Journal of Thrombosis and Haemostasis, 10: 22642269

DOI: 10.1111/j.1538-7836.2012.04895.x

ORIGINAL ARTICLE

The Wells rule and D-dimer for the diagnosis of isolated distal
deep vein thrombosis
M . S A R T O R I , B . C O S M I , C . L E G N A N I , E . F A V A R E T T O , L . V A L D R E , G . G U A Z Z A L O C A , G . R O D O R I G O ,
M . C I N I and G . P A L A R E T I
Department of Angiology and Blood Coagulation Marino Golinelli, S. Orsola-Malpighi University Hospital, Bologna, Italy

To cite this article: Sartori M, Cosmi B, Legnani C, Favaretto E, Valdre` L, Guazzaloca G, Rodorigo G, Cini M, Palareti G. The Wells rule and D-dimer
for the diagnosis of isolated distal deep vein thrombosis. J Thromb Haemost 2012; 10: 22649.

Summary. Background: Pretest clinical probability with the

Wells rule and D-dimer have been widely investigated for the
diagnosis of symptomatic proximal deep vein thrombosis
(DVT) of the lower limbs, but they have not been formally
tested for symptomatic isolated distal DVT diagnosis.
Objective: To evaluate the diagnostic accuracy of the Wells
rule and D-dimer for isolated distal DVT. Design, Setting, and
Patients: This was a single-center, cross-sectional study including 873 consecutive outpatients with suspected DVT, in whom
pretest clinical probability determination, D-dimer determination (STA Liatest; cut-o of < 500 ng mL)1) and complete
compression ultrasonography of both lower limbs were performed. Results: The isolated distal DVT prevalence was
12.4% (90/725). The sensitivity of the Wells rule for isolated
distal DVT was 47% (95% condence interval [CI] 3657%),
the specicity was 74% (95% CI 7077%), and the negative
and positive predictive values were 91% (95% CI 8893%) and
20% (95% CI 1526%), respectively. Patients with isolated
distal DVT had higher D-dimer levels than patients without
DVT (1759 1576 vs. 862 1079 ng mL)1, P = 0.0001).
D-dimer was negative in 13 patients with isolated distal DVT.
D-dimer sensitivity and specicity for isolated distal DVT were
84% (95% CI 7591%) and 50% (95% CI 4654%),
respectively, with a negative predictive value of 96%
(95% CI 9398%). In patients with low pretest clinical probability, the D-dimer negative predictive value was 99%
(95% CI 95100%). Conclusion: In
clinically
suspected
DVT with negative proximal compression ultrasonography,
pretest clinical probability with the Wells rule has a low
diagnostic accuracy for isolated distal DVT. D-dimer has a
better negative predictive value, but alone it does not exclude
isolated distal DVT. In patients with low pretest clinical
Correspondence: Michelangelo Sartori, U.O. di Angiologia e Malattie
della Coagulazione Marino Golinelli, Azienda Ospedaliera di
Bologna, Policlinico SantOrsola Malpighi, Pad. 2, Via Albertoni, 15,
40138 Bologna, Italy.
Tel.: +39 51 6362482; fax: +39 51 636 2517.
E-mail: michelangelo.sartori@aosp.bo.it
Received 12 April 2012, accepted 12 August 2012

probability, D-dimer had a negative predictive value of

> 95% for isolated distal DVT.
Keywords: calf thrombosis, compression ultrasonography,
D-dimer, deep vein thrombosis, diagnosis, sensitivity, specicity, Wells score.

Introduction
Isolated distal deep vein thrombosis (IDDVT), i.e. thrombosis
conned to the infrapopliteal veins of the lower limbs, is a
frequent nding in symptomatic outpatients [1]. Compression
ultrasonography in combination with a clinical decision rule
and/or D-dimer testing has been widely investigated for the
diagnosis of deep vein thrombosis (DVT) of the lower limbs
[2]. However, validation studies have revealed that the
sensitivity of ultrasonography for IDDVT diagnosis, even in
symptomatic patients, is signicantly lower than that for
proximal DVT [1]. Wells et al. [3] developed a diagnostic rule
to estimate the pretest clinical probability (PCP) of DVT, but
its accuracy has not been validated in patients in whom
IDDVT is suspected. The D-dimer test has been shown to have
a high sensitivity and a high negative predictive value for DVT
exclusion [4,5]. However, most studies employing D-dimer
were performed without examination of the calf veins, or they
were carried out in patient populations with a predominance of
proximal DVT. As a result, these studies did not report the
diagnostic accuracy for the subgroups of patients with
IDDVT.
The purpose of this study was to evaluate the diagnostic
accuracy of the Wells rule and D-dimer testing for IDDVT
diagnosis in clinically suspected DVT with negative proximal
compression ultrasonography.
Methods
Study population

