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The Role of D-dimer Testing in Patients with Suspected Venous

Thromboembolism

Article  in  Seminars in Thrombosis and Hemostasis · March 2009

DOI: 10.1055/s-0029-1214148 · Source: PubMed

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 The Role of D-dimer Testing in Patients
with Suspected Venous Thromboembolism
Domenico Prisco, M.D.,1 and Elisa Grifoni, M.D.1

ABSTRACT

D-dimer, the final degradation product of cross-linked fibrin, is typically elevated

in patients with acute venous thromboembolism. With its high sensitivity and negative
predictive value, D-dimer testing may have a role for ruling-out the diagnosis in patients
with suspected deep vein thrombosis or pulmonary embolism. For this purpose, D-dimer
testing has been integrated in sequential diagnostic strategies including those using pretest
clinical probability assessment and imaging techniques. A large variety of assays are now
available for D-dimer measurement, with different sensitivities and specificities for the
diagnosis of venous thromboembolism. Attempts to standardize the various D-dimer
assays have been made but without any definitive answers as yet. The diagnostic yield of
D-dimer testing is affected not only by the choice of the appropriate assay but also by
patient characteristics. As a consequence, the clinical usefulness of D-dimer testing for the
exclusion of suspected venous thromboembolism should be carefully evaluated in special
clinical settings.

KEYWORDS: D-dimer, venous thromboembolism, diagnosis

S uspicion of venous thromboembolism (VTE) is
a frequent clinical problem, and prompt recognition of
the disease is mandatory. However, specific diagnostic
tests, such as compression ultrasonography for deep vein
thrombosis (DVT) and computed tomography or lung
scanning for pulmonary embolism (PE), are expensive
and not always readily available. Moreover, only
25%
of the suspected VTE episodes are confirmed by objec-
tive testing.1 To avoid unnecessary anticoagulant treat-
ment and the associated risk of bleeding, it is therefore
crucial to accurately identify the 75% of patients with
symptoms prompting a suspicion of VTE who do not
have the disease. In the past two decades, extensive
research has been performed to develop easier and
more cost-effective diagnostic strategies for VTE.2 In
this context, D-dimer (DD) represents a simple, rela-
tively noninvasive test that may allow clinicians to
exclude the disease without a requirement for further
imaging tests in a substantial proportion of patients.3
In this review, we describe the currently available
assays for DD measurement and their performance in
diagnosing VTE. The role of DD testing in patients
with suspected DVT or PE is analyzed in the context of
different diagnostic strategies and clinical settings.
D-DIMER: PATHOPHYSIOLOGY
DD is the final product of the plasmin-mediated
degradation of cross-linked fibrin. Its blood concen-
tration depends on clotting activation with fibrin

1
Department of Medical and Surgical Critical Care, University of
Florence; and Department of Heart and Vessels, Thrombosis Centre,
Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
Address for correspondence and reprint requests: Domenico
Prisco, M.D., Centro Trombosi, Azienda Ospedaliero-Universitaria
Careggi, V. le Morgagni, 85 – 50134 Firenze, Italy (e-mail: priscod
@aou-careggi.toscana.it).
Laboratory Diagnostics and Therapy in Thrombosis and Hemo-
50
stasis: From Bedside to Bench to Bedside; Guest Editors, Giuseppe
Lippi, M.D., Emmanuel J. Favaloro, Ph.D., M.A.I.M.S., and Massimo
Franchini, M.D.
Semin Thromb Hemost 2009;35:50–59. Copyright # 2009 by
Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York,
NY 10001, USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-0029-1214148. ISSN 0094-6176.
 ROLE OF D-DIMER TESTING/PRISCO, GRIFONI 51

