Journal of Internal Medicine 2003; 254: 335–342
MINISYMPOSIUM
Short- and long-acting synthetic pentasaccharides
M . M . W . K O O P M A N & H . R . B Ü L L E R
From the Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands
Abstract. Koopman MMW, Büller HR (Academic
Medical Centre, Amsterdam, The Netherlands).
Short- and long-acting synthetic pentasaccharides
(Minisymposium). J Intern Med 2003; 254: 335–
342.
Inhibition of activated coagulation factor X (FXa) is an
attractive target for antithrombotic treatment strat-
egies, because of the central position of FXa in the
coagulation cascade. Most of the now available anti-
coagulant drugs have inhibitory effects not only on
FXa, but also on thrombin. With the development of
pentasaccharides, a new class of antithrombotic
agents has emerged that acts by specific inhibition of
Introduction
The treatment of thrombotic disorders was until
recently based on the use of unfractionated heparin,
low-molecular weight heparin (LMWH) and vitamin
K antagonists. The disadvantages of unfractionated
heparin are the unpredictable pharmacological
effect, the variable bioavailability and short half-life.
Therefore, it is necessary to treat most of these
patients with an activated partial thromboplastin
time (aPTT)-controlled intravenous (i.v.) continuous
infusion in hospital [1].
The development of LMWH has overcome the
majority of these disadvantages and treatment with
LMWH is at least as effective and safe as unfract-
ionated heparin [1]. Furthermore, there is evidence
that it is feasible and safe to treat patients with deep-
vein thrombosis and even selected patients with

2003 Blackwell Publishing Ltd
FXa and lacks activity against FIIa. Fondaparinux,
the first synthetic short-acting pentasaccharide, has
been evaluated, in a large phase II and III clinical
programme concerning prophylaxis and treatment of
venous thromboembolism and also in phase II studies
in patients with acute coronary syndromes. Idrapar-
inux, the long-acting pentasaccharide, has been
studied in a dose-finding study in patients with
established deep-vein thrombosis and phase III stud-
ies are now planned in patients with venous throm-
boembolism and in patients with atrial fibrillation.
Keywords: anticoagulant, factor Xa inhibitor,
pentasaccharide.
pulmonary embolism at home with these com-
pounds [2, 3]. Vitamin K antagonists have a narrow
therapeutic window and are characterized by drug–
drug and drug–food interactions [4].
Although LMWH and vitamin K antagonists are
effective and safe to prevent recurrent venous
thromboembolism in patients with established
venous thromboembolism there is still room for
improvement. This is especially true for the pre-
vention of venous thromboembolism in a high-risk
situation such as orthopaedic surgery and in the
long-term treatment of established venous throm-
boembolism.
With the introduction of fondaparinux, the first
synthetic pentasaccharide, a new class of antithrom-
botic agents has emerged, that acts by specific
inhibition of factor Xa (FXa) and lacks activity
against FIIa. Theoretically, it is expected that these
335
336 M . M . W . K O O P M A N & H . R . B Ü L L E R
drugs have better antithrombotic properties with an
acceptable bleeding rate.
In this review, we will discuss the mechanism of
action and pharmacological properties of this novel
compound. Furthermore, we will review the avail-
able clinical data; the strategy to reverse the
anticoagulant effect and we will finish with some
data on the long-acting pentasaccharide idrapari-
nux and some future perspectives.
Mechanism of action
Fondaparinux sodium is an analogue of the penta-
saccharide sequence of heparin. In contrast to
unfractionated and LMWH, which comes from
animal sources, fondaparinux is produced by chem-
ical synthesis. This indicates that the preparation of
fondaparinux is homogeneous and that there are no
differences between batches [5].
The molecule binds selectively and reversible to
antithrombin, inducing a conformational change in
the antithrombin molecule that increases the affinity
to FXa more than 300-fold. This irreversible anti-
thrombin-FXa complex inhibits the action of FXa,
resulting in inhibition of thrombin formation. The
inhibition of FXa is highly selective without any direct
effect against the thrombin molecule itself [6]. Fur-
thermore, there is also no binding to platelet factor 4
or other proteins or components in the plasma,
resulting in a predicting pharmacological effect [7].
This is in contrast to the interaction with unfract-
ionated heparin and antithrombin that besides FIIa
and FXa also inhibits factors IXa, XIa and XIIa.
