Direct thrombin inhibitors - Wiley Online Library

Anaesthesia, 2005, 60, pages 565–574 .....................................................................................................................................................................................................................

REVIEW ARTICLE

Direct thrombin inhibitors: pharmacology and clinical relevance P. C. A. Kam,1 N. Kaur2 and C. L. Thong3 1 Professor of Anaesthesia, 2 Anaesthetic Registrar, 3 Fellow in Anaesthesia, Department of Anaesthesia, University of New South Wales, St George Hospital, Kogarah, NSW 2217, Australia Summary

Although heparin has been a cornerstone of treatment for the prevention of thrombosis, it is limited by its adverse effects and unpredictable bioavailability. Direct thrombin inhibitors are a novel class of drugs that have been developed as an effective alternative mode of anticoagulation in patients who suffer from heparin-induced thrombocytopaenia, and for the management of thromboembolic disorders and acute coronary syndromes. The main disadvantages of the direct thrombin inhibitors are the lack of an antidote or readily available clinical monitoring. The mechanism of action, the properties of direct thrombin inhibitors and their potential to replace currently available anticoagulants are reviewed. . ......................................................................................................

Correspondence to: Professor P. C. A. Kam E-mail: [email protected] Accepted: 16 February 2005

Direct thrombin inhibitors are a novel class of drugs that have been developed as an effective alternative mode of anticoagulation, especially in patients who suffer from heparin-induced thrombocytopaenia, who require dialysis, cardiopulmonary bypass, and for the management of thromboembolic disorders and acute coronary syndromes. A knowledge of the pharmacology of these drugs is needed for peri-operative management of these patients. This article aims to review the pharmacology of the direct thrombin inhibitors and to discuss the clinical implications of these drugs. Brief review of the physiology of thrombosis

Thrombosis occurs when an imbalance exists between natural anticoagulation factors and fibrinolytic systems [1, 2]. Venous thrombi form under low shear conditions and are often triggered by vascular injury during surgery or trauma or by mechanical damage due to indwelling central venous catheters. They consist mainly of red cells and fibrin [1]. Thrombosis commonly arises in the deep veins of the leg through an interaction of three factors: vessel wall damage, venous stasis and a hypercoaguable state [3]. These thrombi often originate in either the valve cusps or muscular sinuses of deep veins in the 2005 Blackwell Publishing Ltd

calf. Immobility delays the emptying of muscular veins, causing venous stasis and diminished clearance of activated clotting factors. Stasis leads to hypoxaemia and activates the endothelial cells lining the avascular valve cusps. Leucocytes tethered to these activated endothelial cells express tissue factor, and platelet activation and aggregation are enhanced [4]. Arterial thrombi, composed primarily of platelet aggregates held together by fibrin strands, form under high shear conditions usually existing on disrupted arterial plaques [5]. When the endothelium of veins or arteries is damaged, circulating platelets adhere to the exposed subendothelial collagen via von Willebrand factor. Platelet activation occurs and releases thromboxane A2 and adenosine diphosphate (ADP), which recruit additional platelets [6]. Platelet activation induces conformational changes in glycoprotein (GP) IIb ⁄ IIIa receptors, which mediate the cross linking of adjacent platelets resulting in platelet aggregation. Damage to the vascular wall exposes tissue factor (TF)expressing cells to blood and this initiates intravascular coagulation. Tissue factor is abundant in atherosclerotic vessel walls but is not present in healthy subendothelium [7]. In the presence of calcium, TF binds to activated factor VII (factor VIIa) in the plasma to form factor 565

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P. C. A. Kam et al. Direct thrombin inhibitors Anaesthesia, 2005, 60, pages 565–574 . .................................................................................................................................................................................................................... TF.VII X

activates protein C, which functions as an anticoagulant by the down regulation of thrombin generation via the inactivation of factors Va and VIIIa [11].

