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Direct thrombin inhibitors: Pharmacology and clinical relevance

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DOI: 10.1111/j.1365-2044.2005.04192.x · Source: PubMed

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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: p.kam@unsw.edu.au
Accepted: 16 February 2005

Direct thrombin inhibitors are a novel class of drugs that calf. Immobility delays the emptying of muscular veins,
have been developed as an effective alternative mode of causing venous stasis and diminished clearance of activa-
anticoagulation, especially in patients who suffer from ted clotting factors. Stasis leads to hypoxaemia and
heparin-induced thrombocytopaenia, who require dialy- activates the endothelial cells lining the avascular valve
sis, cardiopulmonary bypass, and for the management of cusps. Leucocytes tethered to these activated endothelial
thromboembolic disorders and acute coronary syndromes. cells express tissue factor, and platelet activation and
A knowledge of the pharmacology of these drugs is needed aggregation are enhanced [4]. Arterial thrombi, composed
for peri-operative management of these patients. primarily of platelet aggregates held together by fibrin
This article aims to review the pharmacology of the strands, form under high shear conditions usually existing
direct thrombin inhibitors and to discuss the clinical on disrupted arterial plaques [5].
implications of these drugs. When the endothelium of veins or arteries is damaged,
circulating platelets adhere to the exposed subendothelial
collagen via von Willebrand factor. Platelet activation
Brief review of the physiology of thrombosis
occurs and releases thromboxane A2 and adenosine
Thrombosis occurs when an imbalance exists between diphosphate (ADP), which recruit additional platelets
natural anticoagulation factors and fibrinolytic systems [6]. Platelet activation induces conformational changes in
[1, 2]. Venous thrombi form under low shear conditions glycoprotein (GP) IIb ⁄ IIIa receptors, which mediate the
and are often triggered by vascular injury during surgery cross linking of adjacent platelets resulting in platelet
or trauma or by mechanical damage due to indwelling aggregation.
central venous catheters. They consist mainly of red cells Damage to the vascular wall exposes tissue factor (TF)-
and fibrin [1]. Thrombosis commonly arises in the deep expressing cells to blood and this initiates intravascular
veins of the leg through an interaction of three factors: coagulation. Tissue factor is abundant in atherosclerotic
vessel wall damage, venous stasis and a hypercoaguable vessel walls but is not present in healthy subendothelium
state [3]. These thrombi often originate in either the [7]. In the presence of calcium, TF binds to activated
valve cusps or muscular sinuses of deep veins in the factor VII (factor VIIa) in the plasma to form factor

2005 Blackwell Publishing Ltd 565

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

TF.VII activates protein C, which functions as an anticoagulant

CONTACT
vessel IX by the down regulation of thrombin generation via the
X
Injury
inactivation of factors Va and VIIIa [11].
TF. VIIa XIa XI
Platelet

VIIIa. IXa
+ phospholipid
Tenase
complex
VIII. vWF
Xa.Va V
+ phospholipid
THROMBIN
prothrombinase
Platelet
complex
PROTHROMBIN
Fibrinogen
Fibrin
Polymer
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. Throm-
bin 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
Development of thrombin inhibitors
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 vita-
min K antagonists such as warfarin. These indirect
thrombin inhibitors act by blocking the generation and
action of thrombin either by activating naturally occur-
ring thrombin inhibitors or by inhibiting specific coagu-
lation factors [11].
Until recently, heparin has been the cornerstone of
treatment of venous and arterial thrombosis. Although it
Fibrin is effective, it is not without limitations [15]. UFH binds
monomer
to plasma proteins at variable levels in different patients,
XIII resulting in an unpredictable response [16]. UFH is also
neutralised by platelet factor 4 (PF4) released from
XIIIa
activated platelets [17]. Furthermore, IgG antibodies
against the UFH ⁄ PF4 complex trigger heparin-induced
thrombocytopaenia (HITS), an immune-mediated reac-
tion 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 coagu-
lation [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 win-
dow. In addition, the anticoagulant effect of warfarin is
unpredictable because of multiple food and drug inter-
actions 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

