Fff

* inhibited by warfarin ° inhibited by heparin

* activated by thrombin

PL phospholipid; TF tissue factor Proteins C and S inhibit factors V and VIII Antithrombin inhibits thrombin, Xa, IXa, XIa, Xlla a: activated factor

HMWK: high molecular weight kininogen

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.

The prothrombin time (PT), 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

Vitamin K (Koagulation vitamin) is essential to normal haemostatic and antithrombotic mechanisms. This vitamin occurs naturally in two forms. Vitamin K, (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 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- or-descarboxylated protein is called 'protein induced in vitamin K absence' or PIVKA.

Deficiency may arise from:

• 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 K^ acts within about 12 h and should correct the INR 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 INR 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 Ky Synkavit), the synthetic analogue of vitamin K, being water-soluble, 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.

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 acetome-naphthone and menaphthone.

Indications for vitamin K or its analogues

• 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) 1 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 2 mg at one month of age. Formula-fed babies do 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.

DRUGS THAT 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.

1 British National Formulary.

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 haemor-rhagic 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 y-

2 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.

3 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.

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 tV2 6 h, IX and X t'/2 24 h, prothrombin \\ 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 t1/, 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\ 36 h) is a racemic mixture of approximately equal amounts of two isomers S (t1/, 35 h) and R (t1/, 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 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 2 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.

4 Fennerty A et al 1988 British Medical Journal 297: 1285-1288.

5 British Society for Haematology 1990 Guidelines on oral anticoagulants, 2nd edn. Journal of Clinical Pathology 43: 177-183 (Reproduced with permission).

Cutaneous reactions, apart from purpura and ecchymoses in those who are excessively antico-agulated, 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 6 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 5 mg is then given by slow i.v. injection. This renders the patient refractory to oral anticoagulant (but not to heparin) for about 2 weeks. The thrombotic risk so created must be assessed for each patient and may be judged

6 A study of 261 patients who received warfarin for 221 patient-years reported major haemorrhage in 5.3% after 1 year and 10.6% after 2 years. Gitter M J et al 1995 Mayo Clinic Proceedings 70: 725-733.

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 > 7 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.

7 Based on recommendations of the British Society for Haematology.

• Antimicrobials. Aztreonam, cefamandole, chloramphenicol, ciprofloxacin, co-trimoxazole, erythromycin, fluconazole, itraconazole, ketoconazole, metronidazole, miconazole, ofloxacin and sulphonamides (including co-trimoxazole) increase anticoagulant effect by mechanisms that include interference with warfarin or vitamin K metabolism. Rifampicin and griseofulvin 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 do not interfere.

• Antidepressants. Serotonin reuptake inhibitors may enhance the effect of warfarin but tricyclics may be used.

• Gastrointestinal drugs. Avoid Cimetidine and omeprazole which inhibit the clearance of R warfarin, and sucralfate which may impair its absorption. Ranitidine may be used 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 used; it is eliminated in the urine mainly in unchanged form (t'/2 24 h). Indandione anticoagulants are practically obsolete because of allergic adverse reactions unrelated to coagulation; phenindione (t\ 5 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 30 000 (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 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 oCj-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

8 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.

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 t]/2 alters disproportionately with dose, being 60 min after 75 units per kg and 150 min 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 \}/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 do not prolong the APTT and, having predictable pharmacokinetics, they can be administered using a body-weight 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 un-fractionated 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 6 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 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.91011 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 8 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,

9 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 Simortneau 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.

but patients with impaired hepatic or renal function, with carcinoma, and those over 60 years appear to be most at risk. An APPT ratio > 3 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 5 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 6 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, 1 mg by slow i.v. injection, neutralises about 100 units of heparin derived from mucosa (mucous) or 80 units of heparin from lung;

but if the heparin was given more than 15 min 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.

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