Accuracy of D-Dimers to Rule Out Venous Thromboembolism Events across Age Categories.
ABSTRACT Background. Strategies combining pretest clinical assessment and D-dimers measurement efficiently and safely rule out venous thromboembolism events (VTE) in low- and intermediate-risk patients. Objectives. As process of ageing is associated with altered concentrations of coagulation markers including an increase in D-dimers levels, we investigated whether D-dimers could reliably rule out VTE across age categories. Method. We prospectively assessed the test performance in 1,004 patients visiting the emergency department during the 6-month period with low or intermediate risk of VTE who also received additional diagnostic procedures. Results. 67 patients had VTE with D-dimers levels above the threshold, and 3 patients displayed D-dimers levels below the threshold. We observed that specificity of D-dimers test decreased in an age-dependent manner. However, sensitivity and negative predictive value remained at very high level in each age category including older patients. Conclusion. We conclude that, even though D-dimers level could provide numerous false positive results in elderly patients, its high sensitivity could reliably help physicians to exclude the diagnosis of VTE in every low- and intermediate-risk patient.
- SourceAvailable from: Fahad Al-Hameed[Show abstract] [Hide abstract]
ABSTRACT: The diagnosis of deep venous thrombosis (DVT) may be challenging due to the inaccuracy of clinical assessment and diversity of diagnostic tests. On one hand, missed diagnosis may result in life-threatening conditions. On the other hand, unnecessary treatment may lead to serious complications. As a result of an initiative of the Ministry of Health of the Kingdom of Saudi Arabia (KSA), an expert panel led by the Saudi Association for Venous Thrombo-Embolism (SAVTE; a subsidiary of the Saudi Thoracic Society) with the methodological support of the McMaster University Working Group, produced this clinical practice guideline to assist healthcare providers in evidence-based clinical decision-making for the diagnosis of a suspected first DVT of the lower extremity. Twenty-four questions were identified and corresponding recommendations were made following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. These recommendations included assessing the clinical probability of DVT using Wells criteria before requesting any test and undergoing a sequential diagnostic evaluation, mainly using highly sensitive D-dimer by enzyme-linked immunosorbent assay (ELISA) and compression ultrasound. Although venography is the reference standard test for the diagnosis of DVT, its use was not recommended.Annals of Thoracic Medicine 01/2015; 10(1):3-15. · 1.34 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Hintergrund Mit steigendem Alter kommt es zu einem unspezifischen Anstieg von Fibrinabbauprodukten im Blut. Daher fällt eine D-Dimer-Testung zum Ausschluss thrombembolischer Ereignisse bei älteren Patienten häufig falsch-positiv aus. Ziel dieser Studie war es, einen altersadjustierten D-Dimer-Grenzwert zu validieren und anschließend dessen Nutzen für ältere Patienten zu beurteilen. Methode In einer retrospektiven Kohorte von Patienten der interdisziplinären Notaufnahme (n = 1033) mit dem Verdacht einer akuten Lungenembolie und/oder tiefen Beinvenenthrombose (LE/TVT) wurden mittels Receiver-Operating-Characteristic(ROC)-Kurvenanalyse altersadjustierte Grenzwerte für D-Dimere berechnet. Anschließend wurden der Patientenanteil mit normwertigen D-Dimeren bzw. falsch-negativen Testresultaten sowie die Anzahl notwendiger Testungen („number needed to test“, NNT) für den konventionellen D-Dimer-Grenzwert mit dem altersadjustierten D-Dimer-Grenzwert verglichen. Ergebnisse Anhand des konventionellen D-Dimer-Grenzwerts von 0,5 mg/l wurde eine LE/TVT bei 68 % der Patienten ausgeschlossen, während dies unter Verwendung des altersadjustierten Grenzwerts [Alter (Jahre) × 0,016 mg/l] bei 77 % der Patienten möglich war. Bei Patienten über 70 Jahre konnte die negative Vorhersagegenauigkeit zum Ausschluss einer LE/TVT mittels altersadjustierter Grenzwerte am deutlichsten erhöht werden. Die Fehlerquote des altersadjustierten D-Dimer-Grenzwerts betrug 0,8 % (95%-Konfidenzintervall 0,3–1,6 %). Schlussfolgerung Durch die Verwendung der altersadjustierten D-Dimer-Grenzwerte wird der Anteil älterer Patienten, bei denen ein akutes thrombembolisches Ereignis ausgeschlossen werden kann, erhöht.Medizinische Klinik - Intensivmedizin und Notfallmedizin. 06/2014;