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

Heparin
Exosite 2 Heparin

ANTITHROMBIN MELAGATRAN
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 Figure 3 Univalent direct thrombin inhibitors bind competit-
domain). To catalyse thrombin inactivation by antithrombin, ively and reversibly to the catalytic site on thrombin.
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 Hirudin or
changes at the catalytic site on thrombin reduce its reactivity Bivalirudin
with antithrombin. THROMBIN

thrombin and its inhibitor (antithrombin) in close

contact. Heparin simultaneously binds to exosite 1 and
exosite 2 on thrombin to form a ternary heparin ⁄ throm-
bin ⁄ fibrin complex (Fig. 2). When thrombin is bound
within this ternary complex, antithrombin-bound hep-
arin can no longer gain access to exosite 2, a step which Fibrin
Exosite 1
is necessary for antithrombin-mediated inactivation of
thrombin. Consequently, fibrin-bound thrombin is
Figure 4 Bivalent thrombin inhibitors bind irreversibly to the
resistant to inactivation by the heparin–antithrombin catalytic site and the fibrin binding site (exosite 1) on thrombin.
complex [23].

Hirudin, bivalirudin and argatroban are parenteral

Direct thrombin inhibitors
direct thrombin inhibitors approved by the US Food
Direct thrombin inhibitors were developed in an attempt and Drug Administration. Hirudin and argatroban are
to overcome the limitations of indirect thrombin inhib- licensed for treatment of patients with heparin-induced
itors. They produce a predictable anticoagulant response thrombocytopaenia. Bivalirudin is approved as an alter-
because they are minimally bound to plasma proteins. native anticoagulant for heparin in patients undergoing
They do not bind to PF4 and do not cause HITS. coronary angioplasty [13]. Ximelagatran is the first orally
Moreover, direct thrombin inhibitors can inhibit both available direct thrombin inhibitor [9].
fibrin-bound and fluid-phase thrombin because they bind
directly to thrombin and function independently of Hirudins
antithrombin [11]. In contrast to heparin, direct thrombin Hirudins are natural single chain-peptides of 7000 Da
inhibitors inactivate fibrin-bound thrombin. [25]. They were originally isolated from the saliva of the
The direct thrombin inhibitors can be classified into medicinal leech (Hirudo medicinalis) [26, 27].
univalent direct thrombin inhibitors, which bind only to In the late 1950s, the action of hirudin as an
the catalytic (active) site of thrombin (Fig. 3), and antithrombin and its peptide nature were described
bivalent thrombin inhibitors, which bind to both the [28, 29]. Recombinant hirudins are known as desulph-
exosite 1 and the catalytic site (Fig. 4). The univalent atohirudins or desirudins because of the lack of the
direct thrombin inhibitors are low molecular weight sulphated tyrosine residue in position 63 [30].
peptides such as argatroban, melagatran (the active form Hirudin binds irreversibly to the thrombin molecule at
of ximelagatran), efegatran and inogatran [9]. Bivalent the catalytic site (via its globular amino-terminal domain)
direct thrombin inhibitors are hirudin (desirudin or and to exosite 1 (via its carboxy-terminal domain) and
lepirudin) and bivalirudin (previously called hirulog). forms a slowly reversible complex [25, 29]. As a result of

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. ....................................................................................................................................................................................................................

