Predictive Value of D-Dimer Test for Recurrent Venous
Thromboembolism After Anticoagulation Withdrawal in
Subjects With a Previous Idiopathic Event and in Carriers
of Congenital Thrombophilia
Gualtiero Palareti, MD; Cristina Legnani, MS; Benilde Cosmi, MD; Lelia Valdré, MD;
Barbara Lunghi, MS; Francesco Bernardi, MS; Sergio Coccheri, MD
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Background—We have shown that normal D-dimer levels obtained after the discontinuation of oral anticoagulant
treatment (OAT) has a high negative predictive value for recurrent venous thromboembolism (VTE). The aim of the
present study was to assess the predictive value of D-dimer for recurrent VTE in subjects with a previous unprovoked
event who are either carriers of inherited thrombophilia or not.
Methods and Results—We prospectively evaluated 599 patients (301 males) with a previous VTE episode. They were
repeatedly examined for D-dimer levels after OAT withdrawal and were screened for inherited thrombophilic
alterations. Alterations were detected in 130 patients (21.7%), factor V Leiden (70 patients; 2 of whom were
homozygotes) and prothrombin mutation (38 patients) were the most prevalent ones. Recurrent events were recorded in
58 subjects (9.7%) during a follow-up of 870.7 patient-years. Altered D-dimer levels at 1 month after OAT withdrawal
were associated with a higher rate of subsequent recurrence in all subjects investigated, especially in those with an
unprovoked qualifying VTE event (hazard ratio, 2.43; 95% confidence interval, 1.18 to 4.61) and in those with
thrombophilia (hazard ratio, 8.34; 95% confidence interval, 2.72 to 17.43). The higher relative risk for recurrence of
altered D-dimer was confirmed by multivariate analysis after adjustment for other risk factors. The negative predictive
value of D-dimer was 92.9% and 95.8% in subjects with an unprovoked qualifying event or with thrombophilia,
respectively.
Conclusions—D-dimer levels measured 1 month after OAT withdrawal have a high negative predictive value for
recurrence in subjects with unprovoked VTE who are either carriers or not carriers of congenital thrombophilia.
(Circulation. 2003;108:313-318.)
Key Words: thrombophilia 䡲 fibrin fibrinogen degradation product 䡲 thromboembolism 䡲 thrombosis
A
fter a first episode of acute venous thromboembolism
(VTE), the risk of recurrence is relatively high and
clinical consequences are important because early (fatal in
5% of patients1) and late (post-thrombotic syndrome) complications are frequent. Although long-term treatment with
oral anticoagulants is indicated to reduce this risk, the
incidence of treatment-associated complications is not negligible because major bleeding can be expected in ⬇2%
patient-years.2 The duration of anticoagulant treatment should
therefore be tailored to optimize the preventive action of
treatment with the minimum risk of complications. It is now
well accepted that patients whose first VTE event was
associated or triggered by a circumstantial risk factor have a
lower risk of recurrence and need shorter anticoagulation
periods than patients whose event was unprovoked (idiopath-
ic) or who carry persistent risk factors.3 Although in recent
years a number of clinical studies have investigated the
effects of different treatment periods in subjects after an
idiopathic VTE event, the optimal duration of oral anticoagulant treatment (OAT) in these patients is still uncertain.4 –7
It is still a matter of debate whether inherited thrombophilia should be considered a persistent risk factor and
whether it requires a longer course of OAT.8,9 A higher
incidence of recurrence has been shown in patients with an
antithrombin, protein C, or protein S deficiency,10 in patients
with multiple thrombophilic defects,11,12 and in patients with
a homozygosity for factor V Leiden.13–15 It is still debated
whether carriers of heterozygous factor V Leiden or the
G20210A prothrombin mutation, the two most common
thrombophilic alterations, are at higher risk of recurrence.
Received January 16, 2003; revision received April 18, 2003; accepted April 21, 2003.
From the Dipartimento di Angiologia, Unità Ricerca Clinica sulla Trombofilia “Marino Golinelli,” University Hospital S Orsola-Malpighi, Bologna,
and Dipartimento di Biochimica e Biologia Molecolare, University of Ferrara, Ferrara, Italy (B.L., F.B.).
Correspondence to Gualtiero Palareti, Department of Angiology, University Hospital S. Orsola-Malpighi, Via Massarenti 9, 40138 Bologna, Italy.