Table 1 Conditions Associated with Increased D-dimer
Plasma Levels
Nonpathologic Pathologic
Age Trauma
Race (black population) Preeclampsia
Cigarette smoking Malignancy
Pregnancy and Infection
puerperium
Postoperatively Chronic inflammatory diseases
Disseminated intravascular coagulation
Sickle cell disease
Arterial or venous thromboembolism
Acute coronary syndromes
Stroke
Peripheral artery disease
Atrial fibrillation
Congestive heart failure
Hemorrhages
generation, stabilization by factor XIIIa, and subse-
quent degradation by the endogenous fibrinolytic sys-
tem. DD (molecular weight around 180,000 Da)
consists of two identical subunits derived from two
fibrin monomer molecules. Its plasma half-life is

8 hours, and clearance occurs via the kidney and
the reticuloendothelial system. Because 2 to 3% of
plasma fibrinogen is physiologically converted to fibrin
and then degraded, small amounts of DD are detect-
able in the plasma of healthy individuals, thus sug-
gesting a balance between fibrin formation and lysis
even under normal physiologic conditions. DD plasma
concentration is increased in all physiologic and
pathologic circumstances associated with enhanced
fibrin formation and subsequent degradation by plas-
min (Table 1). DD is typically elevated in patients
with VTE. Indeed, thrombus formation is normally
followed by an immediate fibrinolytic response, with
the release of fibrin degradation products into the
circulation. It follows that the absence of a rise in
DD implies that thrombosis is not occurring. Because
of its association with clinical conditions related to
thrombosis, assessment of DD has become very pop-
ular, but its use by clinicians is often inappropriate.4,5
Actually, it should be noted that many factors can
influence DD plasma levels measured in these pa-
tients: thrombus age and size, fibrinolytic potential,
presence of anticoagulant treatment, and other intra-
vascular and extravascular fibrin depositions as addi-
tional sources of fibrin degradation products.6,7
D-DIMER MEASUREMENT
Types of D-dimer Assays
A large variety of assays are available for DD measure-
ment. All methods are based on use of monoclonal
antibodies, which recognize epitopes on the DD frag-
ment that are virtually lacking on fibrinogen and non–
cross-linked fragments of fibrin.8 The resulting anti-
body-antigen complexes can be detected by enzyme-
linked immunosorbent assay (ELISA) or agglutination
techniques (Table 2).
ELISA TESTS
The classic microplate ELISA technique was considered
the gold standard and was used in early clinical studies to
assess the value of DD measurement for diagnosing
VTE. The sensitivity and negative predictive value
(NPV) were high enough to allow its use as a rule-out
test in diagnostic strategies for VTE. Unfortunately, this
method is suitable only for batch analysis and, therefore,
is not useful for real-time single testing in emergency
contexts.9 Subsequently, modified ELISA tests that are
more rapid and suitable for single samples have been
developed. These tests combine the ELISA technique
with a final detection by fluorescence (DD enzyme-
linked immunofluorescence assay [ELFA]), chemilumi-
nescence, or time-resolved fluorescence. Their main
limitation is the requirement of a dedicated immunoa-
nalyzer.10–13 Another rapid assay is based on an immu-
nofiltration method, in which capture antibodies are
coated onto a permeable membrane; a signal is generated
by a colloid gold-labeled tag antibody and quantified
with a reflectometer.14