this irreversible binding there is no antidote for hirudin cardiopulmonary bypass or with haemodilution. The
[4]. clotting time is increased by greater than 30% [42].
Hirudin is administered intravenously or by subcuta- Hirudin is currently approved for the treatment of
neous injection because it is not absorbed in the arterial or venous thrombosis complicated by heparin-
gastrointestinal tract [31, 32]. In patients with normal induced thrombocytopaenia and as an alternative to
renal function, a bolus of 0.4 mg.kg)1 has been suggested, heparin for cardiopulmonary bypass surgery in these
followed by an infusion of 0.15 mg.kg)1.h)1 [33]. patients. It has also been evaluated in acute coronary
Because hirudin is predominantly cleared by the kidneys, syndromes [43] and for venous thromboprophylaxis in
it must used with caution in patients with impaired renal high risk orthopaedic patients [44].
function [31]. It has a plasma half life of approximately Lepirudin, a recombinant hirudin derived from yeast
60 min after intravenous injection, and approximately cells, is an irreversible and specific direct thrombin
120 min after subcutaneous injection [4]. In patients inhibitor. It is exclusively renally excreted and has an
with renal failure, the half life can be prolonged up to elimination half-life of 1.3 h. It should be used with
> 300 h [34]. caution with renal failure. The usual dose is 0.4 mg.kg)1
Accidental over-dosage of hirudin in patients with as a bolus dose followed by an infusion of 0.21
renal insufficiency can be managed with dialysis using mg.kg)1.h)1, with infusion rate adjustments made on the
polymethyl-methyl acrylate (PMMA) membranes, which basis of APTT measurements.
avidly bind hirudin. Dialysis with other membranes does
not effectively remove hirudin [35]. The narrow thera- Bivalirudin
peutic window of hirudin makes anticoagulant monitor- Bivalirudin is a synthetic 20-amino-acid polypeptide
ing necessary. The treatment is monitored with the aim of [45] with a molecular mass of 2000 Da [11]. Bivaliru-
maintaining the activated partial thromboplastin time din binds bivalently to the active catalytic site and the
(APTT), approximately 1.5–2.5 times the median of the substrate recognition (exosite 1) site of thrombin
laboratory normal range [36]. This should be measured molecule. The active catalytic site is slowly cleaved
before treatment, 4 h after the commencement of by thrombin itself, leaving a smaller molecule that is
intravenous hirudin therapy, 4 h after each dosage bound to the fibrinogen-binding or exosite site with
change, and at least once daily [37]. However, the APTT lower affinity [46, 47]. Unlike hirudin, this bivalent
is not an optimal method of monitoring hirudin activity binding is reversible because plasma enzymes (including
because it reflects inhibition of factors IIa, IXa and Xa and thrombin itself) cleave the arginine–proline bond at the
lacks a linear correlation with plasma hirudin levels [38, catalytic site [46]. Peak bivalirudin concentrations are
39]. Although the APTT may be acceptable for routine achieved 15–20 min after intravenous infusion. In
monitoring of therapeutic-dose hirudin treatment of patients with normal renal function the plasma half
HIT-associated thrombosis, it cannot be used to monitor life of bivalirudin is 25–36 min [48]. Although it is
the high doses needed for cardiopulmonary bypass as the predominantly eliminated by plasma enzymes (peptid-
APTT curve flattens out at high doses [40]. The ecarin ases), approximately 20% of the drug is excreted via the
clotting time (ECT) is a suitable test for monitoring kidneys [46, 49], making it a safer alternative to hirudin
hirudin anticoagulation because it has a more linear in patients with renal failure [24]. The half life of
correlation with plasma hirudin levels [41]. Ecarin is a bivalirudin in patients on chronic dialysis is 3.5 h
metalloproteinase enzyme found naturally in snake and the infusion dosage should be reduced by 90% in
venom that activates prothrombin to meizothrombin this group of patients. Twenty-five per cent of the
and prevents the conversion of fibrinogen to fibrin and bivalirudin dose is cleared by haemodialysis [48].
thrombin formation [40]. The principle behind the ECT In patients with coronary artery disease undergoing
is that after the addition of a specific quantity of ecarin to coronary angioplasty who receive bivalirudin, the activa-
blood that contains a direct thrombin inhibitor, meizo- ted clotting time [ACT] should be closely monitored.
thrombin is generated. Meizothrombin will then react The activated clotting time increases in patients infused
with the direct thrombin inhibitor and neutralise it. The with bivalirudin (0.15 mg.kg)1 bolus followed by
remaining free meizothrombin can then activate the 0.6 mg.kg)1.h)1) from a median of 148 s to 238 s
clotting process by stimulating the conversion of fibrin- 15 min post dose, compared with an increase in ACT
ogen to fibrin. Therefore, serum concentrations of direct from 124 to 277 s with a 5000-unit heparin bolus [50].
thrombin inhibitors are correlated with the degree of Bivalirudin is approved as a heparin alternative in
clotting time prolongation. The accuracy of ECT is patients undergoing percutaneous coronary angioplasty.
reduced in patients within plasma depleted of fibrinogen This is based on the results of a phase III study that
or prothrombin [39] which is found in patients during compared bivalirudin with heparin in 4 098 patients

