Phytomenadione

(Konakion), the naturally occurring fat-soluble vitamin K₁, acts within about 12 h and should reduce the anticoagulant effect of warfarin within 24–48 h when given orally in a dose of 5–10 mg. The intravenous formulation will begin to reverse a vitamin K-deficient coagulopathy within 6 h in a patient with normal liver function. It should be administered slowly to reduce the risk of an anaphylactoid reaction with facial flushing, sweating, fever, chest tightness, cyanosis and peripheral vascular collapse. Phytomenadione may also be given orally using either tablet formulations or the preparation for intravenous use. Oral administration will result in a slower and often incomplete correction of coagulopathy. Otherwise phytomenadione may be given intramuscularly, subcutaneously or orally. The preferred route depends on the degree of coagulopathy and urgency of correcting the haemorrhagic tendency. The intramuscular route should not be used if the INR is increased, as local intramuscular haemorrhage may be induced; subcutaneous absorption is variable and, despite the risk of allergic reaction, the intravenous route ensures rapid delivery.

Menadiol

sodium phosphate (vitamin K₃), the synthetic analogue of vitamin K, being water soluble, is preferred in intestinal malabsorption or in states in which bile flow is deficient. The main disadvantage is that it takes 24 h to act, but its effect lasts for several days. The dose is 5–40 mg daily, orally. Menadiol sodium phosphate in moderate doses causes haemolytic anaemia and, for this reason, neonates should not receive it, especially those that are deficient in glucose 6-phosphate dehydrogenase; their immature livers are unable to cope with the heavy bilirubin load and there is danger of kernicterus.

Fat-soluble analogues of vitamin K that are available in some countries include acetomenaphthone and menaphthone.

Vitamin K is used to treat the following:

Adverse effects

Water retention and hyponatraemia may complicate therapy and very young children (< 1 year) should not receive DDAVP. Fluid intake should not exceed 1 L in the 8 h following treatment and with repeated doses the plasma sodium should be monitored. Tachyphylaxis (progressively diminishing response to the same dose) can occur.

Adrenaline/epinephrine

is effective as a topical agent for epistaxis, applied in ribbon gauze that is packed into the nostril, haemorrhage being arrested by local vasoconstriction.

Fibrin glue

consists of fibrinogen and thrombin contained in two syringes, the tips of which form a common port that allows delivery of the two components to a bleeding point where fibrinogen converts to fibrin at a rate determined by the concentration of thrombin. Fibrin glue can be used to secure surgical haemostasis, e.g. on a large raw surface, and to prevent external oozing of blood in patients with haemophilia (see also above).

Sclerosing agents

produce inflammation and thrombosis in veins to induce permanent obliteration, e.g. ethanolamine oleate injection, sodium tetradecyl sulphate (given intravenously for varicose veins) and oily phenol injection (given submucosally for haemorrhoids). Local reactions and tissue necrosis may occur.

Pharmacokinetics

Warfarin is readily absorbed from the gastrointestinal tract and, like all the current oral anticoagulants, is more than 90% bound to plasma proteins. Metabolism in the liver terminates its action. Warfarin (t_½ 36 h) is a racemic mixture of approximately equal amounts of two isomers, S (t_½ 27 h) and R (t_½ 40 h) warfarin, i.e. it is in effect two drugs. S warfarin is four times more potent than R warfarin. The isomers respond differently to drugs that interact with warfarin.

Pharmacodynamics

During the γ-carboxylation of factors II (prothrombin), VII, IX and X (and also the natural anticoagulant proteins C and S), active vitamin K (KH₂) is oxidised to an epoxide and must be reduced by the enzymes vitamin K epoxide reductase and vitamin K reductase to become active again (see the vitamin K cycle, p. 483). Coumarins³ are structurally similar to vitamin K and competitively inhibit vitamin K epoxide reductase and vitamin K reductase, so limiting availability of the active reduced form of the vitamin to form coagulant (and anticoagulant) proteins. The overall result is a shift in haemostatic balance in favour of anticoagulation because of the accumulation of clotting proteins with absent or decreased γ-carboxylation sites (PIVKAs).⁴