Table 2 Summary of the Characteristics of Various D-Dimer Assays

Type of DD Assay Characteristics

ELISA assays
Classic microplate ELISA
Rapid ELISA assays
Agglutination assays
Semiquantitative assays
Quantitative assays
(immunoturbidimetric assays)
Whole-blood assays
High sensitivity, low specificity; observer-independent; not suitable for real-time single testing
High sensitivity, low specificity; observer-independent; suitable for real-time single-testing
Intermediate sensitivity and specificity; rapid; observer-dependent
High sensitivity, intermediate specificity; rapid; observer-independent
High-intermediate sensitivity, intermediate specificity; rapid bedside execution; observer-dependent
52 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 35, NUMBER 1
LATEX AGGLUTINATION ASSAYS
Latex-based methods rely on the ability of the analyte to
agglutinate latex particles coated with the antibody. Two
types of latex tests are available: semiquantitative assays
or quantitative assays. Semiquantitative agglutination
assays are the simplest and less expensive methods
because they are fast and do not require complicated
instrumentation. However, as reading is visual and
observer-dependent, some interobserver variability in
estimating the relative presence or absence of agglutina-
tion is unavoidable.14
Quantitative automated agglutination assays are
photometric or turbidimetric methods, and these have
been more recently introduced. They have been designed
to be performed on routine coagulation or clinical
chemistry analyzers and do not require dedicated instru-
ments. The main advantage of these methods is that
results, usually available in 5 to 10 minutes, are observer-
independent, and full automation reduces other sources
of variability. However, the analytical sensitivity and the
low limit of detection may be a cause of concern. The
calibration curve usually covers a wide range of concen-
trations, but the upper reference range of normal values
and the detection limit for VTE exclusion often lies in
the lower part of the calibration curve, where the signal is
weaker.15,16
WHOLE-BLOOD AGGLUTINATION ASSAYS
Manual and semiquantitative DD assays that use whole
blood can be performed at patient’s bedside (point-
of-care testing). The SimpliRED (Agen Biomedical,
Brisbane, Australia) test was the first of these to be
developed. It is a red blood cell agglutination assay
designed for use with fresh capillary or venous whole
blood. Recently, a novel qualitative immunochromato-
graphic method has been introduced. With both assays,
results are available in less than 5 minutes. However, as
the reading is visual and observer-dependent, some
interobserver variability has also been reported.17–20
Another assay performed on whole blood and using a
dedicated device has the advantage of observer-inde-
pendence of results.21
Standardization of D-dimer Assays
One of the main problems with DD measurement is
represented by the difficulty in standardization of the
different available assays. Despite various attempts, the
probability of standardization still seems to be distant in
time. As a consequence, direct comparison of results
obtained with different methods is impossible, and each
result should be considered method-specific.22 This
difficulty in standardization can be due to several rea-
sons. First, the heterogeneity of the analyte itself: DD is
not a single entity but a complex mixture of degradation
products of different sizes, with a large interindividual
2009
and intraindividual variability. Second, the type of cal-
ibrators used: purified DD fragments, with results
expressed as DD concentration, or fibrin degradation
products obtained from controlled plasmin digestion,
with results expressed in fibrinogen equivalent units
(FEU). Finally, the use of various types of monoclonal
antibodies with different specificity and affinity: this
means that the same degradation product can be
detected to different extents by different assay reagents.
The lack of a DD reference standard could be overcome
by conversion of DD values from different assays to a
common scale by using a conversion factor related to the
median values obtained with a sufficiently large set of
clinical plasma samples.23 Some mathematical models
for the harmonization of DD test results have been
proposed but have not obtained a universal consensus
as yet.24–26
D-DIMER TESTING FOR VTE DIAGNOSIS
Role of D-dimer Testing for the Exclusion of VTE
DD is a sensitive but not specific marker for VTE, so
that a positive DD result has a low capability of estab-
lishing the diagnosis of DVT or PE. Instead, the real
value of DD testing is with a negative result that allows
one to lower the likelihood of the diagnosis. Therefore,
with its high sensitivity and NPV, DD testing has
gained a role in the diagnostic workup of VTE for the
exclusion of the disease, potentially reducing the need for
imaging tests.3
Various integrated strategies for VTE diagnosis
have been proposed in which DD testing has a different
place in the diagnostic sequence.
(a) Initial DD testing for the exclusion of VTE with addi-
tional imaging tests only in patients with a positive DD
result (Fig. 1). This strategy was adopted in a large
prospective management study of more than 900
consecutive outpatients with suspected DVT or PE
referred to the Emergency Department of Geneva
Hospital.27 DD was measured by the rapid quantita-
tive ELISA Vidas (bioMérieux, Marcy l’Etoilé,
France) test. This method showed a sensitivity and
a NPV of 98.2% and 98.4%, respectively. At a 3-
month follow-up, the risk of thromboembolic com-
plications in patients with a negative DD result and
no further evaluation with imaging tests was 2.6%
(95% confidence interval [CI], 0.2 to 4.9%).
(b) DD testing after a first negative imaging test to identify
patients who require a new specific evaluation (Fig. 2).
In this diagnostic strategy for suspected DVT, a
positive DD result allows one to select patients
who require a new ultrasonographic evaluation 1
week after an initial negative ultrasonographic eval-
uation to detect extending calf DVT that may have