The study was performed from September 2009 to January

2011 in a tertiary-care teaching hospital (University Hospital S.
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Wells rule, D-dimer, and distal deep vein thrombosis 2265

Orsola-Malpighi, Bologna, Italy). Symptomatic outpatients

referred by general practitioners or the emergency department
to the vascular emergency room for suspected acute DVT of
the lower limbs were eligible for the study. Patients were
excluded if they were younger than 18 years, had been receiving
vitamin K antagonists, low molecular weight heparin or
fondaparinux for > 24 h, or were pregnant or in puerperium,
with clinical suspicion of either pulmonary embolism or acute
supercial vein thrombosis.
A personal and family history was obtained from each
patient by the physician in charge, who also performed a
physical examination and lled in the PCP questionnaire.
Patients then underwent: (i) D-dimer testing; and (ii) whole-leg
compression ultrasonography of both lower limbs. Patients
with proximal DVT were excluded from the study.
The design of the study was cross-sectional. It was not
possible to enroll all consecutive eligible patients, but the rst
three eligible patient of each day were included, to minimize
selection bias. The enrollment was performed during business
days.
The study was approved by the local Ethics Committee.
Written informed consent was obtained from all patients.
PCP score

The PCP score for DVT was assessed with a questionnaire

developed by Wells et al. [6]. One point was added for each of
the following positive ndings: (i) active cancer treatment
ongoing or within the previous 6 months, or palliative treatment; (ii) paralysis, paresis or recent plaster immobilization of
the lower legs; (iii) recent immobilization for > 3 days or
major surgery within the last 4 weeks; (iv) localized tenderness/
pain along the distribution of the deep venous system; (v) entire
leg swollen; (vi) calf swelling by > 2 cm when compared with
the asymptomatic leg; (vii) pitting edema greater in the
symptomatic leg; and (viii) collateral supercial veins. Two
points were subtracted from the total points if an alternative
diagnosis as likely as or more likely than DVT was found. On
the basis of such a checklist, PCP for DVT could be estimated
to be low (score of 0), moderate (score of 1 or 2), or high
(score of 3).
D-dimer

Blood samples for D-dimer testing were taken before ultrasonography investigation. Blood was drawn by clean venipuncture from an antecubital vein with a 19-gauge buttery
needle, and collected into 4-mL plastic tubes containing
0.4 mL of 0.106 M trisodium citrate. Whole blood was
centrifuged at 2000 g for 20 min at 20 C. Technicians
performing D-dimer testing were unaware of the symptoms of
the patients.
The STA Liatest D-dimer (Diagnostica Stago, Asnie`res,
France) is an automated and rapid microlatex D-dimer assay.
Special mAb-coated latex particles agglutinate in the presence
of D-dimer brin degradation products. The STA Liatest
 2012 International Society on Thrombosis and Haemostasis

D-dimer assay was performed on the STA Compact

coagulation analyzer, as previously described [7]. Agglutination
causes greater light scattering which is recorded as an increase
in OD. The results were expressed in ng mL)1 (expressed in
brinogen equivalent units). As previously described, the
cut-off value for DVT exclusion was 500 ng mL)1 [8].
Whole-leg ultrasonography investigation