This shift does not take place until functioning vitamin K-dependent proteins, made before the drug was administered, have been cleared from the circulation. The process occurs at different rates for individual coagulation factors (VII t_½ 6 h, IX and X t_½ 18–24 h, prothrombin t_½ 72 h). The anticoagulant proteins C and S have a shorter t_½ than the pro-coagulant proteins and their more rapid decline in concentration may create a transient hypercoagulable state. This can be dangerous in individuals with inherited protein C or S deficiency who may develop thrombotic skin necrosis during initiation of oral anticoagulant therapy with vitamin K antagonists. Anticoagulation with heparin until the effect of warfarin is well established reduces the risk of skin necrosis when rapid induction of anticoagulation is required.

The therapeutic anticoagulant effect of warfarin develops only after 4–5 days. Furthermore, the INR does not reliably reflect anticoagulant protection during this initial phase, as the vitamin K-dependent factors diminish at different rates and the INR is particularly sensitive to the level of factor VII, which is not a principal determinant of thrombotic or bleeding risk.

Warfarin is the oral anticoagulant of choice, for it is reliably effective and has the lowest incidence of adverse effects. Because of the delay in onset of anticoagulant effect with oral vitamin K antagonists (VKAs) there is a need for an immediate-acting anticoagulant, such as a heparin, in the first few days of therapy if rapid anticoagulation is required.

The response to warfarin, and other coumarins, varies within and between individuals and therefore regular monitoring of dose is essential. The pharmacokinetics (absorption and metabolism) and pharmocodynamics (haemostatic effect) are influenced by vitamin K intake and absorption, by heritable functional polymorphisms affecting metabolism such as P450 CYP 2 C9 polymorphisms, by rates of synthesis and clearance of coagulation proteins, and by drugs. The effectiveness of anticoagulant therapy with oral VKAs is determined by the INR, a standardised method derived from the prothrombin time that permits comparison between different laboratories.

Dose

There is much inter-individual variation in dose requirements. It is usual to initiate therapy with 10-mg doses, depending on the daily INR, with the maintenance dose then adjusted according to the INR using an established protocol.

The level of anticoagulation matches the perceived risk of thrombosis (see below). The target INR for deep vein thrombosis (DVT) is 2.5 (typical range 2.0–3.0).

Adverse effects

The major complication of treatment with warfarin is bleeding. As well as a risk of haemorrhage after trauma or surgery, spontaneous bleeding may occur. Each year a patient is on treatment there is a 1 in 20 (5%) risk of minor haemorrhage. The annual risk of major bleeding is 1 in 100, of which one-quarter are fatal. The risk of bleeding relates to the INR, not the dose of warfarin: the higher the INR, the greater the chance of bleeding. The risk of over-anticoagulation increases with intercurrent illness and interaction with other drugs, and is more likely in patients whose anticoagulant control is unstable. Therefore, it is essential to:

Warfarin is a small molecule that crosses the placenta and can produce harmful effects in the developing fetus.

Warfarin embryopathy develops only after exposure to oral anticoagulant during the first trimester of pregnancy. The most common feature is chondrodysplasia punctata, characterised by abnormal cartilage and bone formation (with stippling of epiphyses visible on radiography) in vertebrae and femur, and the bones of the hands and feet during infancy and early childhood; these disappear with age (warfarin is not the only cause of this abnormality). Other less common skeletal abnormalities include nasal hypoplasia and hypertelorism (wide-set eyes).

Bleeding into the central nervous system is a danger throughout pregnancy but particularly at the time of delivery.

As a consequence of the above, warfarin is contraindicated in the first 6–12 weeks of pregnancy and should be replaced by heparin before the anticipated date of delivery, as the action of the latter drug can be terminated rapidly prior to the birth.

Withdrawal of oral anticoagulant therapy

The balance of evidence is that abrupt, as opposed to gradual, withdrawal of oral anticoagulant therapy does not of itself add to the risk of thromboembolism, for renewed synthesis of functional vitamin K-dependent clotting factors takes several days.