At the end of reaction fondaparinux is released
without any conformational or chemical change
and can be used again to bind to another anti-
thrombin molecule. If all antithrombin molecules
are saturated, the kidneys will remove the excess of
fondaparinux molecules [8].
Pharmacological aspects
Phase I studies have been performed in young and
elderly healthy volunteers. The young male volun-
teers received up to 30 mg fondaparinux and the
elderly persons received up to 18 mg, in both groups
the peak plasma level was reached after 2 h. The
elimination plasma half-life of fondaparinux is about
17 h and is independent of dose. After a single dose
of 2.5 mg in young healthy volunteers the mean

2003 Blackwell Publishing Ltd Journal of Internal Medicine 254: 335–342
Cmax of 0.34 ± 0.04 mg dL)1 was reached after
1.7 ± 0.4 h, this indicate a rapid absorption. The
interperson variability was low for Cmax (11.6%) and
for AUC (17.5%). The molecule is not metabolized
and is eliminated by the kidneys up to 84% of the
injected dose. This indicates that a dosing scheme of
once daily injections is sufficient and that laboratory
control is not necessary. Patients with renal insuf-
ficiency may need reduced dosages [8–11].
Another important issue is the lack of interaction
with other pharmacological compounds. It has been
well documented that in volunteers the concomitant
use of aspirin neither results in any changes in the
pharmacokinetic properties of fondaparinux nor
increases bleeding time measurements. There was
also no interaction with the vitamin K antagonist
warfarin or with the nonsteroidal anti-inflammatory
drug (NSAID) piroxicam [12, 13]. Furthermore, the
lack of inhibition of the CYP450s implies that
interaction with drugs metabolized by the CYP route
is very unlikely [14].
Clinical studies
To date the safety and efficacy of fondaparinux have
been studied in a large clinical phase II and III
programme concerning prophylaxis and treatment
of venous thromboembolism. Furthermore, some
phase-II studies have been carried out in patients
with acute coronary syndromes.
Prevention of venous thromboembolism
Venous thromboembolism is a frequent complica-
tion of surgical procedures especially orthopaedic
operations. Despite anticoagulant prophylactic strat-
egies such as LMWH, low-dose heparin or warfarin,
the postoperative rate of venographically proven
deep-vein thrombosis still ranges from 15 to 30%
after hip surgery and up to 50% after knee replace-
ment procedures [15].
Therefore, there is a need to improve thrombo-
prophylactic treatment in these patients and also in
other high-risk patient categories.
So far, one dose-ranging study, and four large
clinical trials have been conducted to test the
hypothesis that fondaparinux is more effective and
safer than LMWH to prevent venous thromboembo-
lism in patient undergoing orthopaedic surgery
[16–20].

All studies will be discussed briefly including a
meta-analysis of those four studies.
In the double-blind dose-ranging study in total
hip replacements 593 patients were randomized to
postoperative administration of one of the five daily
dosages of pentasaccharide ranging from 0.75 to 8 mg,
and 260 patients were allocated to receive 30 mg
enoxaparin twice daily. Fondaparinux was started 6 h
postoperatively, whereas enoxaparin was administered
12–24 h after the operation. All study drugs were
given with a minimum of 5 days and a maximum of
10 days and all patients underwent bilateral venogra-
phy on the last day of drug administration.
The venographically proven rate of venous throm-
bosis was 11.8, 6.7, 1.7, 4.4 and 0% in the 0.75, 1.5,
3.0, 6.0 and 8 mg group, respectively, when com-
pared with a rate of 9.4% in the enoxaparin group.
The risk of a major bleeding was significantly lower
in the 0.75, 1.5 and 3.0 mg group than in the 6.0
and 8.0 mg group, 0, 0.5, 4.5, 16.7 and 17.3%,
respectively (P < 0.001). Major bleeding occurred in
3.5% of the enoxaparin-treated patients and this was
significantly higher than in the 0.75 mg group
(P ¼ 0.01) and 1.5 mg group (P ¼ 0.05), but not
different from the 3.0 mg group [16].
This indicates a dose–response effect in patients
receiving fondaparinux and there was a 29% risk
reduction of venous thrombosis in the 1.5 mg group
and an 82% risk reduction in the 3.0 mg group
when compared with enoxaparin. Interpolation of
the efficacy and safety data revealed an optimal dose
of 2.5 mg once daily. This dosage was chosen for the
phase III trials.