Patients underwent a comprehensive real-time B-mode and

color Doppler compression ultrasonography examination of
both legs by a vascular medicine physician, as previously
described [9]. Ultrasonography investigation was carried out
with an EnVisor C HD instrument (Philips Medical System,
Monza, Italy), with an L 125-MHz high-resolution broadband width linear array transducer, according to the method
of Schellong [10]. The proximal deep veins were examined
rst, and then, in patients with normal proximal ndings, the
calf veins were evaluated. The following veins were scanned in
the transverse plane over their entire length: posterior tibial
veins, bular veins, internal and external gastrocnemius veins,
and soleal veins. The diagnosis of DVT was conrmed if there
was lack of compression of the vein, combined with the
absence of venous ow with distal compression. Patients with
IDDVT were divided into three groups: those with thrombosis
conned only to the muscle veins (internal and external
gastrocnemius veins, and soleal veins), patients with axial calf
vein thrombosis, and patients with both muscular and axial
calf DVT. The vascular medicine physician was blind to
D-dimer results.
In cases of suspected recurrent DVT, recurrence was
diagnosed if a previously fully compressible segment (contralateral or ipsilateral) was no longer compressible, or if an
increase of at least 4 mm in the diameter of the residual
thrombus during compression was detected [11]. When
thrombus diameter changed between 1.1 and 3.9 mm, or in
cases of high/moderate clinical probability and normal proximal compression ultrasonography, the examination was
repeated 57 days later.
Statistical analysis

Analysis was carried out with SPSS, version 15.0 (SPSS,

Chicago, IL, USA). Relationships between variables were
assessed with Pearson correlation for continuous variables, and
the chi-square or Fisher exact test for categorical variables.
Multivariate analysis of variance with Bonferronis correction
for multiple comparisons was used to compare means among
groups for normally distributed variables. Receiver operating
characteristic (ROC) curves were prepared by plotting the
sensitivity vs. 1 specicity, and the area under the ROC curve
(AUC) and the 95% condence interval (CI) of the AUC for
the D-dimer test were calculated. Categorical variables are
expressed as frequency and percentage with 95% CI; continuous variables are expressed as mean standard deviation,

2266 M. Sartori et al
Table 1 Characteristic of the study population

Blood sample for D-dimer

n = 875

Pretest clinical probability

Proximal compression ultrasonography

n = 873

Proximal DVT
(excluded)
n = 148
B-mode and color Doppler
ultrasonography of infrapopliteal deep
veins
n = 725

IDDVT
n = 90

Fig. 1. Flow chart of the study. DVT, deep vein thrombosis; IDDVT,
isolated distal deep vein thrombosis.

and interquartile range is also reported. The signicance level

was set at 0.05.
Results
Figure 1 shows the study ow chart. Among 875 screened
patients, two did not meet the inclusion criteria, and were
excluded from the study. Proximal DVT was diagnosed at
proximal compression ultrasonography in 148 patients, who
were excluded from the study. The characteristics of enrolled
patient (n = 725) are summarized in Table 1. The most
frequent symptoms were leg pain and edema, and the most
frequent risk factors for thrombosis were obesity, trauma, and
history of vein thrombosis. The median time between the onset
of symptoms and inclusion in the study was 6 days (range:
190 days). The time between the onset of symptoms and
inclusion in the study was 7 days for 65% of the study
population.
The prevalence of IDDVT was 12.4% (n = 90). Thrombosis conned only to the muscle veins was detected in 49 patients
(54.4%), axial calf DVT in 26 patients (28.9%), and both
muscular and axial calf DVT in 15 patients (16.7%).
As shown in Table 2, age and body mass index were similar
in patients with and without IDDVT. Venous thromboembolism risk factors, such as reduced mobility, bed connement,
trauma of the symptomatic limb, and the use of hormone
replacement therapy/estrogen-containing therapy, were more
prevalent in patients with IDDVT than in those without.

Age (years) SD (IQR)

Male/female, no. (%)
BMI (kg m)2) SD (IQR)
Venous thromboembolism risk factors (%)
Active cancer
Surgery
Mobility signicantly reduced
Bed connement
Trauma in symptomatic leg
History of vein thrombosis
Obesity
Use of HRT/estrogen-containing therapy
Symptoms (%)
Pain
Edema
Redness or rash
Leg warmth

63.5 17.2 (26.5)

291/435 (59.9)
27.0 4.8 (5.8)
4.7
9.7
13.4
5.0
16.9
16.1
22.5
3.9
77.8
72.6
20.5
15.4

BMI, body mass index; HRT, hormone replacement therapy; IQR,

interquartile range.