Reversal of anticoagulation

can be gradual or rapid depending on the circumstances, i.e. from undue prolongation of INR to frank bleeding. Vitamin K 5–10 mg is usually adequate for complete reversal, oral administration being less rapid than intravenous. Immediate reversal is more readily achieved with a factor concentrate than fresh frozen plasma. Detailed guidance on corrective therapy in relation to the degree of over-anticoagulation is available, e.g. from the British National Formulary.

Drug interactions

Oral anticoagulant control must be precise for safety and efficacy. If a drug that alters the action of warfarin is essential, monitor the INR frequently and adjust the dose of warfarin during the period of institution of the new drug until a new stable therapeutic dose of warfarin results; careful monitoring is also needed on withdrawal of the interacting drug.

Analgesics. Avoid, if possible, non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin because of their irritant effect on gastric mucosa and action on platelets. Paracetamol is acceptable but doses above 1.5 g/day may raise the INR. Dextropropoxyphene inhibits warfarin metabolism, and compounds that contain it, e.g. co-proxamol, should be avoided. Codeine, dihydrocodeine and combinations with paracetamol, e.g. co-dydramol, are preferred. Concomitant use of misoprostol with a NSAID may reduce the risk of gastric bleeding and a selective cyclo-oxygenase (COX)-2 inhibitor may be associated with a lower bleeding risk in patients taking oral anticoagulants.

Antimicrobials. Aztreonam, cefamandole, chloramphenicol, ciprofloxacin, co-trimoxazole, erythromycin, fluconazole, itraconazole, ketoconazole, metronidazole, miconazole, ofloxacin and sulphonamides (including co-trimoxazole) increase anticoagulant effect by mechanisms that include interference with warfarin or vitamin K metabolism. Rifampicin and griseofulvin induce relevant hepatic enzymes and accelerate warfarin metabolism, reducing its effect. Intensive broad-spectrum antibiotics, e.g. eradication regimens for Helicobacter pylori, may increase sensitivity to warfarin by reducing the intestinal flora that provide vitamin K.

Anticonvulsants. Carbamazepine, phenobarbital and primidone accelerate warfarin metabolism (by enzyme induction); the effect of phenytoin is variable. Clonazepam and sodium valproate are safe.

Antiarrhythmics. Amiodarone, propafenone and possibly quinidine potentiate the effect of warfarin and dose adjustment is required, but atropine, disopyramide and lidocaine do not interfere.

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

Gastrointestinal drugs. Avoid cimetidine and omeprazole, which inhibit the clearance of R warfarin, and sucralfate, which may impair its absorption. Ranitidine may be used. Most antacids are safe.

Lipid-lowering drugs. Fibrates, and some statins, enhance anticoagulant effect. Avoid colestyramine as it may impair the absorption of both warfarin and vitamin K.

Sex hormones and hormone antagonists. The hormone antagonists danazol, flutamide and tamoxifen enhance the effect of warfarin.

Sedatives and anxiolytics. Benzodiazepines may be used.

Elective surgery

Warfarin is withdrawn 5 days before the operation and recommenced when the patient resumes oral intake; heparin (low molecular weight heparin (LMWH) or unfractionated heparin (UFH); see below) provides cover in the intervening period. In patients with mechanical mitral prosthetic valves, LMWH or UFH is added when the INR is subtherapeutic.

Emergency surgery

Proceed as for bleeding (above).

Dental extractions

Anticoagulation may continue for patients whose INR is less than 4.0. The INR is measured no more than 72 h before the procedure to ensure that the INR will be less than 4.0 on the day of the extraction.

Pharmacokinetics

Heparin is poorly absorbed from the gastrointestinal tract and is given intravenously or subcutaneously; once in the blood its effect is immediate. Heparin binds to several plasma proteins, to endothelial cells, and is taken up by reticuloendothelial cells; the kidney excretes a proportion. Because of these different mechanisms, elimination of heparin from the plasma involves a combination of zero- and first-order processes. The result is that the plasma biological effect t_½ alters disproportionately with dose, being 60 min after 75 units/kg and increasing to 150 min after 400 units/kg.