CONTACT

IX

vessel Injury TF. VIIa

XIa

XI

Platelet

Development of thrombin inhibitors

VIIIa. IXa + phospholipid Tenase complex

VIII. vWF Xa.Va

V

+ phospholipid

THROMBIN prothrombinase complex

Platelet

PROTHROMBIN Fibrinogen Fibrin Polymer

Fibrin monomer XIII

XIIIa STABLE CLOT

Figure 1 Blood coagulation is initiated when factor VII binds to

tissue factor (TF). The TF-activated VII complex activates X and IX. VIIIa–IXa complex enhances Xa production. Thrombin is generated from prothrombin by Xa–Va complex and fibrin is formed. Thrombin also activates XI, V, and XIII, and cleaves von Willebrand factor (vWF) increasing the formation of VIIIa–IXa and therefore Xa–Va.

VIIa ⁄ TF (tenase) complex [8]. The tenase complex activates factor IX and X. Factor Xa then converts small amounts of prothrombin to thrombin [4]. Factor Xa assembles on the surface of activated platelets as part of the prothrombin activating (prothrombinase) complex. The prothrombinase complex consists of Factor Xa, Factor Va and calcium. This complex generates thrombin from prothrombin [9, 10]. Thrombin also activates factor XI, which increases production of activated factor IX (Fig. 1). Thrombin, a multifunctional serine protease, hydrolyses fibrinogen to form fibrin monomers and releases two small polypeptides, fibrinopepetide-A and fibrinopeptide-B [7, 11, 12]. It also activates factor XIII which stabilises the fibrin polymers with the formation of covalent cross links [4]. Thrombin is also a potent platelet agonist, and recruits additional platelets to the site of vascular injury [13]. The intact endothelium inhibits thrombosis normally. This is mediated by thrombomodulin, a thrombin receptor on the surface of the endothelial cells that binds to thrombin. The thrombin ⁄ thrombomodulin complex 566

Thrombin inhibitors can be classified as either indirect or direct agents. Indirect thrombin inhibitors include unfractionated heparin (UFH) and low molecular weight heparins (LMWH), derived from UFH by controlled chemical or enzymatic depolymerisation [14], and vitamin K antagonists such as warfarin. These indirect thrombin inhibitors act by blocking the generation and action of thrombin either by activating naturally occurring thrombin inhibitors or by inhibiting specific coagulation factors [11]. Until recently, heparin has been the cornerstone of treatment of venous and arterial thrombosis. Although it is effective, it is not without limitations [15]. UFH binds to plasma proteins at variable levels in different patients, resulting in an unpredictable response [16]. UFH is also neutralised by platelet factor 4 (PF4) released from activated platelets [17]. Furthermore, IgG antibodies against the UFH ⁄ PF4 complex trigger heparin-induced thrombocytopaenia (HITS), an immune-mediated reaction associated with catastrophic venous and ⁄ or arterial thrombosis [18]. LWMH, which binds less to plasma proteins and platelets, has a more predictable anticoagulant response (9) Neither LWMH nor UFH can completely inactivate thrombin once it is bound to fibrin. Thrombin bound to fibrin within a thrombus remains enzymatically active because it is protected from inactivation by antithrombin [19] and can locally activate platelets and trigger coagulation [16]. Warfarin, a vitamin K antagonist, is a widely used and efficacious orally administered agent [20]. However, it has several disadvantages. It has a narrow therapeutic window. In addition, the anticoagulant effect of warfarin is unpredictable because of multiple food and drug interactions and consequently frequent monitoring is necessary to ensure a therapeutic anticoagulant effect [11]. Three distinct domains or binding sites are present on the thrombin molecule; an active or catalytic site, and two positively charged ‘exosites’ located at opposite poles of the enzyme [21]. Exosite 1 or fibrin binding site is a ‘docking’ site for fibrin and it orientates the appropriate peptide bonds onto the active site. Exosite 2 is the heparin-binding domain. Thrombin binds to fibrinogen via exosite 1 [22]. Heparin exerts its anticoagulant action by catalysing the inhibition of thrombin by antithrombin. To achieve this, heparin simultaneously binds to antithrombin and to the heparin-binding site, thereby bringing the 2005 Blackwell Publishing Ltd

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Anaesthesia, 2005, 60, pages 565–574 P. C. A. Kam et al. Direct thrombin inhibitors . ....................................................................................................................................................................................................................