E-mail [email protected]
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000079162.69615.0F
313
314
Circulation
July 22, 2003
Such a conclusion has been drawn in some studies16,17 but
was not confirmed by other authors.18,19
In a recent prospective study20 in subjects with a previous
first VTE event, we showed that normal D-dimer levels
obtained after OAT withdrawal had a very high negative
predictive value for VTE recurrence. Conversely, increased
D-dimer levels were associated with a significantly higher
hazard ratio for recurrence.
The aim of the present prospective, inception-cohort study
was to investigate the predictive value for recurrent VTE of
D-dimer levels measured 1 month after OAT interruption in
patients with a previous unprovoked event who were either
carriers or not carriers of congenital thrombophilia.
Methods
Patients
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As described elsewhere,20 consecutive patients with a previous first
episode of deep vein thrombosis (DVT) of the lower limbs and/or
pulmonary embolism (PE) were prospectively investigated after
OAT discontinuation. All patients had attended our clinic for the
surveillance of OAT and were treated with warfarin or acenocoumarol at a therapeutic intensity of 2.0 to 3.0 International Normalized
Ratio (target, 2.5). The overall quality of laboratory anticoagulation
control in patients treated for VTE at our clinic is periodically
checked by a specific software program that calculates the percentage of time spent within, below, and above the intended therapeutic
range.21 For the year 2002, the results were 60.1%, 27.9%, and
12.0% for the time spent within, below, and above the therapeutic
range, respectively. The decision to stop anticoagulation was made
during a periodic examination after a minimum of 3 months from the
index event. Physical examinations were scheduled at 3 months after
OAT interruption and every 6 months thereafter. Patients were
instructed to wear 40-mm Hg elastic stockings and to contact our
department immediately if they experienced symptoms attributable
to a new or recurrent VTE episode. Follow-up ended on the 21st
month after OAT interruption or earlier in case of death, VTE
recurrence, or resumption of OAT for any other indication. The
patient and/or family doctor were contacted if a periodic examination
was missed.
Index VTE events were classified as unprovoked (in the absence
of any clinical risk factors), as secondary to nonremovable risk
factors (mainly cancer), and as secondary to circumstantial and
removable risk factors, such as surgery, trauma, prolonged immobilization, oral contraception or hormonal replacement therapy, pregnancy, or puerperium. Our institutional review committee approved
the study, and all the procedures were in accordance with our
institutional guidelines. Informed consent was obtained from all
subjects.
Timing of Blood Sampling and Thrombophilia
Work-Up
Venous blood samples were taken on 3 different occasions: the day
OAT was discontinued (T1), 21 to 37 days afterward (T2), and 3
months (⫾10 days) afterward (T3). For the sake of brevity, only
results obtained in T2 samples or, in their absence, in T1, are
considered in the present report.
Thrombophilia screening was performed using blood sampled at
T2 (on average, 33 days after OAT discontinuation) and only in a
few cases during follow-up. The screening included: prothrombin
time, activated partial thromboplastin time, fibrinogen plasma levels,
antithrombin, protein C, protein S, and activated protein C resistance.
DNA analysis for R506Q factor V mutation was performed in all
cases with an activated protein C resistance normalized ratio ⬍0.80.
Patients also had a DNA analysis for the G20210A mutation of the
prothrombin gene and tests for lupus anticoagulant. All tests included in the thrombophilic screening were performed using standard methods.
D-Dimer Measurement
Plasma D-dimer levels were measured by the VIDAS D-Dimer
ELISA method (bioMerieux; normal value ⱕ500 ng/mL). Only
D-dimer results obtained in samples collected at T2 were analyzed in
the present report (or in T1 in the few cases in which T2 samples
were not available). For technical and organizational reasons, it was
not possible to test for D-dimer in 8 patients. The results of D-dimer
and other blood coagulation tests performed after OAT withdrawal
were not used for management purposes.