LMW heparins are less protein bound and have a predictable dose–response profile when administered subcutaneously or intravenously. They also have a longer t_½ than standard heparin preparations.

Pharmacodynamics

Heparin depends for its anticoagulant action on the presence in plasma of a single-chain glycoprotein called antithrombin (formerly antithrombin III), a naturally occurring inhibitor of activated coagulation proteases (factors) that include thrombin, factor Xa and factor IXa. Heparin binds to antithrombin, inducing a conformational change that leads to rapid inhibition of the proteases of the coagulation pathway. In the presence of heparin, antithrombin becomes approximately 1000-fold more active and inhibition is essentially instantaneous. Following destruction of the proteases, the affinity of antithrombin for heparin falls; heparin then dissociates from the antithrombin–protease complex and catalyses further antithrombin–protease interactions.

Factor Xa is critical to thrombin generation (see Fig. 29.1) and heparin has the capacity to inhibit factor Xa in small quantities by virtue of a specific pentasaccharide sequence. This provides the rationale for using low-dose subcutaneous heparin to prevent thrombus formation.

LMWHs inhibit factor Xa at a dose similar to that for UFH, but have much less antithrombin activity, the principal action of conventional heparin. Fibrin formed in the circulation binds to thrombin and protects it from inactivation by the heparin–antithrombin complex; this may provide a further explanation for the higher doses of heparin needed to stop extension of a thrombus than to prevent it.

Fondaparinux is a synthetic pentasaccharide that inhibits factor Xa by an antithrombin-dependent mechanism. Fondaparinux, has a molecular weight of 1728. Its specific anti-Xa activity is higher than that of LMWH and its half-life after subcutaneous injection is longer than that of LMWH. Based on its almost complete bioavailability after subcutaneous injection, lack of variability in anticoagulant response and long half-life, fondaparinux can be administered subcutaneously once daily in fixed doses without coagulation monitoring. Fondaparinux is contraindicated in patients with renal insufficiency (CrCl < 30 mL/min). It is used used for prevention and treatment of venous thromboembolism in the same way as traditional LMWHs. The risk of HIT(T) (see below) is lower, but the risk of bleeding may be greater than that associated with LMWHs.

Monitoring heparin therapy

Control of standard heparin therapy is by the activated partial thromboplastin time (APTT), the target therapeutic range being 1.5–2.5 times the control. An alternative method is to measure the plasma concentration of heparin by anti-Xa assay. Therapeutic amounts of LMWH do not prolong the APTT and, because the pharmacokinetics are predictable, a safe and effective dose can be calculated without laboratory monitoring, using an algorithm that is adjusted for body-weight.

Adverse effects

Bleeding is the main acute complication of heparin therapy. Patients with impaired hepatic or renal function, with carcinoma, and those aged over 60 years are most at risk. An APTT ratio greater than 3 is associated with an increased risk of bleeding.

Heparin-induced thrombocytopenia (HIT), some times accompanied by thrombosis (HIT/T), is due to an autoantibody against heparin in association with platelet factor 4, which activates platelets. It occurs most commonly with heparin derived from bovine lung and is more common with UFHs than with LMWHs. Suspect HIT in any patient in whom the platelet count falls by 50% or more after starting heparin. It usually occurs after 5 days or more of heparin exposure (or sooner if the patient has previously been exposed to heparin). Thrombosis occurs in less than 1% of patients treated with LMWHs but is associated with a mortality and limb amputation rate in excess of 30%. Patients with HIT/T should discontinue all heparin (UF and LMW) and receive an alternative thrombin inhibitor, such as danaparoid or lepirudin. Warfarin should not be commenced until there is adequate anticoagulation with one of these agents and the platelet count has returned to normal.

Osteoporosis may complicate long-term heparin exposure. It is dose related and most frequently observed during pregnancy. The relative risk between LMWHs is not yet established but it appears to be less than with UFHs.

Hypersensitivity reactions and skin necrosis (similar to that seen with warfarin) occur but are rare. Transient alopecia may occur.