Heparin

Exosite 2

Heparin MELAGATRAN

ANTITHROMBIN

THROMBIN

THROMBIN

Active catalytic site

FIBRIN

Exosite 1 FIBRIN

EXOSITE 1

Figure 2 Thrombin binds to fibrin via exosite 1. Heparin sim-

ultaneously binds to fibrin and exosite 2 (heparin-binding domain). To catalyse thrombin inactivation by antithrombin, heparin binds to thrombin at exosite 2 and to antithrombin. The heparin-antithrombin complex cannot inactivate thrombin bound within the ternary heparin–fibrin–thrombin complex because 1) exosite 2 is occupied and 2) induced conformational changes at the catalytic site on thrombin reduce its reactivity with antithrombin.

thrombin and its inhibitor (antithrombin) in close contact. Heparin simultaneously binds to exosite 1 and exosite 2 on thrombin to form a ternary heparin ⁄ thrombin ⁄ fibrin complex (Fig. 2). When thrombin is bound within this ternary complex, antithrombin-bound heparin can no longer gain access to exosite 2, a step which is necessary for antithrombin-mediated inactivation of thrombin. Consequently, fibrin-bound thrombin is resistant to inactivation by the heparin–antithrombin complex [23]. Direct thrombin inhibitors

Direct thrombin inhibitors were developed in an attempt to overcome the limitations of indirect thrombin inhibitors. They produce a predictable anticoagulant response because they are minimally bound to plasma proteins. They do not bind to PF4 and do not cause HITS. Moreover, direct thrombin inhibitors can inhibit both fibrin-bound and fluid-phase thrombin because they bind directly to thrombin and function independently of antithrombin [11]. In contrast to heparin, direct thrombin inhibitors inactivate fibrin-bound thrombin. The direct thrombin inhibitors can be classified into univalent direct thrombin inhibitors, which bind only to the catalytic (active) site of thrombin (Fig. 3), and bivalent thrombin inhibitors, which bind to both the exosite 1 and the catalytic site (Fig. 4). The univalent direct thrombin inhibitors are low molecular weight peptides such as argatroban, melagatran (the active form of ximelagatran), efegatran and inogatran [9]. Bivalent direct thrombin inhibitors are hirudin (desirudin or lepirudin) and bivalirudin (previously called hirulog). 2005 Blackwell Publishing Ltd

Figure 3 Univalent direct thrombin inhibitors bind competit-

ively and reversibly to the catalytic site on thrombin.

Hirudin or Bivalirudin THROMBIN

Fibrin

Exosite 1

Figure 4 Bivalent thrombin inhibitors bind irreversibly to the

catalytic site and the fibrin binding site (exosite 1) on thrombin.

Hirudin, bivalirudin and argatroban are parenteral direct thrombin inhibitors approved by the US Food and Drug Administration. Hirudin and argatroban are licensed for treatment of patients with heparin-induced thrombocytopaenia. Bivalirudin is approved as an alternative anticoagulant for heparin in patients undergoing coronary angioplasty [13]. Ximelagatran is the first orally available direct thrombin inhibitor [9]. Hirudins Hirudins are natural single chain-peptides of 7000 Da [25]. They were originally isolated from the saliva of the medicinal leech (Hirudo medicinalis) [26, 27]. In the late 1950s, the action of hirudin as an antithrombin and its peptide nature were described [28, 29]. Recombinant hirudins are known as desulphatohirudins or desirudins because of the lack of the sulphated tyrosine residue in position 63 [30]. Hirudin binds irreversibly to the thrombin molecule at the catalytic site (via its globular amino-terminal domain) and to exosite 1 (via its carboxy-terminal domain) and forms a slowly reversible complex [25, 29]. As a result of 567