The Ephesus study and Pentathlon 2000 study
recruited 2309 and 2275 consecutive patients,
respectively, undergoing primary elective total hip
replacement [17, 18]. Patients were randomized to
receive either 2.5 mg fondaparinux once daily or to
receive 40 mg enoxaparin in the Ephesus, or 30 mg
enoxaparin every 12 h in the Pentathlon study.
Fondaparinux was started 6 h postoperatively,
Table 1 Primary efficacy outcome
of the four different studies. Inci-
dence of venous thromboembolism
by day 11, according to screening
Ephesus [17]
with venography
Penthathlon [18]
Penthifra [19]
Pentamaks [20]
RRR, relative risk reduction.

2003 Blackwell Publishing Ltd Journal of Internal Medicine 254: 335–342
MINISYMPOSIUM: PENTASACCHARIDES 337
whereas enoxaparin was started 12 h preoperatively
in Europe and 12 h postoperatively in the US, and
continued for a minimum period of 5 days or a
maximum period of 9 days or until bilateral venog-
raphy was performed.
Venous thromboembolism was venographically
present in 4.1 and 6.1% of the fondaparinux-treated
patients, when compared with 9.2 and 8.3% in the
enoxaparin group, a relative risk reduction of 55.9
and 26.3%, respectively (Table 1). The incidence of
major bleeding was not different between the two
groups in both studies (Table 2).
In the Penthifra study, 1071 consecutive patients
undergoing fractured hip surgery were included and
in the Pentamaks study a total of 1049 patients
undergoing elective knee surgery were enrolled. The
study design was comparable with the Ephesus and
Pentathlon 2000. The relative risk reduction of
venous thrombosis was 56.4% in favour of fondapar-
inux in the Penthifra study and 55.2% in the elective
knee-surgery patients also in favour of fondaparinux
(Table 1). In addition, the rate of clinically significant
bleeding complications was comparable between the
different groups [19, 20] (Table 2).
Although the study design was comparable
amongst the four trials, there was a difference in
initiation of the first doses of fondaparinux when
compared with enoxaparin. It could be argued
that this difference in initiation could affect
efficacy and safety outcome parameters. However,
in a recent systematic review it has been shown
that the incidence of postoperative deep-vein
thrombosis was not different in the group who
received 12 h preoperative LMWH when compared
with the group in whom prophylaxis was started
12 h postoperatively 19.2 (95% CI; 17–21%) and
14.4% (95% CI; 12–17%), respectively. However,
if half of the doses of LMWH were given 1–4 h
before or after surgery, the incidence of deep-vein
thrombosis was 12.4% (95% CI; 10–14%). This
reduced incidence of deep-vein thrombosis was
Fondaparinux Enoxaparin RRR %
[n/n (%)] [n/n (%)] (95% CI)
37/908 (4) 85/919 (9) 55.9 (33.1–72.8)
48/787 (6) 66/797 (8) 26.3 ()10.8–52.8)
52/626 (8.3) 119/624 (19.1) 56.4 (39.0–70.3)
45/361 (12.5) 101/363 (27.8) 55.2 (36.2–70.2)
338 M . M . W . K O O P M A N & H . R . B Ü L L E R

Table 2 Primary safety outcomes

Fondaparinux [n/n (%)] Enoxaparin [n/n (%)] of the four different studies. Inci-
dence of fatal bleeding and bleeding
Ephesus [17]
in critical organ up to day 11
Fatal bleeding 0/1140 0/1133
Bleeding in critical organ 0/1140 0/1133
Bleeding leading to re-operation 5/1140 (0.4%) 3/1133 (0.3%)
Bleeding with a bleeding index ‡2 42/1140 (4%) 29/1133 (3%)
Penthathlon [18]
Fatal bleeding 0/1128 0/1129
Bleeding in critical organ 0/1128 1/1129 (0.1%)
Bleeding leading to re-operation 2/1128 (0.2%) 2/1129 (0.2%)
Bleeding with a bleeding index ‡2 18/1128 (2%) 8/1129 (0.7%)
Penthifra [19]
Fatal bleeding 0/831 1/842 (0.1%)
Bleeding in critical organ 0/831 0/842
Bleeding leading to re-operation 3/831 (0.4%) 2/842 (0.2%)
Bleeding with a bleeding index ‡2 15/831 (1.8%) 16/842 (1.9%)
Pentamaks [20]
Fatal bleeding 0/517 0/517
Bleeding in critical organ 0/517 0/517
Bleeding leading to re-operation 2/517 (0.4%) 1/517 (0.2%)