Heparin reversal

Protamine, a protein obtained from fish sperm, immediately reverses the anticoagulant action of heparin. It is as strongly basic as heparin is acidic, which explains its rapid action. The effect of UFH is short lived, and reversal with protamine sulphate is seldom required except after extracorporeal perfusion for heart surgery. Protamine sulphate, 1 mg by slow intravenous injection, neutralises 80–100 units UFH. The quantity of heparin given and its expected t_½ determine the amount required but the maximum must not exceed 50 mg. Protamine itself has some anticoagulant effect and overdosage is to be avoided. Its effectiveness in patients treated with LMWH is unknown.

Treatment of established venous thromboembolism

Patients with acute venous thromboembolism are treated safely and effectively with LMWH as outpatients. Large-scale studies demonstrate that outpatient treatment of acute DVT with unmonitored, body-weight-adjusted LMWH is as safe and effective as inpatient treatment with adjusted-dose i.v. UFH. Further trials confirm the safety and efficacy of LMWH therapy in acute PE.

The traditional regimen for standard UFH is a bolus i.v. injection of 5000 units (or 10 000 units in major PE) followed by a constant rate i.v. infusion of 1000–2000 units/h. The APTT should be measured 6 h after starting therapy and the administration rate adjusted to keep it in the optimal therapeutic range of 1.5–2.5; this usually requires daily measurement of APTT.

Coincident with commencing heparin, patients usually start taking an oral vitamin K antagonist, typically warfarin in the UK. The INR is monitored and loading doses of VKA are given according to a validated loading protocol in order to minimise the risk of over-anticoagulation and bleeding. Ideally the INR should be measured daily during the first 4 days of loading with a VKA; guidance is available at http://www.bcshguidelines.com.

Prevention of venous thromboembolism

LMWHs are preferred for perioperative prophylaxis because of their convenience. They are as effective and safe as UFH at preventing venous thrombosis. Once-daily subcutaneous administration suffices, as their duration of action is longer than that of UFH and no laboratory monitoring is required.

If UFH is used, 5000 units should be given subcutaneously every 8 or 12 h without monitoring (this dose does not prolong the APTT), or in pregnancy 5000–10 000 units subcutaneously every 12 h with monitoring (except for pregnant women with prosthetic heart valves, for whom specialist monitoring is needed).

Cardiac disease

LMWHs are at least as effective as standard heparin for unstable angina. Patients undergoing angioplasty may also receive LMWHs.

Heparin is used to reduce the risk of venous thromboembolism, and the size of emboli from mural thrombi following acute myocardial infarction.

Peripheral arterial occlusion

In the acute phase following thrombosis or arterial embolism, heparin may prevent extension of a thrombus and hasten its recanalisation. Long-term antithrombotic therapy for patients with ischaemic peripheral vascular disease generally requires specific antiplatelet therapy (see p. 494).

Plasminogen activators

that convert plasminogen to plasmin initiate the process. A trypsin-like protease, plasmin, then degrades fibrin into soluble fibrin degradation products (Fig. 29.3).

Fig. 29.3 The blood fibrinolytic system. tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator.

Two immunologically distinct plasminogen activators are found in blood, namely tissue-type (tPA) and urokinase-type (uPA), both of which are synthesised and released from endothelial cells. Intravascular plasminogen activation is initiated by tPA. In this process, plasminogen and tPA bind to fibrin and the enzymatic activity of tPA is enhanced by fibrin. The result is that plasmin formation takes place only on the fibrin surface and not generally in the circulation, where widespread defibrination would occur and compromise the whole coagulation mechanism. tPA is the plasminogen activator used for the treatment of coronary occlusion.

Plasminogen activator inhibitors

The most important is endothelial cell-derived type 1 plasminogen activator inhibitor (PAI-1), which blocks the action of tPA. Another inhibitor, α₂-antiplasmin, rapidly complexes with and inactivates free plasmin. Fibrin-bound plasmin is relatively protected from inactivation so that fibrinolysis can occur despite physiological plasma concentrations of this inhibitor.