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P. C. A. Kam et al. Direct thrombin inhibitors Anaesthesia, 2005, 60, pages 565–574 . ....................................................................................................................................................................................................................

this irreversible binding there is no antidote for hirudin [4]. Hirudin is administered intravenously or by subcutaneous injection because it is not absorbed in the gastrointestinal tract [31, 32]. In patients with normal renal function, a bolus of 0.4 mg.kg)1 has been suggested, followed by an infusion of 0.15 mg.kg)1.h)1 [33]. Because hirudin is predominantly cleared by the kidneys, it must used with caution in patients with impaired renal function [31]. It has a plasma half life of approximately 60 min after intravenous injection, and approximately 120 min after subcutaneous injection [4]. In patients with renal failure, the half life can be prolonged up to > 300 h [34]. Accidental over-dosage of hirudin in patients with renal insufficiency can be managed with dialysis using polymethyl-methyl acrylate (PMMA) membranes, which avidly bind hirudin. Dialysis with other membranes does not effectively remove hirudin [35]. The narrow therapeutic window of hirudin makes anticoagulant monitoring necessary. The treatment is monitored with the aim of maintaining the activated partial thromboplastin time (APTT), approximately 1.5–2.5 times the median of the laboratory normal range [36]. This should be measured before treatment, 4 h after the commencement of intravenous hirudin therapy, 4 h after each dosage change, and at least once daily [37]. However, the APTT is not an optimal method of monitoring hirudin activity because it reflects inhibition of factors IIa, IXa and Xa and lacks a linear correlation with plasma hirudin levels [38, 39]. Although the APTT may be acceptable for routine monitoring of therapeutic-dose hirudin treatment of HIT-associated thrombosis, it cannot be used to monitor the high doses needed for cardiopulmonary bypass as the APTT curve flattens out at high doses [40]. The ecarin clotting time (ECT) is a suitable test for monitoring hirudin anticoagulation because it has a more linear correlation with plasma hirudin levels [41]. Ecarin is a metalloproteinase enzyme found naturally in snake venom that activates prothrombin to meizothrombin and prevents the conversion of fibrinogen to fibrin and thrombin formation [40]. The principle behind the ECT is that after the addition of a specific quantity of ecarin to blood that contains a direct thrombin inhibitor, meizothrombin is generated. Meizothrombin will then react with the direct thrombin inhibitor and neutralise it. The remaining free meizothrombin can then activate the clotting process by stimulating the conversion of fibrinogen to fibrin. Therefore, serum concentrations of direct thrombin inhibitors are correlated with the degree of clotting time prolongation. The accuracy of ECT is reduced in patients within plasma depleted of fibrinogen or prothrombin [39] which is found in patients during 568