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

with unstable angina undergoing percutaneous angio- Argatroban may be preferable to the other agents in
plasty [51]. Although bivalirudin did not reduce the treatment of HITS or during percutaneous intervention
primary end point (a composite of in-hospital death, because of its short half life and its predictable dose-
myocardial infarction, abrupt vessel closure, and clinical dependent therapeutic response that can be monitored by
deterioration of cardiac origin necessitating coronary APTT.
intervention), the incidence of major bleeding was
significantly less frequent in those patients randomly Ximelagatran
allocated to receive bivalirudin than in those given Ximelagatran is an uncharged lipophilic univalent drug
heparin (3.8% vs. 9.8%) [13]. that has negligible intrinsic activity [62]. It is a prodrug
Bleeding secondary to bivalirudin can be controlled by and is rapidly metabolised to the active metabolite,
a triple therapeutic approach using modified ultrafiltration melagatran [4]. Melagatran is a dipeptide and binds to
(MUF) and haemodialysis, administration of recombinant the active catalytic site of the thrombin molecule. It is a
factor VIIa, and cryoprecipitate and FFP. Bivalirudin (45– competitive and reversible univalent direct thrombin
69%) is eliminated by modified ultrafiltration [52, 53]. inhibitor. Ximelagatran is better absorbed from the
The smaller fragment of the bivalirudin molecule bound gastrointestinal tract with an oral bioavailability of about
to exosite 1 can be competitively displaced. This is the 20%, whereas the oral bioavailibility of melagatran is
rationale for the administration of fibrinogen in the form 3–7% [62, 63]. It undergoes rapid biotransformation by
of cryoprecipitate and FFP to treat bleeding associated a reduction process to melagatran [64, 65], which is
with bivalirudin [54]. accomplished by enzyme systems located within micro-
somes and mitochondria of the liver and kidney [66, 67].
Argatroban It has a plasma half life of 3 h after intravenous
Argatroban, an arginine derivative, is a synthetic small administration. The drug produces a predictable antico-
molecule with a molecular mass of 508.7 Da [55]. It is a agulant response after oral administration and no coagu-
univalent competitive inhibitor of thrombin and binds lation monitoring is necessary. It has minimal food and
only to the catalytic site of thrombin via a non-covalent drug interactions [68].
bond to form a reversible complex [56]. It is a mixture of Melagatran is eliminated via the kidneys, and dose
21-R and 21-S diastereoisomers (approximately 64 : 36 adjustment is required in patients with renal impairment
ratio) and the S isomer approximately two times more and in the elderly [69]. During ximelagatran therapy, liver
potent [57]. Argatroban has a plasma half life of 39– transaminases are elevated in approximately 6% of patients
51 min and is extensively metabolised by the liver into but the transaminases decrease spontaneously during
four, mostly inactive, metabolites, M1–M4. M1 has 3–5 continued treatment [70].
times weaker activity [58]. Renal dysfunction, age and With its predictable pharmacokinetics, wide therapeu-
gender do not alter the elimination half-life of the drug tic window and no food and drug interactions, laboratory
[59]. monitoring is not necessary during treatment with
Currently, argatroban is approved in Japan for use in ximelagratran [9], which may replace warfarin in the
acute ischaemic stroke and chronic peripheral arterial management of patients with non-valvular atrial fibrilla-
disease. In the USA it is approved for the prophylaxis tion. Ximelagatran can also be administered parenterally.
and treatment of thrombosis in patients with HITS. It may be suitable for extended use in both the
Other indications that are currently awaiting approval prophylaxis and treatment of venous thromboembolism
include the use of argatroban as an adjunct to [4]. Multiple clinical trials conducted in Europe and
thrombolytic therapy in patients with acute myocardial North America have reported that a regimen of sub-
infarction or ischaemic stroke and in patients with cutaneous melagatran for 1–2 days following major
HITS who are undergoing percutaneous coronary orthopaedic surgery followed by oral ximelagatran, started
intervention [60]. in the postoperative period, is as effective as LMWH in
The recommended dose of argatroban in the treatment preventing venous thromboembolism. The METHRO
of HITS is 2 lg.kg)1.min)1 and the dose should be (MElagatran for THRombin inhibition in Orthopaedic
adjusted to maintain the APTT at 1.5–3 times the surgery) II, III and EXPRESS (Expanded Prophylaxis
patient’s baseline, with a maximum infusion rate at Evaluation Surgery Study) studies in which most patients
10 lg.kg)1.min)1. Argatroban increases the APTT and received regional anaesthesia reported no epidural or
activated-clotting time (ACT) in a dose-dependent spinal haematoma [82]. Based on these extensive clinical
manner. In patients with hepatic disease the initial starting trials, ximelagatran may be a potential candidate for the
dose should be reduced to 0.5 lg.kg)1.min)1 and the prevention of venous thromboembolic disease in major
dose adjusted according to APTT [61]. elective orthopaedic surgery.