An enzyme, known as thrombin-activatable fibrinolysis inhibitor (TAFI), attenuates fibrinolysis by cleaving carboxyl-terminal lysine residues from fibrin, the removal of which decreases plasminogen and plasmin binding to fibrin, retarding the lytic process. TAFI thus serves as a link between coagulation and fibrinolysis.

Adverse effects

If bleeding occurs, thrombolytic therapy must cease. Depending on the timing of bleeding in relation to therapy, consider antifibrinolytic therapy with aprotonin (for longer-acting drugs) and raising the fibrinogen concentration with fresh frozen plasma or cryoprecipitate (more likely required after streptokinase therapy). Platelet transfusion may be given to correct the platelet function defect induced by plasmin proteolysis of platelet membrane receptors.

Following thrombolytic therapy intramuscular injections are contraindicated, any venepuncture requires at least 10 min of local compression, and arterial puncture must be avoided.

Hypotension can follow treatment with any thrombolytic drug but febrile allergic reactions are about six times more likely with use of a thrombolytic of bacterial origin. Some milder reactions can be managed with paracetamol, an H₁-receptor antihistamine and corticosteroid.

Pulmonary embolism

Thrombolysis is used in patients with massive pulmonary emboli with cardiovascular compromise; its value in patients with submassive pulmonary embolus is uncertain.

Deep vein thrombosis

Thrombolysis is often not effective in patients with DVT but may be justified when the affected vessels are proximal and risk of pulmonary embolism is high.

Arterial occlusion

Systemic or local thrombolysis may be an option for arterial occlusions distal to the popliteal artery (thrombectomy is the usual therapeutic approach for occlusion of less than 24 h duration proximal to this site). Intravenous streptokinase will lyse 80% of occlusions if infusion begins within 12 h, and 60% if it is delayed for up to 3 days.

Ischaemic stroke

There is little evidence of benefit and most trials have shown increased short-term mortality in patients treated with thrombolysis.

Thrombolysis may also be effective for occluded arteriovenous shunts and for blocked, e.g. central venous, catheters.

Tranexamic acid

competitively inhibits the binding of plasminogen and tPA to fibrin and effectively blocks conversion of plasminogen to plasmin; fibrinolysis is thus retarded. An intravenous bolus passes largely unchanged in the urine with a t_½ of 1.5 h. Oral and topical formulations are available.

Tranexamic acid is used principally to prevent the hyperplasminaemic bleeding state that results from damage to tissues rich in plasminogen activator, e.g. after prostatic surgery, tonsillectomy, uterine cervical cone biopsy and menorrhagia, whether primary or induced by an intrauterine contraceptive device. Tranexamic acid may also reduce bleeding after ocular trauma, and in von Willebrand’s disease and haemophilia after dental extraction (normally combined with DDAVP or factor VIII, respectively).

Some patients with hereditary angioedema may benefit, presumably by prevention of plasmin-induced activation of the complement system.

Tranexamic acid may be of value in thrombocytopenia (idiopathic or following cytotoxic chemotherapy). The natural fibrinolytic destabilisation of small platelet plugs is inhibited, reducing the risk of haemorrhage and requirement for platelet transfusion.

Adverse effects are rare but include nausea, diarrhoea and sometimes orthostatic hypotension. Tranexamic acid is contraindicated for patients with haematuria because clot lysis in the urinary tract is prevented and clot colic results.

Aprotinin

is a naturally occurring inhibitor of plasmin and other proteolytic enzymes that has been used in the past to limit perioperative bleeding during cardiac bypass and liver transplantation surgery. However, a recently recognised association between aprotonin use and serious end-organ damage has resulted in its withdrawal.

Aspirin

(acetylsalicylic acid) acetylates and thus inactivates cyclo-oxygenase (COX), the enzyme responsible for the first step in the formation of prostaglandins, the conversion of arachidonic acid to prostaglandin H₂. As acetylation of COX is irreversible and the platelet is unable to synthesise new enzyme, COX activity is lost for the platelet lifetime (8–10 days).