Figure 1 Diagnostic algorithm based on initial D-dimer testing for the exclusion of VTE with additional imaging tests only in
patients with a positive D-dimer result. (Modified from Perrier A, Desmarais S, Miron MJ, et al. Noninvasive diagnosis of venous
thromboembolism in outpatients. Lancet 1999;353:190–195.)
altered DD test without being detectable on first
ultrasound. In a management study by Bernardi
et al,28 this strategy reduced the need for repeating
ultrasonography from 75 to 9.3%, and thrombotic
complications at 3 months were less than 1%. It
should be mentioned, however, that this study used
a rapid qualitative assay for DD testing, which is no
longer available. A similar use of DD testing was
proved be useful also in patients with suspected PE
after a first negative lung scan.29
(c) DD testing integrated with clinical probability and
subsequent specific tests (Fig. 3). Several studies have
demonstrated that a negative DD result, combined
with a low pretest clinical probability (PCP) of
disease, can safely exclude DVT or PE without
additional diagnostic testing.30–34 In particular, in
a study by Kearon et al30 conducted on 445 out-
patients with suspected DVT, only 1 of the 177
patients with low PCP and negative DD results
ROLE OF D-DIMER TESTING/PRISCO, GRIFONI 53
had a confirmed DVT during a 3-month follow-
up. The NPV for subsequent symptomatic VTE of
low PCP of DVT combined with a negative DD
result was 99.4% (95% CI, 96.9 to 100%). In a
study by Wells et al,31 a similar diagnostic strategy
was applied to 930 patients with suspected PE. Of
the 437 patients with a negative DD result and
low PCP, only one developed PE during follow-
up; the NPV for the combined strategy of using
the clinical model with DD testing in these
patients was 99.5% (95% CI, 99.1 to 100%). In
both studies, a rapid qualitative test for DD
measurement (SimpliRED) was used. Recently, a
systematic review of 11 management studies using
a combination of PCP and DD test results to rule-
out VTE was performed.35 The overall rate of
thromboembolic events was 0.45% (95% CI, 0.22
to 0.83%) among patients in whom anticoagulant
treatment was withheld on the basis of a low
54 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 35, NUMBER 1 2009

Figure 2 Diagnostic algorithm based on D-dimer testing after a first negative imaging test to identify patients who require a new
specific evaluation. (Modified from Bernardi E, Prandoni P, Lensing AWA, et al. D-dimer testing as an adjunct to ultrasonography in
patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998;317:1037–1040.)

clinical score and a negative DD result, thus
demonstrating the safety of this diagnostic workup
for the exclusion of both DVT and PE. No
significant difference in safety was observed with
qualitative and quantitative DD tests and with
different decision rules. This diagnostic strategy,
requiring further specific tests only in patients
with positive DD and/or intermediate or high
PCP, has also been reported to be the most
advantageous in a cost-effectiveness analysis.36
The use of DD testing in the diagnostic strategies
for VTE requires the identification of a cutoff level that
allows clinicians to reliably exclude the disease. The
cutoff value for VTE exclusion, as determined in clinical
studies by receiver operating characteristics (ROC) curve
analysis, is the point within the measuring range that

Figure 3 Diagnostic algorithm based on D-dimer testing integrated with pretest clinical probability and subsequent specific
tests. (Modified from Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism at the bedside without
diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by
using a simple clinical model and D-dimer. Ann Intern Med 2001;135:98–107.)