- [Show abstract] [Hide abstract]
ABSTRACT: In elderly patients, an unspecific increase of fibrin degradation products in blood is observed. Thus, the D-dimer test to rule out thromboembolic events has a high false-positive rate in elderly patients. Our aim was to validate an age-adjusted D-dimer cut-off and to assess its utility in elderly patients. In a retrospective cohort of outpatients (n = 1033) presenting to our emergency department with suspected acute pulmonary embolism and/or deep vein thrombosis (PE/DVT), age-adjusted D-dimer cut-off values were derived using receiver operating characteristic (ROC) curve analysis. Subsequently, the proportion of patients with normal D-dimer and false-negative test results, respectively, and the number needed-to-test (NNT) were compared for conventional and age-adjusted cut-off values. Using the conventional cut-off of 0.5 mg/dl, PE/DVT could be excluded in 68 % of patients, whereas the age-adjusted cut-off [(age × 0.016) mg/l] ruled out 77 % of patients. Particularly in patients > 70 years, the negative prediction accuracy of excluding a PE/DVT increased explicitly. The failure rate of the age-adjusted cut-off value was 0.8 % (95 % confidence interval 0.3-1.6 %). The age-adjusted D-dimer cut-off point increases the proportion of older patients, in whom an acute thromboembolic event can be excluded.Medizinische Klinik, Intensivmedizin und Notfallmedizin. 07/2013;
Hindawi Publishing Corporation
Emergency Medicine International
Volume 2010, Article ID 185453, 4 pages
Accuracyof D-Dimers to RuleOutVenousThromboembolism
Events acrossAge Categories
G.DerSahakian,Y.E.Claessens,J. C.Allo,J. Kansao,G.Kierzek,and J. L.Pourriat
Emergency Department, Hˆ otel Dieu-Cochin Hospital, Paris Descartes University, Assistance Publique-Hˆ opitaux de Paris,
Place du Parvis Notre-Dame, 75004 Paris, France
Correspondence should be addressed to G. Der Sahakian, email@example.com
Received 21 January 2010; Revised 29 May 2010; Accepted 18 June 2010
Academic Editor: Massimo Gallerani
Copyright © 2010 G. Der Sahakian et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Background. Strategies combining pretest clinical assessment and D-dimers measurement efficiently and safely rule out venous
thromboembolism events (VTE) in low- and intermediate-risk patients. Objectives. As process of ageing is associated with altered
concentrations of coagulation markers including an increase in D-dimers levels, we investigated whether D-dimers could reliably
department during the 6-month period with low or intermediate risk of VTE who also received additional diagnostic procedures.
Results. 67 patients had VTE with D-dimers levels above the threshold, and 3 patients displayed D-dimers levels below the
threshold. We observed that specificity of D-dimers test decreased in an age-dependent manner. However, sensitivity and negative
predictive value remained at very high level in each age category including older patients. Conclusion. We conclude that, even
though D-dimers level could provide numerous false positive results in elderly patients, its high sensitivity could reliably help
physicians to exclude the diagnosis of VTE in every low- and intermediate-risk patient.
Venous thromboembolism events (VTE) are common disor-
ders with major impact on clinical and economic outcomes
safely rule out the occurrence of VTE especially in the setting
of emergency medicine. Several studies have underlined
that D-dimers level below 500ng/ml reliably excluded the
diagnosis of VTE in patients previously identified by clinical
pretest evaluation as low- or intermediate-risk patients [2–
7]. The use of combined strategies including both clinical
assessment and D-dimers measurement have been endorsed
by most professional societies as they improve diagnosis with
acceptable cost efficiency. As frequency of VTE increases
with age, diagnostic strategies should be adjusted to elderly
age groups of patients. However, interpretation of D-dimers
level is altered in older patients, as ageing or underlying
clinical conditions may activate coagulation. Consequently,
performance of diagnostic strategies using D-dimers varies
of Cardiology recommended the avoidance of D-dimers
measurement in patients older than 80 years of age .