cardiopulmonary bypass or with haemodilution. The clotting time is increased by greater than 30% [42]. Hirudin is currently approved for the treatment of arterial or venous thrombosis complicated by heparininduced thrombocytopaenia and as an alternative to heparin for cardiopulmonary bypass surgery in these patients. It has also been evaluated in acute coronary syndromes [43] and for venous thromboprophylaxis in high risk orthopaedic patients [44]. Lepirudin, a recombinant hirudin derived from yeast cells, is an irreversible and specific direct thrombin inhibitor. It is exclusively renally excreted and has an elimination half-life of 1.3 h. It should be used with caution with renal failure. The usual dose is 0.4 mg.kg)1 as a bolus dose followed by an infusion of 0.21 mg.kg)1.h)1, with infusion rate adjustments made on the basis of APTT measurements. Bivalirudin Bivalirudin is a synthetic 20-amino-acid polypeptide [45] with a molecular mass of 2000 Da [11]. Bivalirudin binds bivalently to the active catalytic site and the substrate recognition (exosite 1) site of thrombin molecule. The active catalytic site is slowly cleaved by thrombin itself, leaving a smaller molecule that is bound to the fibrinogen-binding or exosite site with lower affinity [46, 47]. Unlike hirudin, this bivalent binding is reversible because plasma enzymes (including thrombin itself) cleave the arginine–proline bond at the catalytic site [46]. Peak bivalirudin concentrations are achieved 15–20 min after intravenous infusion. In patients with normal renal function the plasma half life of bivalirudin is 25–36 min [48]. Although it is predominantly eliminated by plasma enzymes (peptidases), approximately 20% of the drug is excreted via the kidneys [46, 49], making it a safer alternative to hirudin in patients with renal failure [24]. The half life of bivalirudin in patients on chronic dialysis is 3.5 h and the infusion dosage should be reduced by 90% in this group of patients. Twenty-five per cent of the bivalirudin dose is cleared by haemodialysis [48]. In patients with coronary artery disease undergoing coronary angioplasty who receive bivalirudin, the activated clotting time [ACT] should be closely monitored. The activated clotting time increases in patients infused with bivalirudin (0.15 mg.kg)1 bolus followed by 0.6 mg.kg)1.h)1) from a median of 148 s to 238 s 15 min post dose, compared with an increase in ACT from 124 to 277 s with a 5000-unit heparin bolus [50]. Bivalirudin is approved as a heparin alternative in patients undergoing percutaneous coronary angioplasty. This is based on the results of a phase III study that compared bivalirudin with heparin in 4 098 patients 2005 Blackwell Publishing Ltd

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with unstable angina undergoing percutaneous angioplasty [51]. Although bivalirudin did not reduce the primary end point (a composite of in-hospital death, myocardial infarction, abrupt vessel closure, and clinical deterioration of cardiac origin necessitating coronary intervention), the incidence of major bleeding was significantly less frequent in those patients randomly allocated to receive bivalirudin than in those given heparin (3.8% vs. 9.8%) [13]. Bleeding secondary to bivalirudin can be controlled by a triple therapeutic approach using modified ultrafiltration (MUF) and haemodialysis, administration of recombinant factor VIIa, and cryoprecipitate and FFP. Bivalirudin (45– 69%) is eliminated by modified ultrafiltration [52, 53]. The smaller fragment of the bivalirudin molecule bound to exosite 1 can be competitively displaced. This is the rationale for the administration of fibrinogen in the form of cryoprecipitate and FFP to treat bleeding associated with bivalirudin [54]. Argatroban Argatroban, an arginine derivative, is a synthetic small molecule with a molecular mass of 508.7 Da [55]. It is a univalent competitive inhibitor of thrombin and binds only to the catalytic site of thrombin via a non-covalent bond to form a reversible complex [56]. It is a mixture of 21-R and 21-S diastereoisomers (approximately 64 : 36 ratio) and the S isomer approximately two times more potent [57]. Argatroban has a plasma half life of 39– 51 min and is extensively metabolised by the liver into four, mostly inactive, metabolites, M1–M4. M1 has 3–5 times weaker activity [58]. Renal dysfunction, age and gender do not alter the elimination half-life of the drug [59]. Currently, argatroban is approved in Japan for use in acute ischaemic stroke and chronic peripheral arterial disease. In the USA it is approved for the prophylaxis and treatment of thrombosis in patients with HITS. Other indications that are currently awaiting approval include the use of argatroban as an adjunct to thrombolytic therapy in patients with acute myocardial infarction or ischaemic stroke and in patients with HITS who are undergoing percutaneous coronary intervention [60]. The recommended dose of argatroban in the treatment of HITS is 2 lg.kg)1.min)1 and the dose should be adjusted to maintain the APTT at 1.5–3 times the patient’s baseline, with a maximum infusion rate at 10 lg.kg)1.min)1. Argatroban increases the APTT and activated-clotting time (ACT) in a dose-dependent manner. In patients with hepatic disease the initial starting dose should be reduced to 0.5 lg.kg)1.min)1 and the dose adjusted according to APTT [61]. 2005 Blackwell Publishing Ltd