confers the best sensitivity and specificity to a particular
assay. It should be noted that this value might not
coincide with the upper limit of the reference interval,
which is usually calculated on a healthy population.
When choosing a DD assay to be used in the diagnostic
workup of DVT or PE, its sensitivity and cutoff level
should be carefully evaluated to avoid false-negative
results.37,38 Moreover, only DD assays that have been
validated in prospective outcome studies should be
accepted. Specificity is also important because it influ-
ences the yield of the test determining the proportion of
false-positive results. More specific assays, due to fewer
false-positive results, could be theoretically useful for
excluding VTE in a higher proportion of patients.
Unfortunately, they usually also have a lower sensitivity
that limits their use to patients with a low PCP of VTE.
The choice of the appropriate method for DD measure-
ment also depends on the place of the test in the
diagnostic sequence of VTE. If used as first step with
no additional tests in the presence of a negative result,
the method of choice should have a sensitivity as close as
possible to 100% to minimize the proportion of false-
negative results. On the contrary, if DD test is used in
association with PCP assessment or imaging techniques,
a less sensitive test may be accepted.7
Is There Any Role for D-dimer Testing in Ruling-
in a Diagnosis of VTE?
Because of its low specificity, a DD result above the
cutoff level is currently considered not sufficient to rule-
in the diagnosis of DVT or PE. However, a recent
study39 showed a possible use of high quantitative DD
levels to increase the likelihood of PE in symptomatic
patients. Indeed, PE prevalence was strongly associated
with the height of the DD level and increased fourfold
with DD levels greater than 4000 ng/mL compared with
levels between 500 and 1000 ng/mL. Patients with DD
levels higher than 2000 ng/mL and an unlikely PCP had
a PE prevalence comparable with the PE-likely PCP
group. Moreover, when DD levels were above 4000 ng/
mL, the observed PE prevalence was very high, inde-
pendent of PCP. As the authors concluded, whether this
should translate into more intensive diagnostic and
therapeutic measures in patients with high DD levels
irrespective of PCP remains to be evaluated in prospec-
tive studies. Similar results have been recently reported
also in symptomatic outpatients with suspected DVT.40
Accuracy of Various D-dimer Assays
in the Diagnostic Workup of VTE
In a recent meta-analysis by Di Nisio et al,41 the perform-
ance of several DD tests for either DVT or PE diagnosis
was evaluated. The sensitivities of the ELFA (DVT 96%;
PE 97%), microplate ELISA (DVT 94%; PE 95%), and
ROLE OF D-DIMER TESTING/PRISCO, GRIFONI 55
latex quantitative assays (DVT 93%; PE 95%) were
superior to those of the whole-blood DD assays (DVT
83%; PE 87%), latex semiquantitative assays (DVT 85%;
PE 88%), and latex qualitative assays (DVT 69%; PE
75%). On the other hand, the latex qualitative and whole-
blood DD assays show the highest specificities (99% and
71% for DVT and 99% and 69% for PE, respectively,
compared with
50% for the high sensitivity assays). In a
previous meta-analysis by Stein et al,42 the sensitivity and
NPV of the ELISAs (in particular the quantitative rapid
ELISA) were superior to those of other DD tests,
including latex quantitative assays.
Usefulness of D-dimer Testing for VTE
Diagnosis in Special Clinical Settings
The usefulness of DD testing in the diagnostic workup
of DVT or PE is affected not only by the choice of the
appropriate assay but also by patient characteristics and
clinical context. Extent of thrombosis and fibrinolytic
activity, duration of symptoms, anticoagulant treat-
ments, age, and comorbid conditions represent relevant
sources of variation in DD testing, affecting its sensi-
tivity and specificity.43
DD levels are related with thrombus extension,
being higher in the presence of larger thrombi. This may
explain why DD sensitivity has been reported to be lower
in distal DVT44 or subsegmental PE.45 There is an
inverse relation between DD plasma levels and duration
of symptoms. DD concentration tends to decrease when
a patient has been presenting symptoms for several days
before testing, already reaching 25% of the initial value
after 1 to 2 weeks.46 Anticoagulant therapy (both with
heparin and vitamin K antagonists) also determines a
decrease in DD concentration that has been estimated
around 25% some 24 hours after starting anticoagula-
tion, with a consequent decrease in sensitivity from
95.5% (95% CI, 90 to 99%) to 89.4% (95% CI, 84 to
95%.).47 Therefore, a DD result below the diagnostic
cutoff obtained after starting anticoagulation should be
interpreted with caution to avoid false-negative results.
In several clinical conditions associated with in-
creased DD levels, the specificity of DD testing for VTE
diagnosis may be greatly diminished, due to a higher
number of false-positive results. This is the reason why a
reduced diagnostic usefulness of DD testing for VTE
exclusion has been reported in surgical and nonsurgical
inpatients,48 inflammatory states,49 pregnancy and post-
partum,50,51 elderly patients,52 cancer patients,53 and in
those with previous VTE.54
Several authors have investigated the clinical use-
fulness of DD testing in elderly patients. Two studies55–57
showed that a negative DD test was able to rule-out PE in
a very small proportion of patients older than 75 or
80 years. Moreover, in a cost-effectiveness analysis,58 no
clear economic advantage of measuring DD after the age
56 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 35, NUMBER 1
of 80 was reported, except when the availability of other