Aspirin prevents formation of both thromboxane A₂ (TXA₂) and prostacyclin (PGI₂) (see Fig.16.1, p. 241). Therapeutic interest in the antithrombotic effect of aspirin has centred on separating these actions by using a low dose. In general, 75–100 mg/day by mouth will abolish synthesis of TXA₂ without significant impairment of prostacyclin formation, i.e. amounts substantially below the 2.4 g/day used to control pain and inflammation. Laboratory testing of TXA₂ production or TXA₂-dependent platelet function can provide an assessment of the adequacy of aspirin dose. Among several causes of resistance to aspirin are genetic polymorphisms of COX-1 and other genes involved in thromboxane biosynthesis.⁶

Low-dose aspirin is not without risk: a proportion of peptic ulcer bleeds in people aged over 60 years occur from prophylactic low-dose aspirin.

Dipyridamole

reversibly inhibits platelet phosphodiesterase, and consequently cyclic AMP concentration is increased and platelet activity reduced; evidence also suggests that its antithrombotic effect may derive from release of prostaglandin precursors by vascular endothelium. Dipyridamole is bound extensively to plasma proteins and has a t_½ of 12 h.

Clopidogrel

is a thienopyridine derivative that inhibits ADP-dependent platelet aggregation. The t_½ of the parent drug is 40 h and metabolism by the liver converts it to its active form. Clopidogrel reduces the risk of the combined outcome of stroke, myocardial infarction (MI) or vascular death in patients with thromboembolic stroke. It decreases vascular death and MI in patients with unstable angina, reduces acute occlusion of coronary bypass grafts, and improves walking distance and decreases vascular complications in patients with peripheral vascular disease. Clopidogrel also finds use in the prevention of stroke in patients who are intolerant of aspirin. An initial dose of 300 mg is followed by a daily dose of 75 mg.

Prasugrel

is a thienopyridine derivative like clopidogrel. It inhibits ADP-induced platelet aggregation more rapidly, more consistently, and to a greater extent than standard dose clopidogrel. A 60-mg loading dose results in at least 50% inhibition of platelet aggregation by 1 h in 90% of patients. The subsequent daily dose is 10 mg.

Epoprostenol

(prostacyclin) may be given as an anticoagulant during renal dialysis, with or without heparin; it is infused i.v. and s.c (t_½ 3 min). It is a potent vasodilator.

Abciximab

is a human–murinechimeric monoclonal antibody Fab fragment that binds to the GPIIb–IIIa complex with a high affinity and slow dissociation rate. Given intravenously, it is cleared rapidly from plasma (t_½ 20 min). Abciximab (0.25 mg/kg bolus then 0.125 micrograms/kg/min infusion for 12 h) produces immediate and profound inhibition of platelet activity that lasts for 12–36 h after termination of the infusion. The dose causes and maintains blockade of more than 80% of receptors, with a greater than 80% reduction in aggregation. Patients may also receive heparin and an antiplatelet drug, e.g. aspirin. Abciximab is effective in acute coronary syndromes.

Eptifibatide

is a cyclic heptapeptide based upon the Lys-Gly-Asp sequence. Tirofiban and lamifiban are non-peptide mimetics. All three are competitive inhibitors of the GPIIb–IIIa complex, with lower affinities and higher dissociation rates than abciximab and relatively short plasma t_½ values (2–2.5 h). Platelet aggregation returns to normal from 30 min to 4 h after discontinuation. Eptifibatide and tirofiban are effective in acute coronary syndromes.

Adverse effects

Platelet transfusion after cessation of abciximab is necessary for refractory or life-threatening bleeding. After transfusion, the antibody redistributes to the transfused platelets, reducing the mean level of receptor blockade and improving platelet function. Thrombocytopenia may occur from 1 h to days after commencing treatment in up to 1% of patients. This necessitates platelet counts 2–4 h after commencement and then daily; if severe, therapy must be stopped and, if necessary, platelets transfused. EDTA-induced pseudothrombocytopenia has been reported and a low platelet count should prompt examination of a blood film for agglutination before therapy is stopped.