Outcome Events
Objectively documented DVT recurrence and/or fatal or nonfatal PE
(first event or recurrence) were considered outcomes. Patients with
DVT symptoms in the same or contralateral leg as the previous event
were given a D-dimer test (for its high negative predictive value) and
a compression ultrasound, which was compared with the compression ultrasound examination that was customarily performed in all
patients at the time of OAT interruption. In cases of suspected DVT
recurrence in the same leg as the index event, unequivocal noncompressibility of a previously compressible venous segment or an
increase of at least 4 mm in the residual diameters were the criteria
considered diagnostic for DVT recurrence.22 If the ultrasound result
was nondiagnostic (and D-dimer was altered), an echo color Doppler
or contrast venography was performed. In patients presenting with
symptoms compatible with PE (either first event or recurrence),
diagnosis was based on the results of objective algorithms using
clinical probability, ventilation-perfusion lung scanning, compression ultrasonography (if indicated), and D-dimer testing. Recurrent
events were classified as unprovoked or as secondary to known
triggering factors.
All deaths were recorded and coded as attributable to a venous
event or any other cause. Events were adjudicated by two investigators (G.P. and B.C.) who were unaware of D-dimer and other
blood test results.
Statistical Analysis
Differences between groups were assessed by the ␹2 test (Yates’
correction). Cumulative incidence and hazard ratios for recurrent
VTE in patients with or without high D-dimer levels were calculated
by the method of Kaplan and Meier. The 95% confidence intervals
(CI) were calculated with an approximate method, and a two-sided
Pⱕ0.05 was considered statistically significant. The Prism statistical
software package (Version 3.0, Graphpad Software Incorporated)
was used for data processing. The relative risks of VTE recurrence
associated with normal or altered D-dimer results were analyzed with
the Cox regression analysis after adjustment for age, sex, presence/
absence of congenital thrombophilia, and nature of index event by
using the SPSS statistical package (11.0 release).
Results
Patients
All patients attending our clinic for OAT surveillance after a
first episode of DVT and/or PE and in whom OAT was
discontinued between February 1995 and February 2002 were
considered eligible for the study. Thrombophilia screening
was performed in 620 of 635 subjects. Five patients were
excluded when a lupus anticoagulant phenomenon was detected. Eight patients were lost to follow-up 3 months after
OAT withdrawal because they moved out of town and their
new addresses were not available, and in 8 other patients,
D-dimer testing was not possible. The present report analyzes
the results obtained in 599 patients (301 males). The characteristics of the patients are shown in Table 1. The presence of
one or more thrombophilic alterations was detected in 130
patients (21.7%). A detailed list of alterations is reported in
Table 1.
Palareti et al
TABLE 1.
Characteristics of Patients Included in the Study
Total No. of patients (males)
599 (301)
Age, y
67 (12–91)
Age at first VTE, y
65 (11–90)
Type of VTE, n (%)
Proximal DVT (no PE)
441 (73.6)
DVT⫹symptomatic PE
93 (15.5)
Isolated distal DVT (2 PE)
43 (7.2)
Isolated PE
22 (3.7)
Predisposing factors, n (%)
Unprovoked
Nonremovable risk factors
Removable risk factors
Unknown
Subjects with congenital thrombophilic alterations, n (%)
282 (47.1)
59 (9.8)
254 (42.4)
4 (0.7)
130 (21.7)
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Factor V Leiden (2 homozygous)
70
Prothrombin mutation
38
Protein C deficiency
10
Factor V Leiden⫹prothrombin mutation
4
Protein S deficiency
4
Antithrombin III deficiency
1
Other combined alterations
3
Duration of previous anticoagulant treatment, n (%)
ⱕ5 mo
304 (50.7)
5–12 mo
240 (40.1)
⬎1 y
55 (9.2)
Total duration of follow-up, y
870.7
Median follow-up, y
1.45
Values are median (range) or n (%).
During the 870.7 patient-years of follow-up, 58 VTE
recurrences (9.7% of patients) were recorded (35 males). The
events included 50 patients with DVT (27 ipsilateral and 23
contralateral), 9 of whom also had PE, and 8 patients with
apparently isolated PE (with no diagnosis of associated acute
DVT). In 36 cases, the recurrent events seemed to be
unprovoked. In 16 cases, a condition of malignancy or
chronic disease (chronic heart failure and chronic tuberculosis infection, 1 each) was found; 6 patients had a recurrence
due to a transient factor (prolonged bed rest, 4 patients;
plaster cast, 2 patients). During follow-up, 7 patients died;
death was attributed to cancer in 2 patients, chronic heart
disease in 2 patients, and to sudden death in 3 patients. The
latter cases were considered outcomes for the study, although
an autopsy was not performed.