diagnostic tests was limited or the risk of imaging using
computed tomography was too high because of impaired
renal function. Recently, in contrast with previous results,
a pooled analysis of three large prospective studies eval-
uating consecutive outpatients with suspected DVT59
showed that the combination of a low or unlikely PCP
with a negative DD result can effectively and safely
exclude DVT in elderly outpatients, despite the lower
specificity of DD in this age group. Indeed, this strategy
allowed the exclusion of DVT in 22 to 31% of patients
aged 80 years and older compared with 33 to 46% of
younger patients, with similar NPVs (ranging from 99 to
100%) for all age groups. However, these results need to
be prospectively validated with different DD assays in this
specific population. Attempts to increase the specificity of
DD testing in elderly people by increasing the diagnostic
cutoff values have also been made, with discordant re-
sults.52,60–62
The evidence about the safety and clinical utility
of DD testing in cancer patients with suspected DVT is
limited, with conflicting data in the literature. Lee et al63
retrospectively assessed the value of the SimpliRED DD
assay in 1068 consecutive outpatients with suspected
DVT. Although the sensitivity of DD was comparable
in patients with and without malignancy (86% vs. 83%),
the NPV of the test was found significantly lower in
cancer patients (79% vs. 96%, p ¼ 0.008). In contrast, in
a study by ten Wolde et al64 evaluating 1739 outpatients
with suspected DVT with a diagnostic strategy including
the SimpliRED DD test and ultrasonography, the NPV
of DD test was found high both in cancer and in
noncancer patients (97% [95% CI, 89 to 100%] and
97% [95% CI, 96 to 98%], respectively). The discrepancy
in the findings of the previous two studies may be
partially explained by the different reference tests used,
differences in the populations included, as well as in the
design characteristics of the studies. Recently, the use-
fulness of DD testing combined with PCP to rule-out
DVT in cancer patients was evaluated by Di Nisio et al65
in a study conducted with a cohort of 2066 consecutive
outpatients with clinically suspected DVT. The NPV of
DD test was 100% (95% CI, 85 to 97%) and 97% (95%
CI, 88 to 99%) among cancer patients with low PCP or
low-moderate PCP. The specificity of DD testing pro-
gressively decreased moving from low to high PCP.
However, low PCP was uncommon in cancer patients
because the presence of malignancy is one of the major
criteria for scoring PCP, so more patients would be
subjected to imaging. The clinical usefulness of DD
testing in cancer patients with suspected PE has been
evaluated in two recent studies53,66 in which different
DD assays (a turbidimetric [Tinaquant; Roche,
Mannheim, Germany] and an ELISA [Vidas]) were
used. Both DD tests showed a sensitivity and NPV of
100% in patients with cancer, whereas specificity was
2009
lower in these patients (21% for Tinaquant and 16% for
Vidas) when compared with that for patients without
cancer (53% for Tinaquant and 41% for Vidas).
Several studies67–69 have investigated the per-
formance of various DD assays in asymptomatic preg-
nant women. Both rapid ELISA DD tests and latex
agglutination tests, at current cutoff values, demon-
strated limited diagnostic usefulness in pregnant women
suspected of having DVT. In the case of the rapid
ELISA, most asymptomatic pregnant women had DD
levels that exceeded the reference limit after 16 weeks of
gestation.67 In the case of one latex agglutination assay,
only 22% of women in the second trimester and none in
the third trimester had levels lower than the reference
limit.68 In contrast, results using the SimpliRED assay
were negative in at least 75% of pregnant women with-
out DVT in the first two trimesters of pregnancy and in
half of the women by the third trimester.69 The utility of
the SimpliRED DD assay to exclude DVT in pregnancy
has been evaluated in a prospective study conducted on
149 consecutive pregnant women with suspected
DVT.70 This method showed a sensitivity of 100%
(95% CI, 77 to 100%), a NPV of 100% (95% CI, 95
to 100%), and a specificity of 60% (95% CI, 52 to 68%).
Despite the relatively small sample size and the wide
confidence interval for sensitivity, this study confirmed
the high clinical utility that can be obtained with a
whole-blood agglutination test in low-risk populations
(DVT incidence in this study was 8.7%).
Diagnosis of recurrent VTE may be difficult. The
potential usefulness of DD testing for this purpose has
been evaluated. In a recent prospective study,71 a highly
sensitive DD test (the STA Liatest D-Di; Diagnostica
Stago, Asnières, France) was used to exclude DVT in 300
patients with a previous episode of DVT and suspected
recurrent event. The DD result was negative at presenta-
tion in 134 (45%) patients. After 3 months of follow-up, 1
of 134 patients with negative DD at presentation had
confirmed recurrent VTE (0.75% [95% CI, 0.02 to
4.09%]). However, VTE on follow-up could not be
definitively excluded in six patients because of the lack
of a diagnostic reference standard for recurrent DVT. The
safety and usefulness of DD testing in patients with
suspected PE who had experienced a previous episode of
VTE has been assessed in a recent study.54 PE was ruled-
out by a negative DD test in only 15.9% of patients with
previous VTE compared with 32.7% in those without a
previous event (p < 0.0001). At a 3-month follow-up, the
risk of thromboembolic complications was 0% (95% CI,
0.0 to 7.9%) in patients with previous VTE and a negative
DD test who did not receive anticoagulant treatment.
CONCLUSION
DD has gained an important place in the diagnostic
workup of suspected DVT or PE as a simple, relatively

