and proximal to this site). Intravenous streptokinase result in 'clot colic'. will lyse 80% of occlusions if infusion begins within Aprotinin is a naturally-occurring inhibitor of 12 h, and 60% if it is delayed for up to 3 days. plasmin and other proteolytic enzymes which has been used to limit bleeding following open heart Ischaemic stroke. There is little evidence of benefit surgery with extracorporeal circulation, and for the and most trials have shown increased short-term treatment of life-threatening haemorrhage due to mortality in patients treated with thrombolysis. hyperplasminaemia complicating surgery of malig- Thrombolysis may also be considered for ocular nant tumours or thrombolytic therapy or in Jehovah's thrombosis (urokinase) and for thrombosed arterio- witnesses.19 It must be administered intravenously venous shunts (streptokinase). or topically. DRUGSTHAT PREVENT FIBRINOLYSIS Platelets Antifibrinolytics are useful in a number of bleeding disorders. Platelets support haemostasis in three ways: first by sticking to exposed collagen to form a physical barrier Tranexamic acid competitively inhibits the binding at the site of vessel injury; second by accelerating of plasminogen and t-PA to fibrin and effectively the activation of coagulation proteins and finally by blocks conversion of plasminogen to plasmin release of storage granule contents promotes (which causes dissolution of fibrin); fibrinolysis is vasoconstriction and wound healing. thus retarded. After an i.v. bolus injection it is excreted largely unchanged in the urine; the tl/2 is SOME PHYSIOLOGY 1.5 h. It may also be administered orally or topically. Circulating 'resting' platelets do not stick to healthy The principal indication for tranexamic acid is to endothelium or each other but if a vessel wall is prevent the hyperplasminaemic bleeding state that results from damage to certain tissues rich in plasminogen activator, e.g. after prostatic surgery, 19 A religious sect that is opposed to blood transfusion on a tonsillectomy, uterine cervical conisation, and scriptural basis. 580
  17. PLATE LETS 28 breached they react at the site by four steps: release of active substances (see above), and low attachment, spreading, secretion and aggregation. concentrations of cyclic AMP have the opposite effect. 1. Exposure of constituents of the subendothelial 2. The quantity of cyclic AMP within platelets is matrix most notably collagen initiates platelet under enzymatic control, for it is formed by the attachment which is stabilised by von action of adenylate cyclase and degraded by Willebrand factor. phosphodiesterase. 2. Shape change of the attached platelets, 3. Platelet adenylate cyclase formation in turn is spreading along the fibrils permits multiple stimulated by prostacyclin (from the endothelium, tight contacts with the matrix and there is also called PGI2) and inhibited by thromboxane- simultaneous release of thromboxane-A2 (TXA2) A2 (from within platelets, also called TXA2). and adenosine diphosphate (ADP) which recruit Hence the action of thromboxane-A2 lowers cyclic additional platelets. AMP concentration and promotes platelet 3. Agonists in the microenvironment also trigger adhesion; prostacyclin raises cyclic AMP secretion of the contents of intracellular storage concentration and prevents platelet adhesion. granules which activate circulating platelets and 4. Prostacyclin and thromboxane-A2 are derived vasoconstriction (including proteins, enzymes, from arachidonic acid which is a constituent of enzyme inhibitors, vasoactive and other cell walls, both platelet and endothelial. Cyclo- peptides and agents that participate in the oxygenase (COX, PGH synthase), an enzyme coagulation process) and translocation of present in cells at both sites, converts negatively charged phospholipids to the outer arachidonic acid to cyclic endoperoxides which surface of the plasma membrane providing a are further metabolised by prostacyclin synthase binding site for coagulation proteins (an activity to prostacyclin in the endothelium and by known as 'platelet factor 3'). thromboxane synthase to thromboxane-A2 in 4. These platelets interact with each other and platelets. Thus prostacyclin is principally 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 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. 1. Cyclic AMP plays a key role. High concentrations of intraplatelet cyclic AMP inhibit platelet adhesion, aggregation and the cyclic AMP 581