The rate of recurrence was 11.7% in subjects whose index
event was idiopathic; it was lower (4.3%) in those with
transient risk factors and much higher (23.7%) in subjects
whose event was associated with non-removable risk factors.
The recurrences were significantly more frequent in patients
with thrombophilia (14.6%) than in those without thrombophilia (8.3%), with a hazard ratio of 1.78 (95% CI, 1.04 to
3.66; P⫽0.036).
D-Dimer and VTE Recurrence
315
D-Dimer Results and VTE Recurrence
Increased D-dimer levels were recorded in 37.1% of subjects
(Table 2). The presence of altered rather than normal D-dimer
results was associated with a significantly higher rate of
recurrences. This was found in all subjects investigated
(16.5% recurrences in patients with altered D-dimer versus
5.8% recurrences in patients with normal D-dimer;
P⬍0.0001), and in some subgroups, such as patients whose
index event was unprovoked (16.5% versus 7.0%;
P⫽0.0226), carriers of thrombophilia (27.1% versus 4.2%;
P⬍0.0001), and noncarriers of thrombophilia (12.3% versus
6.2%; P⫽0.038; Table 2).
The cumulative probabilities for VTE recurrence (KaplanMeier curves) of abnormal versus normal D-dimer results 1
month after OAT interruption are shown in Figures 1 and 2.
They are calculated in subjects with an unprovoked index
event (hazard ratio, 2.43; 95% CI, 1.18 to 4.61; P⫽0.0153)
and in subjects with thrombophilia (hazard ratio, 8.34; 95%
CI, 2.72 to 17.43; P⬍0.0001) or without thrombophilia
(hazard ratio, 2.04; 95% CI, 1.11 to 4.18; P⫽0.0232).
At the multivariate analysis, after adjustment for other
relevant factors (Table 3), the presence of altered D-dimer
results remained significantly associated with a higher risk of
VTE recurrence in all of the investigated subjects, in those
with an unprovoked index event, and in subjects with or
without thrombophilia. Altered D-dimer levels were not
associated with the risk of recurrence in those subjects whose
index event was associated with cancer or was secondary to
transient factors.
The sensitivity, specificity, and positive and negative
predictive values for VTE recurrence of D-dimer levels are
shown in Table 4. D-Dimer results at 3 months (data not
shown) were altered in a higher percentage of all investigated
subjects (47.6%), and sensitivity and negative predictive
value were similar to those of tests obtained at 1 month
(71.1% [95% CI, 57.0 to 82.9] and 94.9% [95% CI, 91.7 to
97.1], respectively).
Discussion
The results of the present study, which are in line with
those of the previous one,20 confirmed that the rate of VTE
recurrence was significantly lower in subjects whose
D-dimer levels were normal when obtained 1 month after
anticoagulation was stopped. We hypothesize that this test
may be relevant for the management of anticoagulant
treatment in VTE patients; we believe that results obtained
a few weeks after OAT withdrawal can be clinically
relevant as criteria to decide whether or not OAT should be
resumed. It might be argued that the management of
patients with a previous VTE event would be easier if
D-dimer levels were tested before discontinuing oral
anticoagulation. In our previous article,20 we noted that
most patients had normal D-dimer levels at the time of
OAT withdrawal. Altered D-dimer levels were found in
only 15.6% of subjects at that time, whereas altered levels
increased to 40.3% and 46.2% after 1 and 3 months,
respectively. This implies, therefore, that most subjects
should be retested at least 1 month after from OAT
withdrawal.
316
Circulation
July 22, 2003
TABLE 2.