Bleeding with a bleeding index >2 9/517 (1.7%) 0/517

offset by an increase in postoperative major Table 3 Meta-analysis of all studies. Incidence of venous throm-
bleeding 6.3% (95% CI; 5–7%), when compared boembolism up to day 11. Estimated common odds reduction
(95% CI) in the different subgroups [21]
with 1.4% (95% CI; 1–2%) in the preoperative
started group and 2.5% (95% CI; 1–3%) in the Odds reduction in
postoperative group [21]. Therefore, there is no Number of favour of fondapari-
patients (N) nux [% (95% CI)]
difference on efficacy and safety outcomes whether
LMWH is started 12 h preoperative or postopera- Overall VTE 5385 55.2 (45.8–63.1)
tive, there is an increase in major bleeding rates M 2175 54.2 (36.3–67.4)
F 3210 54.6 (42.6–64.2)
when LMWH is started 1–4 h before or after
Regional anaesthesia 2496 57.3 (43.7–67.8)
surgery. In this review no studies were included Other anaesthesia 2889 51.4 (36.8–62.8)
with initiation of LMWH 6 h postoperatively. It is Duration of surgery <2 h 2350 53.0 (38.3–64.4)
therefore uncertain what the effect on efficacy and Duration of surgery >2 h 3029 55.3 (41.6–65.9)
safety outcomes is of the 6 h postoperative dosing VTE, venous thromboembolism; M, male patients; F, female
of LMWH. patients.
Recently, a meta-analysis was published of these
four large clinical trials. The incidence of venous
thromboembolism 11 days after surgery was signi- significant relationship between the incidence of
ficantly reduced by fondaparinux when compared major bleeding and the timing after surgery of the
with enoxaparin with a common odds reduction of first fondaparinux injection (3–9 h after surgery)
55.2% (95% CI; 45.8–63.1%; P < 0.001). This [22]. It was also shown that the incidence of overt
reduction was consistent for all types of surgery, bleeding associated with a bleeding index of 2 or
for the duration of surgery, and type of anaesthesia more was related to the timing of the first
used (Table 3) [22]. postoperative fondaparinux injection. However,
The rate of major bleeding was 2.7% in the when fondaparinux was given 6 h after surgery
fondaparinux group when compared with 1.7% in the bleeding index was comparable with the
the enoxaparin group (P ¼ 0.08). Bleeding rates enoxaparin group [22]. In conclusion, all the
leading to death, re-operation or occurring in above-mentioned studies have shown very consis-
critical organs was comparable between the tently that fondaparinux reduces the risk of post-
groups. Post hoc analyses have shown that in a operative venous thrombosis, as demonstrated by
logistic regression model there was a statistically screening with venography, in patients undergoing

2003 Blackwell Publishing Ltd Journal of Internal Medicine 254: 335–342
 MINISYMPOSIUM: PENTASACCHARIDES
high-risk operations with about 50%. In the
Penthifra-Plus study 656 hip fracture surgery
patients were randomized, after an initial treatment
with fondaparinux for 7 days, to fondaparinux or
placebo for 21 days. The primary efficacy outcome
was venographically proven deep-vein thrombosis
or symptomatic objectivated venous thromboembo-
lism. The incidence of venous thrombosis after
4 weeks was 1.4% in the fondaparinux group,
compared with 35% in the placebo group [relative
risk reduction (RRR): 95.9%, P < 0.001]. More-
over, the incidence of symptomatic venous throm-
boembolism was also significantly lower with
fondaparinux (0.3%) than with placebo 2.7%
(RRR: 88.8%, P ¼ 0.021) [23].
Treatment of venous thromboembolism
The incidence of acute symptomatic venous throm-
boembolism is approximately two to three per 1000
inhabitants per year [24]. The main goal of therapy
is to prevent extension of the disease, to prevent
recurrent venous thromboembolism and to minim-
ize occurrence of the postthrombotic syndrome. The
current standard therapy relies on an initial course
of LMWH and long-term treatment with vitamin K
antagonists.