noninvasive test that can be useful, especially in con-
junction with PCP assessment, to rule-out the diagnosis,
limiting the number of patients requiring further eval-
uation with imaging techniques.
Among the large variety of available DD assays,
the ELISAs and automated latex turbidimetric tests
show the highest sensitivity and no interobserver varia-
bility, whereas manual latex and whole-blood assays are
less sensitive but have the advantage of quick and easy
bed-side performance. Several studies have demon-
strated that highly sensitive DD tests can be safely
used to exclude VTE in outpatients with a low or
intermediate PCP. Instead, less sensitive tests should
be restricted to ruling-out the disease in patients with a
low PCP.
The specificity and hence clinical utility of DD
testing to exclude VTE is reduced in specific patient
populations and clinical settings, such as elderly patients,
cancer patients, pregnant women, and patients with
previous VTE, although the test retains its high sensi-
tivity in these situations. Moreover, a DD result below
the diagnostic cutoff obtained after starting anticoagu-
lation or in patients having symptoms for several days
before testing should be carefully interpreted to avoid
false-negative results. Therefore, substantial effort
should be made to avoid inappropriate DD testing,
limiting its use to clinical settings in which a DD-based
management of suspected VTE has been proved effica-
cious and safe.
ABBREVIATIONS
CI confidence interval
DD D-dimer
DVT deep vein thrombosis
ELFA enzyme-linked immunofluorescence assay
ELISA enzyme-linked immunosorbent assay
FEU fibrinogen equivalent units
NPV negative predictive value
PCP pretest clinical probability
PE pulmonary embolism
ROC receiver operating characteristics
VTE venous thromboembolism
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