D-Dimer Results and Number of Recurrences
Subjects
Altered
D-Dimer
Normal
D-Dimer
222 (37.1)
377 (62.9)
36 (16.5)
22 (5.8)
139 (49.3)
143 (50.7)
23 (16.5)
10 (7.0)
P
⬍0.0001
All (n⫽599)
D-Dimer
Recurrences
Unprovoked index event (n⫽282)
0.0226
D-Dimer
Recurrences
Cancer-associated index event (n⫽59)
0.201
D-Dimer
23 (39)
Recurrences
36 (61)
8 (34.8)
6 (16.7)
59 (23.2)
195 (76.8)
5 (8.5)
6 (3.1)
163 (34.8)
306 (65.2)
20 (12.3)
19 (6.2)
D-Dimer
59 (45.4)
71 (54.6)
Recurrences
16 (27.1)
3 (4.2)
Removable risk factor (n⫽254)
0.166
D-Dimer
Recurrences
Without thrombophilia (n⫽ 469)
0.038
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D-Dimer
Recurrences
⬍0.000
With thrombophilia (n⫽130)
Types of thrombophilic alterations (No. of recurrences)
Heterozygosity for factor V Leiden
33 (13)
Homozygosity for factor V Leiden
1
Heterozygosity for prothrombin mutation
Protein C deficiency
13 (2)
35 (2)
1
25 (1)
4 (1)
6
Factor V Leiden⫹prothrombin mutation
2
2
Protein S deficiency
4
0
Antithrombin III deficiency
1
0
Other combined alterations
1
2
Values are n (%), except for types of alterations, which is number of patients with alteration
(number of recurrences).
An important new finding of the present study is that the
predictive value of D-dimer can be expected in patients
whose qualifying VTE event was idiopathic but not when
the index event was associated with cancer or was triggered by circumstantial risk factors. Furthermore, this
study showed that D-dimer has a predictive value in
patients independent of the presence or absence of congenital thrombophilic alterations. A significantly higher
relative risk for VTE recurrence in subjects with altered
D-dimer levels was confirmed in all the investigated
Figure 1. Cumulative probability of recurrence in subjects with
an unprovoked qualifying venous thromboembolic event with
normal (ⱕ500 ng/mL) or altered (⬎500 ng/mL) D-dimer results
obtained 1 month after OAT interruption.
Figure 2. Cumulative probability of VTE recurrence in subjects
with congenital thrombophilic alterations according to normal
(ⱕ500 ng/mL) or altered (⬎500 ng/mL) D-dimer results obtained
1 month after anticoagulation was stopped.
Palareti et al
TABLE 3. Multivariate Regression Analysis of Relative Risks of
Altered D-Dimer Results Obtained in All Subjects and in
Subgroups
Relative Risk (95% CI)*
P
All subjects
2.61 (1.45–4.71)
0.001
Idiopathic index event
2.75 (1.24–6.12)
0.013
Cancer-associated index event
2.96 (0.80–10.88)
0.103
Secondary index event
1.90 (0.50–7.28)
0.349
With thrombophilic alterations
5.88 (1.46–23.72)
0.013
Without thrombophilic alterations
2.19 (1.10–4.35)
0.026
*Risks were calculated with adjustment for age, sex, duration of previous
oral anticoagulant treatment, and presence/absence of congenital thrombophilic alterations or nature of index event, as appropriate.
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patients and in various subgroups by a multivariate analysis after adjustment for several factors.
In the present study, we found that the rate of VTE
recurrence was higher in carriers of inherited thrombophilia (10.2% versus 5.7% for carriers versus noncarriers;
P⬍0.05; hazard ratio, 1.78). However, the risk was not
uniform, even in carriers of the same alteration. In fact,
thrombophilic subjects with normal D-dimer levels had a
very low risk of recurrence (3 events in 71 subjects); the
negative predictive value was as high as 95.8% (range,
88.2% to 99.1%). However, carriers with altered D-dimer
levels were at high risk for recurrence (16 events in 59
subjects), with a very high hazard ratio (8.34; 95% CI, 2.72
to 17.43; P⬍0.0001). This difference was particularly
important in carriers of the frequent but clinically mild
alterations, such as heterozygosity for factor V Leiden and
prothrombin mutation. VTE recurrences occurred in 39.4%
and 5.7% of carriers of the former alteration with abnormal
or normal D-dimer levels, respectively, and in 15.4% and
8.0% of carriers of the latter. Our data suggest that in
thrombophilic subjects, altered D-dimer may indicate the
presence of other prothrombotic factors contributing to a
more marked hypercoagulable condition. In line with this
interpretation is the surprising finding of no recurrence
among subjects with antithrombin deficiency or combined
alterations during 21 months of follow-up. Although these
subjects were candidates for long-term anticoagulation,
OAT was not resumed because of refusal by the patient
with ATIII deficiency and because in all these cases, the
first VTE event was provoked.