Argatroban may be preferable to the other agents in treatment of HITS or during percutaneous intervention because of its short half life and its predictable dosedependent therapeutic response that can be monitored by APTT. Ximelagatran Ximelagatran is an uncharged lipophilic univalent drug that has negligible intrinsic activity [62]. It is a prodrug and is rapidly metabolised to the active metabolite, melagatran [4]. Melagatran is a dipeptide and binds to the active catalytic site of the thrombin molecule. It is a competitive and reversible univalent direct thrombin inhibitor. Ximelagatran is better absorbed from the gastrointestinal tract with an oral bioavailability of about 20%, whereas the oral bioavailibility of melagatran is 3–7% [62, 63]. It undergoes rapid biotransformation by a reduction process to melagatran [64, 65], which is accomplished by enzyme systems located within microsomes and mitochondria of the liver and kidney [66, 67]. It has a plasma half life of 3 h after intravenous administration. The drug produces a predictable anticoagulant response after oral administration and no coagulation monitoring is necessary. It has minimal food and drug interactions [68]. Melagatran is eliminated via the kidneys, and dose adjustment is required in patients with renal impairment and in the elderly [69]. During ximelagatran therapy, liver transaminases are elevated in approximately 6% of patients but the transaminases decrease spontaneously during continued treatment [70]. With its predictable pharmacokinetics, wide therapeutic window and no food and drug interactions, laboratory monitoring is not necessary during treatment with ximelagratran [9], which may replace warfarin in the management of patients with non-valvular atrial fibrillation. Ximelagatran can also be administered parenterally. It may be suitable for extended use in both the prophylaxis and treatment of venous thromboembolism [4]. Multiple clinical trials conducted in Europe and North America have reported that a regimen of subcutaneous melagatran for 1–2 days following major orthopaedic surgery followed by oral ximelagatran, started in the postoperative period, is as effective as LMWH in preventing venous thromboembolism. The METHRO (MElagatran for THRombin inhibition in Orthopaedic surgery) II, III and EXPRESS (Expanded Prophylaxis Evaluation Surgery Study) studies in which most patients received regional anaesthesia reported no epidural or spinal haematoma [82]. Based on these extensive clinical trials, ximelagatran may be a potential candidate for the prevention of venous thromboembolic disease in major elective orthopaedic surgery. 569

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Adverse effects

Increased bleeding tendencies are a major concern with the use of the direct thrombin inhibitors. Although there are no specific antidotes to the direct thrombin inhibitors, experimental studies have shown that prothrombin complex concentrates, fresh frozen plasma or recombinant factor VIIa [64] can antagonise the anticoagulant effects and form thrombin to form an inactive complex with the thrombin inhibitor. Prothrombin complex concentrates (PCC) are prepared from the pooled plasma of thousands of blood donors (currently manufactured using vapour-heat treatment to kill viruses) and also contain the vitamin K dependent procoagulant and anticoagulant factors. Because they do not contain vitamin K, intravenous vitamin K should be given with PCC to reverse the effects of the direct thrombin inhibitors [36]. Activated PCCs can reverse bleeding caused by high doses of melagatran but are associated with a higher risk of thrombogenicity and myocardial infarction (which may be caused by the presence of activated FVII) [71]. Recombinant Factor VIIa (rFVIIa) is a prohaemostatic drug that enhances the tissue factor pathway by activating factor X into Xa directly as well as by binding to platelets [72]. This, in the presence of Factor Va, leads to an increase in thrombin generation [73]. A recent clinical study in healthy subjects taking melagatran reported that the effects of melagatran on APTT, thrombin generation and platelet activation were not reversed by the administration of rFVIIa [74]. It suggested that rFVIIa was not effective in reversing direct thrombin inhibition. However, rFVIIa did correct the melagatran-induced prolongation of PT and increased thrombin precursor protein concentrations [74]. Further studies of these antidotes are required to establish their role in the reversal of the direct thrombin inhibitors. Clinical applications