  18. 28 DRUGS AND HAEMOSTASIS formed in the endothelium whereas some 13% of episodes of peptic ulcer bleeds in people thromboxane-A2 is formed mainly in platelets. over 60 years can be attributed to prophylactic 5. These differences in the prostaglandins asprin (use in the community about 8%).20 synthesised in endothelium and platelets are important. Intact vascular endothelium does not Dipyridamole reversibly inhibits platelet phos- activate platelets because of the high phodiesterase (see Fig. 28.3) and in consequence concentration of prostacyclin in the intima. cyclic AMP concentration is increased and platelet Subintimal tissues contain little prostacyclin and (thrombotic) reactivity reduced; evidence also platelets, under the influence of thromboxane- suggests that its antithrombotic effect may derive A2/ immediately adhere and aggregate at any from release of prostaglandin precursors by vascular breach in the intima. Atheromatous plaques do endothelium. Dipyridamole is extensively bound to not generate prostacyclin—which explains plasma proteins and has a tl/2 of 12 h. platelet adhesion and thrombosis at these sites. 6. Endothelial cells also produce nitric oxide which Ticlopidine is a thienopyridine derivative that raises cyclic GMP levels in platelets to inhibit inhibits ADP-dependent platelet aggregation. It is activation and have on their surface ecto- converted to its active form by metabolism by the ADPase (CD39) that metabolises secreted ADP liver and the tl/2 of the parent drug is 40 h. before it can cause platelet activation. Ticlopidine is more effective than aspirin in reducing stroke in patients with transient ischaemic Inhibitors or activators of platelet aggregation act attacks (TIA) but aspirin is safer and less expensive. directly or indirectly by altering the rate of for- It is also effective in reducing the risk of the mation or degradation of platelet cyclic AMP. Local combined outcome of stroke, myocardial infarction concentrations of these substances determine whether (MI) or vascular death in patients with thrombo- the platelet adhesion/aggregation process will occur. embolic stroke, decreasing vascular death and MI in patients with unstable angina, reducing acute occlusion of coronary bypass grafts and improving DRUGSTHAT INHIBIT PLATELET walking distance and decreasing vascular com- ACTIVITY (ANTIPLATELET DRUGS) plications in patients with peripheral vascular disease. (See also Myocardial infarction Ch. 23) It may be used to prevent stroke in patients who are intolerant of aspirin. Neutropenia is the most serious Aspirin (acetylsalicylic acid) acetylates and thus adverse effect (risk 2.4%) and is greatest in the first inactivates COX, the enzyme responsible for the 12 weeks of therapy; leucocyte counts should be first step in the formation of prostaglandins, the checked every 2 weeks during this period. Diarrhoea conversion of arachidonic acid to prostaglandin H2. and other gastrointestinal symptoms may be induced It follows from the diagram on page 281 (Fig. 15.1) in a third of patients. that aspirin can prevent formation of both Clopidogrel is also a thienopyridine derivative thromboxane-A2 (TXA2) and prostacyclin (PGI2). which is also more effective than aspirin for the Acylation of COX is irreversible and, as the platelet prevention of ischaemic stroke, MI or vascular is unable to synthesise new enzyme, COX activity is death in patients at high risk but it is not associated irreversibly lost for its lifetime (8-10 d). Therapeutic with neutropenia. It is more expensive than aspirin interest in the antithrombotic effect of aspirin has though safer than ticlodipine. centred on separating its actions on thromboxane- A2 and prostacyclin formation, and this can be Epoprostenol (prostacyclin) may be given to prevent achieved by using a low dose. Thus 75-100 mg/d by platelet loss during renal dialysis, with or without mouth is sufficient to abolish synthesis of heparin; it is infused i.v. and s.c (tl/2 3 min). It is a thromboxane-A2 without significant impairment of potent vasodilator. prostacyclin formation, i.e. amounts substantially below the 2.4 g/d used to control pain and inflam- 20 Weil J et al 1995 Prophylactic aspirin and risk of peptic mation. Low-dose aspirin is yet not without risk: ulcer bleeding. British Medical Journal 310: 827-830. 582