Although the predictive value of the D-dimer test was
particularly marked in subjects carrying inherited thrombophilia, it was also significant in those without thrombo-
D-Dimer and VTE Recurrence
317
philia. In fact, VTE recurrences occurred in 12.3% and
6.2% (P⫽0.038) of nonthrombophilic subjects with altered
or normal D-dimer levels, respectively. Furthermore, it
should be considered that 5 of the 19 recurrences occurring
in this group were secondary to transient risk factors
(prolonged bed rest or trauma and plaster cast). Therefore,
we postulate that in these patients, a hypercoagulable
condition may occur later than a few weeks after OAT is
stopped or episodically and cannot always be detected by
D-dimer levels obtained after 1 month.
Caution is recommended in evaluating the results of this
study. First, although the most important and welldocumented thrombophilic conditions were investigated,
other alterations, such as hyperhomocystinemia and increased factor VIII and IX, were not. Moreover, during the
entire follow-up period, only 58 thrombotic recurrences
(⬇9.7% of patients) were recorded; this figure is lower
than might be expected, although it is similar to those
reported in other studies.23
An Italian collaborative study showed that no long-term
clinical benefit was associated with extending the 3-month
course of anticoagulant treatment to 1 year in patients with
idiopathic proximal DVT. In fact, prolongation of anticoagulation only delays recurrences until anticoagulation is
stopped and does not reduce the risk of recurrence.6 It
seems, therefore, that an important clinical goal is to
evaluate patients according to individual and persistent
risk of recurrence and to identify those who may or may
not need prolonged anticoagulation. It is well known that
patients with cancer have a high risk of recurrence and
deserve prolonged anticoagulation, whereas those with
secondary events have a low risk and need a short period
of anticoagulation. Uncertainty remains about the optimal
duration of anticoagulation in patients with an idiopathic
event and in those with thrombophilic alterations. A recent
clinical trial showed that long-term, low-intensity warfarin
therapy, after an early period with full-dose treatment, was
effective in reducing to 2.6% the rate of VTE recurrences,
in comparison to the 7.2% rate recorded in the placebo
group.24 The results of the present article indicate that in
patients with a previous idiopathic VTE, normal D-dimer
results obtained after anticoagulation is stopped may be
useful in identifying those subjects who are at low risk of
recurrence and excluding them from prolonged
anticoagulation.
In conclusion, the present study showed that normal
D-dimer levels measured 1 month after OAT discontinuation had a very high negative predictive value for VTE
TABLE 4. Sensitivity, Specificity, and Positive and Negative Predictive Values for
Venous Thromboembolism Recurrence Based on D-Dimer Results
All Subjects
Subjects With
an Unprovoked Event
Subjects With
Thrombophilia
Sensitivity, % (95% CI)
62.1 (48.4–74.5)
69.7 (51.3–84.4)
84.2 (60.4–96.6)
Specificity, % (95% CI)
65.6 (61.4–69.7)
52.2 (45.7–58.6)
61.3 (51.6–70.4)
Positive predictive value, % (95% CI)
16.2 (11.6–21.7)
16.2 (10.6–23.3)
27.1 (16.4–40.3)
Negative predictive value, % (95% CI) 94.2 (91.3–96.3)
92.9 (87.3–96.5)
95.8 (88.2–99.1)
318
Circulation
July 22, 2003
recurrence, especially in subjects with an idiopathic previous event and in carriers of congenital thrombophilic
alterations. Increased D-dimer levels were associated with
a significantly higher hazard ratio for VTE recurrence.
These findings suggest that the D-dimer assay may have a
role in tailoring the duration of OAT to optimize prevention of recurrent VTE. Specifically designed clinical studies are needed to assess such a possibility.
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Predictive Value of D-Dimer Test for Recurrent Venous Thromboembolism After
Anticoagulation Withdrawal in Subjects With a Previous Idiopathic Event and in Carriers of
Congenital Thrombophilia
Gualtiero Palareti, Cristina Legnani, Benilde Cosmi, Lelia Valdré, Barbara Lunghi, Francesco
Bernardi and Sergio Coccheri
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Circulation. 2003;108:313-318; originally published online July 7, 2003;
doi: 10.1161/01.CIR.0000079162.69615.0F
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