Direct thrombin inhibitors are being increasingly used in patients who suffer HITS and require anticoagulation for thromboembolic disorders, during dialysis and in those patients undergoing cardiopulmonary bypass. They are also used as a heparin substitute during coronary angioplasty and in the management of acute coronary syndromes. Systemic anticoagulation is required during cardiac surgery with cardiopulmonary bypass to prevent clotting in the extracorporeal circuit and to preserve haemostatic components. A previous history or current diagnosis of HITS poses a clinical dilemma in patients requiring cardiac surgery as the use of heparin during CPB is 570

contra-indicated [75]. Low molecular weight heparins have a high cross-reactivity (approximately 90%) with the antibodies against the heparin–platelet factor 4 complex that causes HITS [76]. If a patient develops acute HIT in the peri-operative period of cardiac surgery, direct thrombin inhibitors are the anticoagulants of choice [77]. In patients with renal dysfunction, hirudin should be used cautiously due to its exclusive renal elimination. Patients who suffer from hepatic disease should not be treated with argatroban. Bivalirudin may prove to become the therapeutic agent of choice in the management of patients with HITS during cardiopulmonary bypass [78]. Dialysis patients are a large group of patients who are at a continual risk of developing HITS. Heparin-induced antibodies occur in 0–12% of haemodialysis patients and an alternative mode of anticoagulation is needed in those patients who develop the clinical symptoms of HITS [79]. Hirudin and argatroban have been used as alternative anticoagulants during haemodialysis but careful monitoring is required. Argatroban has been used as an anticoagulant during extracorporeal circulation in haemodialysis patients with congenital antithrombin deficiency where heparin is not an effective anticoagulant [80]. Disseminated intravascular coagulation is often triggered during sepsis by the release of lipopolysaccharide via the tissue factor-dependent pathway, resulting in massive thrombin generation and fibrin polymerisation. Recent animal studies demonstrated that hirudin reduced fibrin deposition in liver and kidney, decreased mortality and decreased thrombin generation in lipopolysaccharideinduced DIC [81]. Therefore, direct thrombin inhibitors may have an important place in the management of DIC. Ximelagatran appears to hold out great promise for venous thromboembolism prophylaxis in major elective orthopaedic surgical patients because it provides effective anticoagulation without the need for coagulation monitoring and with a low risk of bleeding, including spinal haematomas, if usual precautions are followed [70, 82]. Implications for clinical anaesthesia

As with all anticoagulants, the balance between benefit and risk of major bleeding has to be taken into consideration. This balance is influenced not only by the pharmacology of the drug, but also by the type of surgery, the dose administered and the timing of the first dose of the drug in relation to the surgery. Extreme caution must be taken when patients on direct thrombin inhibitors present to the operating theatre as no specific antidotes are currently available. These agents should therefore be stopped several hours before surgery, as most have short half lives of 1–2 h, and recombinant Factor 2005 Blackwell Publishing Ltd

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Table 1 Properties of direct thrombin inhibitors. Property

Hirudin

Bivalirudin

Argatroban

Ximegalatran or Lepirudin

Thrombin interaction site ⁄ s

1. Active catalytic site 2. exosite 1 irreversible renal Intravenous 60 HIT

1. Active catalytic site 2. exosite 1 reversible Plasma enzymes (peptidases) Intravenous 25 alternative to heparin during PCI

1. Active catalytic site

1. Active catalytic site

reversible Hepatic Intravenous 45 HIT

reversible renal Oral 240 Pending DVT prophylaxis

Type of inhibition Clearance mechanisms Route of administration Elimination half life (min) Approved indications

HIT, Heparin-induced thrombocytopaenia type II. PCI. percutaneous coronary intervention. DVT, deep vein thrombosis.