One dose-finding study and two large clinical
trials in patients with venous thromboembolism
have been carried out to compare the safety and
efficacy of fondaparinux in the initial treatment of
patients with venous thrombosis in comparison with
LMWH [25, 26].
In the Rembrandt study 453 patients with
proven deep-vein thrombosis were randomly allo-
cated to receive either fondaparinux at a dose of
5.0, 7.5 or 10 mg once daily or dalteparin at a
dose of 100 IU kg)1 twice daily. Vitamin K
antagonist were started immediately and contin-
ued for at least 90 days. Efficacy was defined as a
change in thrombus mass at day 7 compared with
baseline as assessed by ultrasonography of the legs
and perfusion lung scanning. A positive outcome
was defined as an improvement on ultrasound
and/or perfusion without deterioration of either
test, whereas all other combinations were consid-
ered as negative outcomes. Other outcome meas-
ures included symptomatic, recurrent venous
thromboembolism and major bleeding during a
follow-up period of 3 months. All recurrent throm-

2003 Blackwell Publishing Ltd Journal of Internal Medicine 254: 335–342
339
boembolic events were documented by objective
tests. A positive outcome was found in 46, 48 and
42% of the 5.0, 7.5 and 10 mg of fondaparinux
groups, respectively compared with 49% in the
dalteparin group (absolute difference: 3.5%; 95%
CI: 7.2–15.0%). Over the 3-month follow-up
period 2.4% (eight of 334) of the patients treated
with fondaparinux had an episode of symptomatic
venous thrombosis confirmed when compared
with 5.0% (six of 119) in the patients in the
dalteparin group (difference 2.6%; 95% CI; )2.1–
10.1%). Major bleeds were rare and not statisti-
cally different amongst the different groups. It was
concluded from this study that 7.5 mg was the
appropriate dose for further evaluation in phase III
trials [25].
The Matisse deep-venous thrombosis (DVT) and
Matisse pulmonary embolism (PE) studies, two phase
III clinical trials, were conducted to assess the
efficacy and safety of fondaparinux 7.5 mg in the
initial treatment of venous thromboembolism. In the
DVT study fondaparinux was compared with enox-
aparin, using a double-blind design, whereas the PE
study was an open label study with continuous i.v.
heparin as the comparator. All patients received
vitamin K antagonist for a period of 3 months. The
primary efficacy and safety parameters were symp-
tomatic objectively confirmed recurrent venous
thrombosis and major bleeding, respectively. The
purpose of these two studies was to show noninfe-
riority for efficacy. In the DVT study a total of 2205
consecutive patients with proven deep-vein throm-
bosis were included, whereas the PE study recruited
2213 patients. Although the results have not been
published yet, the findings confirmed the comparable
efficacy and safety of fondaparinux [26].
Acute coronary syndromes
Coronary thrombus formation plays an important
role in the development of an acute myocardial
infarction. It is well established that treatment of
these patients with thrombolytic agents is of benefit
for the patients and that to prevent re-occlusion of
the coronary arteries additional antithrombotic
agents are needed. Traditionally, unfractionated
heparin was administered immediately after start
of the thrombolytic therapy, but theoretically FXa
inhibitors could be of great value in this group of
patients.
340 M . M . W . K O O P M A N & H . R . B Ü L L E R
In the Pentalyse trial fondaparinux was compared
with unfractionated heparin in 333 patients treated
with alteplase and aspirin for acute myocardial
infarction. Fondaparinux was administered at three
different dosages of 4, 8 and 12 mg once daily for
5–7 days and heparin was given as an i.v. bolus of
5000 IU followed by 1.000 IU h)1 for 48–72 h.
Rates of coronary perfusion at 90 min measured
as thrombolysis in myocardial infarction (TIMI)
grade 3 flow were not different amongst the different
groups. In the patients with TIMI grade 3 flow there
was a trend to less re-occlusion of the infarct related
vessel on days 5–7 in the fondaparinux group when
compared with the heparin group (0.9% vs. 7.0%;
P ¼ 0.065) [27]. Although there was no direct
dose–effect relationship, the efficacy of fondaparinux
was comparable with unfractionated heparin.
Also in the Pentua study, another dose-finding
study with fondaparinux compared with enoxaparin
in patients with acute coronary syndromes no dose–
response relationship was observed. The overall
event rate in the patients treated with fondaparinux
or enoxaparin was comparable [28].