2005 Blackwell Publishing Ltd 569

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

contra-indicated [75]. Low molecular weight heparins

Adverse effects
have a high cross-reactivity (approximately 90%) with the
Increased bleeding tendencies are a major concern with antibodies against the heparin–platelet factor 4 complex
the use of the direct thrombin inhibitors. Although there that causes HITS [76]. If a patient develops acute HIT in
are no specific antidotes to the direct thrombin inhibitors, the peri-operative period of cardiac surgery, direct
experimental studies have shown that prothrombin thrombin inhibitors are the anticoagulants of choice
complex concentrates, fresh frozen plasma or recombin- [77]. In patients with renal dysfunction, hirudin should be
ant factor VIIa [64] can antagonise the anticoagulant used cautiously due to its exclusive renal elimination.
effects and form thrombin to form an inactive complex Patients who suffer from hepatic disease should not be
with the thrombin inhibitor. Prothrombin complex treated with argatroban. Bivalirudin may prove to
concentrates (PCC) are prepared from the pooled plasma become the therapeutic agent of choice in the manage-
of thousands of blood donors (currently manufactured ment of patients with HITS during cardiopulmonary
using vapour-heat treatment to kill viruses) and also bypass [78].
contain the vitamin K dependent procoagulant and Dialysis patients are a large group of patients who are at
anticoagulant factors. Because they do not contain a continual risk of developing HITS. Heparin-induced
vitamin K, intravenous vitamin K should be given with antibodies occur in 0–12% of haemodialysis patients and
PCC to reverse the effects of the direct thrombin an alternative mode of anticoagulation is needed in those
inhibitors [36]. Activated PCCs can reverse bleeding patients who develop the clinical symptoms of HITS [79].
caused by high doses of melagatran but are associated with Hirudin and argatroban have been used as alternative
a higher risk of thrombogenicity and myocardial infarc- anticoagulants during haemodialysis but careful mon-
tion (which may be caused by the presence of activated itoring is required. Argatroban has been used as an
FVII) [71]. anticoagulant during extracorporeal circulation in hae-
Recombinant Factor VIIa (rFVIIa) is a prohaemostatic modialysis patients with congenital antithrombin defici-
drug that enhances the tissue factor pathway by activating ency where heparin is not an effective anticoagulant [80].
factor X into Xa directly as well as by binding to platelets Disseminated intravascular coagulation is often trig-
[72]. This, in the presence of Factor Va, leads to an gered during sepsis by the release of lipopolysaccharide via
increase in thrombin generation [73]. A recent clinical the tissue factor-dependent pathway, resulting in massive
study in healthy subjects taking melagatran reported that thrombin generation and fibrin polymerisation. Recent
the effects of melagatran on APTT, thrombin generation animal studies demonstrated that hirudin reduced fibrin
and platelet activation were not reversed by the admin- deposition in liver and kidney, decreased mortality and
istration of rFVIIa [74]. It suggested that rFVIIa was not decreased thrombin generation in lipopolysaccharide-
effective in reversing direct thrombin inhibition. How- induced DIC [81]. Therefore, direct thrombin inhibitors
ever, rFVIIa did correct the melagatran-induced prolon- may have an important place in the management of DIC.
gation of PT and increased thrombin precursor protein Ximelagatran appears to hold out great promise for
concentrations [74]. Further studies of these antidotes are venous thromboembolism prophylaxis in major elective
required to establish their role in the reversal of the direct orthopaedic surgical patients because it provides effective
thrombin inhibitors. anticoagulation without the need for coagulation mon-
itoring and with a low risk of bleeding, including spinal
haematomas, if usual precautions are followed [70, 82].
Clinical applications
Direct thrombin inhibitors are being increasingly used
Implications for clinical anaesthesia
in patients who suffer HITS and require anticoagulation
for thromboembolic disorders, during dialysis and in As with all anticoagulants, the balance between benefit
those patients undergoing cardiopulmonary bypass. They and risk of major bleeding has to be taken into
are also used as a heparin substitute during coronary consideration. This balance is influenced not only by
angioplasty and in the management of acute coronary the pharmacology of the drug, but also by the type of
syndromes. surgery, the dose administered and the timing of the first
Systemic anticoagulation is required during cardiac dose of the drug in relation to the surgery. Extreme
surgery with cardiopulmonary bypass to prevent clotting caution must be taken when patients on direct thrombin
in the extracorporeal circuit and to preserve haemostatic inhibitors present to the operating theatre as no specific
components. A previous history or current diagnosis of antidotes are currently available. These agents should
HITS poses a clinical dilemma in patients requiring therefore be stopped several hours before surgery, as most
cardiac surgery as the use of heparin during CPB is have short half lives of 1–2 h, and recombinant Factor