Patients with IDDVT more frequently had pain of the calf and
less frequently had edema of the symptomatic limb than those
without IDDVT.
Table 3 shows the distribution of patients with low, moderate and high risk for thrombosis according to the calculated
PCP. In the low-risk PCP category (PCP 0), IDDVT was
identied in 20 patients (8.3%). In contrast, IDDVT was found
in 58 (13.5%) moderate-risk patients (PCP = 12), and in 12
(22.2%) high-risk patients (PCP > 2).
A moderate/high PCP (score 1) had a sensitivity of 78%
(95% CI 6885%), a specicity of 35% (95% CI 3139%),
and negative and positive predictive values of 85%
(95% CI 7989%), and 15% (95% CI 1218%), respectively,
for the diagnosis of IDDVT. A high PCP (score 3) had a
sensitivity of 13% (95% CI 822%), a specicity of 93%
(95% CI 9195%), and negative and positive predictive values
of 88% (95% CI 8691%) and 22% (95% CI 1335%),
respectively, for the diagnosis of IDDVT.
D-dimer plasma levels were higher in patients with than in
those without IDDVT (1759 1576 vs. 862 1079 ng mL)1,
P = 0.0001). D-dimer plasma levels were higher in patients
with both muscular and axial calf DVT than in those with
thrombosis conned only to the muscle veins and in those with
only axial calf vein thrombosis (2869 1902 vs. 1641 1538
vs. 1261 1045 ng mL)1, respectively, P = 0.006). The
ROC curve for the D-dimer test is shown in Fig. 2. The
AUC was 0.73 (95% CI 0.670.79). Assuming a cut-off value
of 500 ng mL)1 as suggested by Sidelmann et al. [8], 13
(14.4%) patients with IDDVT had negative results on a
D-dimer test. All of the patients with negative D-dimer and
IDDVT had a time of 4 days between the onset of symptoms
and study inclusion. All of the patients with both muscular and
axial calf DVT had a D-dimer level of > 500 ng mL)1. The
sensitivity and specicity of D-dimer were 84% (95% CI 75
91%) and 50% (95% CI 4654%), respectively, and the
negative and positive predictive values were 96%
(95% CI 9398%) and 19% (95% CI 1523%), respectively.
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Wells rule, D-dimer, and distal deep vein thrombosis 2267

Table 2 Characteristic of the study population according to the presence/absence of isolated distal deep vein thrombosis (IDDVT)

Age (years) SD
Male/female, no. (%)
BMI (kg m)2) SD
Venous thromboembolism risk factors (%)
Active cancer
Surgery
Mobility signicantly reduced
Bed connement
Trauma in symptomatic leg
History of vein thrombosis
Obesity
HRT/estrogen-containing therapy
Symptoms (%)
Pain
Edema
Redness or rash
Leg warmth

IDDVT-negative

IDDVT-positive

P-value

63.8 16.0
247/388 (61.1)
27.0 4.7

61.0 18.2
44/46 (51.1)
26.9 5.6

0.150
0.084
0.982

4.6
8.8
10.4
3.9
15.4
16.1
22.1
3.1

5.6
15.6
34.4
12.2
27.8
15.7
25.3
8.9

0.599
0.055
0.001
0.003
0.006
0.921
0.487
0.016

76.6
74.0
21.4
15.7

86.7
62.9
14.8
12.8

0.030
0.031
0.190
0.631

BMI, body mass index; HRT, hormone replacement therapy; SD, standard deviation.

Table 3 Prevalence of isolated distal deep vein thrombosis (IDDVT) and

D-dimer levels by pretest clinical probability risk classication

n (%)

Frequency
of IDDVT,
n (%)

>3
3
2
1
0
Total

8
46
181
249
241
725

2
10
32
26
20
90

(1.1)
(6.3)
(25.0)
(34.3)
(33.3)
(100)

(25.0)
(21.7)
(17.7)
(10.4)
(8.3)
(12.4)

1.0

D-dimer (ng mL)1)

2069 2763
1340 1023
899 957
858 1279
933 1183

(2408010)
(1904180)
(306880)
(1013780)
(1012610)

Discussion
Our study shows that the Wells rule is less accurate in
stratifying pretest probability for IDDVT than for proximal
DVT. D-dimer alone has a better predictive negative value, but
does not exclude IDDVT. In patients with negative proximal
compression ultrasonography ndings and at low risk for
proximal DVT (PCP < 1), D-dimer has a negative predictive
value of > 95% for IDDVT diagnosis.
The Wells score was developed in ambulatory patients
referred to a tertiary-care center for a suspected rst episode of
proximal and distal lower limb DVT [3,12]. More recently,
 2012 International Society on Thrombosis and Haemostasis

0.6

0.4

Continuous variables are expressed as mean standard deviation

(range).