  19. PLATE LETS 28 Glycoprotein (GP) IIb-IIIa antagonists. The platelet Eptifibatide is a cyclic heptapeptide based upon glycoprotein Ilb-IIIa complex is the predominant the Lys-Gly-Asp sequence. Tirofiban and lamifiban platelet integrin,21 a molecule restricted to mega- are nonpeptide mimetics. All three are competitive karyocytes and platelets which mediates platelet inhibitors of the GPIIb-IIIa complex with lower aggregation via the binding of adhesive proteins affinities and higher dissociation rates than abciximab such as fibrinogen and von Willebrand factor and short plasma tl/2 (2-2.5 h). Platelet aggregation (vWF). Where there is hereditary absence of the GP returns to normal 30 min to 4 h after discontinuation. Ilb-IIIa complex (Glanzmann's thrombasthenia) Eptifibatide and tirofiban are effective in acute platelets are incapable of aggregation by all physio- coronary syndromes. Lamifiban is undergoing clinical logical agonists. GP Ilb-IIIa antagonists have been development. developed as antiplatelet agents and administered intravenously, they inhibit the final common pathway Adverse effects. Haemorrhage occurs but is less of of platelet aggregation: binding of fibrinogen or a problem with low doses of heparin; it remains a vWF to the GP IIb-IIIa complex. They are more particular risk in patients treated after failed complete inhibitors than either aspirin or clopidogrel fibrinolytic therapy for acute myocardial infarction. which inhibit only the cyclo-oxygenase or ADP Platelet transfusion after cessation of abciximab is pathway respectively. GP IIb-IIIa antagonists also necessary for refractory or life threatening bleeding. have an anticoagulant effect through inhibition of After transfusion, the antibody redistributes to the prothrombin binding to the complex and inhibition transfused platelets, reduces the mean level of of procoagulant platelet-derived microparticle receptor blockade and improves platelet function. formation. Platelet aggregation is inhibited in a Thrombocytopenia may occur from 1 hour to days dose-dependent manner. after commencing treatment in up to 1% of patients. This necessitates platelet counts at 2-4 hours and Abciximab is a human-murine chimeric monoclonal then daily; if severe, therapy must be stopped and, antibody Fab fragment that binds to the GP IIb-IIIa if necessary, platelets transfused. EDTA-induced complex with high affinity and slow dissociation pseudothrombocytopenia has been reported and a rate. After i.v. administration it is cleared rapidly low platelet count should prompt examination of a from plasma (tl/2 20 min). Abciximab (0.25 mg/kg blood film for agglutination before therapy is stopped. bolus then 0.125 microgram/kg/min infusion for 12 h) produces immediate and profound inhibition Other drugs of platelet activity that lasts for 12-36 h after termination of the infusion. This reduces the risk of Dazoxiben, an inhibitor of thromboxane-A2 but death, MI or need for urgent coronary artery bypass not of prostacyclin synthesis, is being evaluated in grafting after percutaneous coronary angioplasty cardiovascular disease. and benefit is maintained up to 3 years. The dose causes and maintains blockade of > 80% receptors, Dextrans, particularly of MW 70 000 (dextran 70), causing > 80% reduction in aggregation. Patients alter platelet function and prolong the bleeding also receive aspirin and heparin and if a coronary time. Dextrans differ from the other antiplatelet stent has been inserted, either clopidogrel or drugs which tend to be used for arterial thrombosis; ticlodipine. Abciximab is also effective in refractory dextran 70 reduces the incidence of postoperative unstable angina prior to percutaneous coronary venous thromboembolism if it is given during or intervention. It has a potential role in combination just after surgery. The dose should not exceed 10% with low dose thrombolysis in acute myocardial of the estimated blood volume. They are rarely used. infarction and as a single agent in stroke. USES OF ANTIPLATELET DRUGS 21 Integrins are cell surface adhesion receptors consisting of Antiplatelet therapy protects 'at risk' patients non-covalently associated alpha- and beta- subunits, now against stroke, myocardial infarction or death. A redesignated integrin aIIb B3. meta-analysis of 145 clinical trials of prolonged 583