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Anaesthesia, 2005, 60, pages 565–574 P. C. A. Kam et al. Æ Direct thrombin inhibitors
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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 1. Active catalytic site 1. Active catalytic site 1. Active catalytic site
2. exosite 1 2. exosite 1
Type of inhibition irreversible reversible reversible reversible
Clearance mechanisms renal Plasma enzymes (peptidases) Hepatic renal
Route of administration Intravenous Intravenous Intravenous Oral
Elimination half life (min) 60 25 45 240
Approved indications HIT alternative to heparin during HIT Pending
PCI DVT prophylaxis

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

V11a and prothrombin complex concentrates should be infusion 0.5 mg.min)1 to achieve target lepirudin plasma
readily available. levels at 2.5 lg.ml)1) has been used in cardiac surgical
There are no large studies available to provide defin- patients undergoing CPB. The APTT cannot be used to
itive recommendations concerning the use of neuraxial monitor anticoagulation of the high doses of lepirudin
anaesthesia in patients who receive the direct thrombin used during CPB because the APPT curve plateaus out
inhibitors. The elimination half life of the current direct at high lepirudin concentrations. Whole blood ecarin
thrombin inhibitors is relatively short (< 4 h, see Table 1). clotting time provides a rapid and reliable method
In a review article on ximelagatran, Rosencher recom- of monitoring lepirudin anticoagulation. Bivalirudin
mended that the precautions associated with the use of (loading dose 1.5 mg.kg)1; 50 mg into prime solution;
ximelagratan in patients undergoing neuraxial anaesthesia maintenance infusion 2.5 mg.kg)1.h)1) has been used
are similar to those with LMWH and the patients should successfully for anticoagulation during CPB in patients
be monitored for signs and symptoms of neurological with HIT.
impairment [82]. The guidelines for the use of enoxaparin
in conjunction with neuraxial blockade recommend that
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