Management of bleeding
There is no specific antidote for this new synthetic
FXa inhibitor. Although the clinically relevant
bleeding risk appeared to be low despite the long
half-life of fondaparinux, reversal of the anticoagu-
lant effect may be necessary in some patients.
In case of bleeding complications administration
of plasma and prothrombin complex concentrates
can be considered, although clinical data are lack-
ing.
Recently, it was shown that recombinant FVIIa,
when administered to healthy volunteers, could
normalize the prolonged thrombin-generation time
induced by fondaparinux. Furthermore, rFVIIa pre-
vented the decrease in plasma levels of fragment
1 + 2 (an indicator of thrombin generation), as
induced by fondaparinux resulting in an increase in
prothrombin activation by 34% from time point 2 to
8 h after administration of fondaparinux and rFVIIa
when compared with the group who received
fondaparinux only (P ¼ 0.022) [29].
Therefore, rFVIIa, although only studied in
healthy volunteers without bleeding complications,
can be considered in the management of patients
with serious bleeding associated with fondaparinux.

2003 Blackwell Publishing Ltd Journal of Internal Medicine 254: 335–342
Long-acting pentasaccharides
Fondaparinux is one of the synthetic pentasaccha-
rides, which mimics the pentasaccharide part in the
heparin molecule most. Several chemical modifica-
tions, such as replacement of N-sulphated groups
from sulphated esters and the methylation of
hydroxylated groups have been made to increase
the affinity to antithrombin and to prolong the half-
life. To date, idraparinux, an O-methyle, O-sulphate
pentasaccharide, have been developed with a higher
affinity to antithrombin and an expected half-life of
80 h [30]. Idraparinux has been studied in phase I
studies and in a phase-II trial, the Persist study. In
this study, patients with proven deep-vein thrombo-
sis were treated with an initial course of 5–7 days of
enoxaparin hereafter they were randomized to
receive 2.5, 5.0 and 7.5 mg of idraparinux subcu-
taneous once weekly or warfarin (international
normalized ratio (INR) 2–3) for a period of
3 months. The primary efficacy outcome was symp-
tomatic objectively proven venous thrombosis or a
change in thrombotic burden as measured by
ultrasonography and perfusion lung scanning at
baseline and after 3 months. A total of 659 patients
were randomized and in 93% of them the primary
efficacy outcome was evaluable. The primary out-
come did not differ between the different dosages of
idraparinux and was comparable with the patients
treated with warfarin. There was a clear dose
relationship for major bleeding, but patients trea-
ted with 2.5 mg idraparinux had less major bleed-
ing when compared with patients treated with
warfarin [31]. Therefore, a dose of 2.5 mg was
selected for further development. Currently, the
van Gogh DVT and PE phase III studies have
now started and a phase-III trial in atrial fibrilla-
tion is about to begin.
Future perspectives
With the introduction of fondaparinux, it has been
shown that selective FXa inhibition is very effective
in the prevention of VTE and probably also in the
treatment of venous and arterial thrombosis.
The 100% bioavailability, stable pharmacokinetic
profile and long half-life allow once daily dosages
without any laboratory control.
Although there was an increased risk of bleeding
as expressed by a bleeding index of at least 2, in the
 MINISYMPOSIUM: PENTASACCHARIDES
thrombosis prophylaxis trials, no increased risk of
fatal bleedings, critical organ bleedings or bleeding
leading to re-operation were observed [22]. This
implies that fondaparinux is a valuable new anti-
thrombotic drug in the prevention of venous throm-
bosis after orthopaedic surgery.
Whether, this is also true for the treatment of
venous thrombosis will become clear in the near
future.
With the development of idraparinux, a long-
acting pentasaccharide, an once weekly dosage
strategy will become available for the long-term
treatment of arterial and venous thrombosis. There
is a great chance that the long-term treatment of
venous thromboembolism definitely would change,
if the results of the now planned phase III trials are
favourable.
Conflict of interest statement
The authors received honoraria from Organon
N.V., Oss, the Netherlands and Sanafi-Synthelabo,
Paris, France for scientific presentations about new
antithrombotic agents.
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Received 12 June 2003; revision received 2 July 2003; accepted
2 July 2003.
Correspondence: Dr Maria M.W. Koopman, Department Vascular
Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ
Amsterdam, The Netherlands (fax: 31 0 6968833; e-mail:
m.m.koopman@amc.uva.nl).