V11a and prothrombin complex concentrates should be readily available. There are no large studies available to provide definitive recommendations concerning the use of neuraxial anaesthesia in patients who receive the direct thrombin inhibitors. The elimination half life of the current direct thrombin inhibitors is relatively short (< 4 h, see Table 1). In a review article on ximelagatran, Rosencher recommended that the precautions associated with the use of ximelagratan in patients undergoing neuraxial anaesthesia are similar to those with LMWH and the patients should be monitored for signs and symptoms of neurological impairment [82]. The guidelines for the use of enoxaparin in conjunction with neuraxial blockade recommend that the placement or removal of an epidural or spinal needle or catheter should be performed at least 12 h after a prophylactic dose (or 24 h after a therapeutic dose) of low molecular weight heparin. The subsequent dose of LMWH should only be administered 4 h after the removal of the epidural catheter. Non-steroidal antiinflammatory drugs should be avoided. Lepirudin and argatroban have been used as antithrombotic agents in the treatment of Type II heparin-induced thrombocytopaenia (HIT) [40, 83–7]. Laboratory monitoring with APTT or escarin clotting time is required and the infusion rate adjusted for a target APTT of 1.5–2.5 times the median value for the normal range. About 40% of patients develop IgG anti-hirudin antibodies that alter the patient’s response to response to lepidurin [85]. The major problems of lepirudin treatment are the lack of an antidote and its immunogenicity. In the event of bleeding induced by the direct thrombin inhibitors, prothrombin complex concentrates or recombinant factor VIIa infusions may be used to secure haemostasis should these patients require urgent surgery. Lepirudin and bivalirudin are useful anticoagulants for cardiopulmonary bypass (CPB) in cardiac surgical patients with on-going type II HIT [78, 88]. Anticoagulation utilising lepirudin (loading dose pre bypass = 0.25 mg.kg)1; 0.2 mg.kg)1 added to prime; maintenance 2005 Blackwell Publishing Ltd

infusion 0.5 mg.min)1 to achieve target lepirudin plasma levels at 2.5 lg.ml)1) has been used in cardiac surgical patients undergoing CPB. The APTT cannot be used to monitor anticoagulation of the high doses of lepirudin used during CPB because the APPT curve plateaus out at high lepirudin concentrations. Whole blood ecarin clotting time provides a rapid and reliable method of monitoring lepirudin anticoagulation. Bivalirudin (loading dose 1.5 mg.kg)1; 50 mg into prime solution; maintenance infusion 2.5 mg.kg)1.h)1) has been used successfully for anticoagulation during CPB in patients with HIT. References 1 Furic B, Furic BC. Molecular and cellular biology of blood coagulation. New England Journal of Medicine 1992; 326: 800–6. 2 Friedman DG. The structure of thrombin. In: Colman RW, Hirsh J, Marder V, Salzman EW, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 2nd edn. Philadelphia: JB Lippincott, 1987: 71–2. 3 Lensing AWA, Prandoni P, Prins MH, Buller HR. Deep vein thrombosis. Lancet 1999; 353: 479–85. 4 Bates S, Weitz J. Emerging anticoagulant drugs. Arteriosclerosis, Thrombosis and Vascular Biology 2003; 23: 1491–500. 5 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657–71. 6 Davie EW. Biochemical and molecular aspects of the coagulation cascade. Thrombosis and Haemostasis 1995; 75: 1–6. 7 Herrmann JP, Serruys P. Thrombin and antithrombotic therapy in interventional cardiology. Texas Heart Institute Journal 1994; 21: 138–47. 8 Mann K, Butenas S, Brummel K. The dynamics of thrombin formation. Arteriosclerosis Thrombosis and Vascular Biology 2003; 23: 17–25. 9 Hirsch J. Current anticoagulant therapy – unmet clinical needs. Thrombosis Research 2003; 109: S1–8. 10 Price GC, Thompson SA, Kam PCA. Tissue factor and tissue factor pathway inhibitor. Anaesthesia 2004; 59: 483–92.

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