  20. 28 DRUGS AND HAEMOSTASIS antiplatelet therapy versus control and 29 trials between antiplatelet regimens found that the chance • Myocardial infarction.Aspirin should be given of nonfatal myocardial infarction and nonfatal indefinitely to patients who have survived myocardial stroke were reduced by one-third, and that there infarction.There is as yet no case for using aspirin to was a one-sixth reduction in the risk of death from prevent myocardial infarction in those without any vascular cause.22 Expressed in another way, in important risk factors for the disease. the first month after an acute myocardial infarction • Transient ischaemic attacks (TIAs) or minor ischaemic stroke.There is grave risk of progression to (a vulnerable period) aspirin prevents death, stroke completed stroke and patients should receive aspirin or a further heart attack in about 4 patients for indefinitely. Before starting treatment it is important every 100 treated. Aspirin is by far the most to exclude intracerebral haemorrhage (by computed commonly used antiplatelet agent. The optimum tomography) and other conditions that mimic TIAs, dose is not certain but one not exceeding aspirin 325 e.g. cardiac arrhythmia, migraine, focal epilepsy and mg is acceptable, and 75-100 mg/d may be as hypoglycaemia. effective and preferred where there is gastric • Unstable angina.The chance of myocardial infarction is high and aspirin should be used with other drugs, i.e. a (3- intolerance. Aspirin alone (mainly) or aspirin plus adrenoceptor antagonists nitrate, a calcium channel dipyridamole greatly reduced the risk of occlusion blocker and possibly heparin i.v. as is judged appropriate. where vascular grafts or arterial patency was • Arterial grafts, peripheral vascular disease.Aspirin studied systematically.23 (possibly combined with dipyridamole for grafts) Many patients who take aspirin for vascular should be given to prevent occlusion.These drugs may disease may also require an NSAID for, e.g. joint also be used to protect against thrombotic occlusion disease, and it may be argued that the NSAID renders following percutaneous transluminal coronary angioplasty. aspirin unnecessary as both act by inhibition of • Inhibitors of ADP-dependent platelet aggregation, e.g. prostaglandin G/H synthase. As inhibition by ticlopidine.clopidorgrel.and glycoprotein llb-llla aspirin is irreversible and that by NSAIDs may not antagomists, e.g. abciximab, can be expected to form be, continued use of aspirin in such circumstances part of regimens for cardiovascular disease, as seems prudent, especially if NSAID use is evidence accumulates. intermittent. Haemostatics Sderosing agents. Chemicals may be used to cause inflammation and thrombosis in veins so as Etamsylate (Dicynene) is given systemically to to induce permanent obliteration, e.g. ethanolamine reduce capillary bleeding, e.g. in menorrhagia. oleate injection, sodium tetradecyl sulphate (given Adrenaline (epinephrine) may be useful for i.v. for varicose veins) and oily phenol injection epistaxis, stopping haemorrhage by local vaso- (given submucously for haemorrhoids). Local constriction when applied by packing the nostril reactions, tissue necrosis and embolus can occur. with ribbon gauze soaked in adrenaline solution. Fibrin glue consists of fibrinogen and thrombin contained in two syringes, the tips of which form a Haemophilia common port. The two components are thus delivered in equal volumes to a bleeding point where Management of the haemophilia A and haemophilia fibrinogen is converted to fibrin at a rate determined B (genetic deficiencies of factor VIII or IX) is a by the concentration of thrombin. Fibrin glue can be matter for those with special expertise but the used to secure surgical haemostasis, e.g. on a large following points are of general interest. raw surface, and to prevent external oozing of blood • Haemorrhage can sometimes be stopped by in patients with haemophilia (see also below). pressure; edges of superficial wounds should be 22 strapped, not stitched. Antiplatelet Trialists' Collaboration 1994 British Medical Journal 308: 81. • Minor bleeding can be stopped with plasma 23 Antiplatelet Trialists' Collaboration 1994 British Medical factor levels of 25-30% but severe bleeding Journal 308:159. requires a level of at least 50% and surgical 584
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