D-dimer plasma levels according to PCP are reported in

Table 3, and they did not correlate with PCP (q = 0.69,
P = 0.71). The sensitivity, specicity and positive and negative
predictive values of D-dimer according to PCP score are
reported in Table 4. In patients with PCP < 1 (low risk for
proximal DVT), D-dimer negative predictive value increased to
99% (95% CI 95100%). Among the patients with IDDVT
and negative D-dimer, seven patients had PCP = 2, ve
patients had PCP = 1, and only one had PCP < 1.

0.8
Sensitivity

Pretest
clinical
probability

0.2

0.0
0.0

0.2

0.4

0.6

0.8

1.0

1 Specificity
Fig. 2. Receiver operating characteristic curve analysis of accuracies of
D-dimer testing for the presence of symptomatic isolated distal deep vein
thrombosis. *Indicates cut-o value of 500 ng mL)1.
Table 4 Sensitivity, specicity, positive predictive value (PPV) and negative predictive value (NPV) of D-dimer (cut-o value: 500 ng mL)1) for
the diagnosis of isolated distal deep vein thrombosis according to pretest
clinical probability score
Pretest clinical
probability
Sensitivity
High
Moderate
Low

Specicity

PPV

NPV

100 (70100) 27 (1642) 27 (1642) 100 (70100)

76 (6386) 52 (4757) 19 (1425) 94 (9097)
95 (75100) 51 (4558) 16 (1023) 99 (95100)

Data are expressed as % (95% condence interval).

Wells et al. [6] published a modied score, adding an item for

previously documented DVT. This modied Wells score has
been validated in outpatients [6,13], emergency department

2268 M. Sartori et al

patients[14], and inpatients from a university hospital [15]. The

initial clinical model by Wells et al. was derived by the inclusion
of IDDVT diagnosed by venography, but the subsequent
validation studies using whole-leg ultrasonography gave contrasting results. Engelberger et al. [15] and Blattler et al. [16]
showed a poor correlation between PCP and IDDVT diagnosis, but they enrolled only 36 patients and 19 patients with
IDDVT, respectively. Other studies demonstrated a better
negative predictive value of PCP for both proximal DVT and
IDDVT [13,17]. However, most studies did not look for distal
DVT [6,18,19], and the Wells score therefore seems to be able
to stratify patients only for the risk of proximal DVT [20]. Our
study, which included more IDDVT patients than previous
studies, demonstrates that the Wells score poorly predicts
IDDVT.
The role of D-dimer assays in the diagnosis of patients with
suspected DVT has been extensively studied [5]. The D-dimer
assay has proven to be a highly sensitive but non-specic test
for the presence of venous thromboembolism [4], and to have a
high negative predictive value for DVT in different patient
populations [2125]. D-dimer seems to have a lower sensitivity
and a lower negative predictive value for IDDVT than for
proximal DVT. Jennersjo et al. [26] reported that 35% of
patients with IDDVT have normal D-dimer levels. Leroyer
et al. [22,27] found that D-dimer had a predictive negative
value for IDDVT diagnosis of < 90%, whereas other studies
reported a negative predictive value for IDDVT diagnosis of
97% [2325]. A meta-analysis showed that all D-dimer
assays had higher sensitivity for proximal than for distal DVT:
98% vs. 86% for ELISA, 94% vs. 79% for latex agglutination,
and 84% vs. 64% for whole-blood agglutination [5]. In our
series, D-dimer with a cut-off value of 500 ng mL)1 had a
similar sensitivity (84%) to that found in the previously
mentioned meta-analysis, but a better predictive negative value
(> 93%), for IDDVT diagnosis. It should be noted that 14%
of total IDDVTs were missed with such a cut-off.
Our study was performed with the STA Compact analyzer.
The studies evaluating the clinical value of the rapid STA
Liatest D-dimer on the STA-R analyzer were carried out on
patient populations with a predominance of proximal thrombosis [27,28], or did not report the sensitivity and diagnostic
accuracy for the subgroups of proximal DVT and distal DVT
separately [29]. Recently, it has been shown that the Liatest Ddimer has areas under the ROC curve of 0.91 for proximal DVT
and 0.58 for IDDVT [8]. We found a better area under the ROC
curve (0.73), suggesting a better sensitivity of D-dimer for
IDDVT diagnosis than previously reported. Nevertheless, our
series shows that D-dimer alone does not rule out the presence
of IDDVT. It should be noted that D-dimer plasma levels
varied with the type of IDDVT: patients with both muscle vein
and deep calf vein thrombosis had higher D-dimer plasma levels
than the others, and such patients had a D-dimer level of > 500
ng mL)1. This nding may reect a higher thrombus burden or
volume. Further studies are needed to address this issue.
We expected to nd a low sensitivity and a low specicity of
both PCP and D-dimer by selecting a population with negative

proximal ultrasonography ndings. We found that the Wells

score still stratied subjects with IDVVT reasonably well
among the low-PCP, moderate-PCP and high-PCP groups.
Similarly to what was found for proximal DVT [5], D-dimer
sensitivity and specicity varied according to PCP value, and,
in patients at low risk (PCP < 1), D-dimer had a negative
predictive value similar to that for proximal DVT diagnosis. In
such patients, a low D-dimer level was able to exclude the
presence not only of proximal DVT, but even of distal DVT. In
patients with moderate risk (PCP = 1 or PCP = 2), we found
several patients with IDDVT in whom D-dimer testing was
negative. In patients with intermediate PCP, recent guidelines
recommend the performance of one of the following initial
tests: a highly sensitive D-dimer assay or proximal compression
ultrasonography, or whole-leg ultrasonography [2]; in the case
of negative D-dimer, no further testing is recommended [2].
With such an approach, several IDDVTs could be missed.
However, the clinical benet of diagnosing and treating
IDDVT is still a matter of controversy [1], and we could
speculate that IDDVT with PCP < 2 and negative D-dimer
could be at low risk of proximal extension. In fact, we recently
found that most untreated calf DVTs have a benign clinical
course, and only some of them may have clinically relevant
thrombotic outcomes [9].
Some limitations of the present study should be acknowledged. The patients investigated were not all consecutive
patients referred to our vascular outpatient service, and a
selection bias cannot be excluded. However, most of the
included patients were subjects who were referred rst in the
morning, with the aim of reducing this bias. Moreover, no
interobserver variability was assessed for IDDVT diagnosis.
Finally, we did not follow up the patients with negative wholeleg ultrasonography ndings, but a larger study has shown that
anticoagulant therapy can be safely withheld after negative
complete compression ultrasonography ndings without further testing in the ambulatory ofce setting [30].
In conclusion, the Wells rule does not guarantee the same
risk estimation of IDDVT as of proximal DVT. D-dimer has
an acceptable negative predictive value in clinically suspected
DVT with negative proximal compression ultrasonography
ndings. D-dimer alone does not exclude the presence of
IDDVT in patients with a time of 4 days between the onset
of symptoms and D-dimer assay. The combination of negative
D-dimer and a low Wells rule score has a negative predictive
value of > 95%. In patients with moderate risk, D-dimer had
a lower negative predictive value, and further studies are
needed to establish whether it is worthwhile diagnosing
IDDVT in such patients.
Addendum
M. Sartori designed the study, analyzed the data and wrote the
paper; B. Cosmi analyzed the data and revised the paper; C.
Legnani was involved in the data analysis, in revising the paper,
and in the laboratory diagnosis; E. Favaretto was involved in
the patient management, collected the data, analyzed the data;
 2012 International Society on Thrombosis and Haemostasis

Wells rule, D-dimer, and distal deep vein thrombosis 2269

L. Valdre, G. Guazzaloca and G. Rodorigo were involved in

the patient management and collected the data; M. Cini was
involved in the laboratory diagnosis and collected the data; G.
Palareti designed the research and revised the paper. All the
authors revised the manuscript and gave nal approval of the
version to be submitted.
Disclosure of Conflict of Interests
The authors state that they have no conict of interest.
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