We therefore assessed the clinical value of D-dimers test
across age categories in patients presenting in the emergency
department with low- or intermediate-risk of VTE.
We conducted a prospective, observational, and single
centred study in the emergency department of a tertiary-
level teaching hospital during the 6-month period. Study
protocol and procedures complied with the principles of the
Declaration of Helsinki. The institutional review board for
the protection of human subjects in our hospital approved
the study protocol and patients information procedures
(study notification letter).
We enrolled all consecutive consenting adults (18 years
old or above) who required D-dimers blood test for the diag-
nostic purposes of venous thromboembolism events (VTE),
that is, deep venous thrombosis (DVT) and pulmonary
embolism (PE). Diagnostic probability of VTE was based on
the Wells score dedicated to DVT or PE, as required [3–6].
2Emergency Medicine International
Patients were excluded if they refused to participate in
the study, if they were less than 18 years of age, if they were
pregnant, if they were perceived as a high risk for VTE after
at the end of the study period.
Patients’ management was based on currently recom-
mended practice guidelines. Briefly, physicians were edu-
cated on diagnostic procedures for DVT and PE including
the Wells pretest clinical scoring system, and computerized
procedures were available at the bedside. According to Wells
scores, D-dimers blood levels were required for the patients
indicating low or intermediate probability for VTE. The
attending physician made the score-based decision and pro-
ceeded to baseline data collection through patient interviews
and standardized review of medical records. Baseline data
consisted of demographic data (age, gender), coexisting
illnesses, symptoms, and Wells score calculation for VTE
probability. Patients were stratified by their age in the fol-
lowing eight age cohorts: <30 years of age (years), 31–39, 40–
49, 50–59, 60–69, 70–79, 80–89, and >90 years. Pulmonary
angiography on a multislice computerised tomography (CT)
scan and lower limb compression ultrasonography were
VTE after the diagnostic procedures, if required, and at the
end of a 3-month followup.
D-dimers were measured using the ELISA quick test
VIDAS. Patients were positive for D-dimers if the level was
>500ng/ml; otherwise, patients were considered negative for
Our objective was to assess the overall effectiveness
of D-dimers levels to detect VTE across age categories in
patients with low and intermediate risk of VTE. A value of
P < .05 was considered statistically significant. Comparisons
between patients with or without VTE were made by the
χ2test for categorical variables and the Mann Whitney
test for continuous variables. All variables were analyzed
based on their association with the presence of a thrombosis
(>500ng/ml) having or not a VTE, using Fisher’s exact test.
Sensitivity, specificity, negative predictive value of D-dimers,
and their 95% confidence interval (95%CI) were calculated
for each age class.
All tests were two-sided, and P-values below .05 were
considered statistically significant. All statistical analyses
were performed using SAS software V9.1 (SAS institute,
During the study period, 1,042 patients were enrolled; 38
could not be evaluated for the primary end point and 1,004
could be evaluated at 3 months for both D-dimers level and
the presence of PE or DVT. Among these, 539 were negative
for D-dimers and 465 were positive. Mean age was 74 years
(18–93 years) for patients negative for D-dimers (P <,001).
Only 12% of patients aged 70 or above had negative D-
dimers. In the group of patients positive for D-dimers, 67
(14%) had a diagnosis of either DVT (n = 15, 3%) or PE
(n = 52, 11%). In patients with negative D-dimers, 3 were
identified with VTE at the end of the followup (one patient
with DVT, two with PE). We observed that incidence of VTE
roughly increased with age, corresponding to 5% or less in
the younger patients, and reaching 13% in 80 to 89 age
Overall sensitivity and specificity of D-dimers were
95,7% [95% CI: 0,880–0,991] and 57,4% [95% CI: 0.542–
0.605], respectively. Negative and positive predictive values
0.179]. The performance of D-dimers across age categories
and dramatically decreased in elderly especially in those who
were 80 years or older. Conversely, sensitivity of the test
remained above 80%, and the negative predictive value of D-
dimers was maintained across age cohorts (Table 1).
Coagulation is a tightly amplified and regulated process.
It generates an intricately related network that contributes
to the adequate response against the primary insult .
During the ageing, these mechanisms are deregulated.
More precisely, with ageing, there is an imbalance in the
coagulation cascade that navigates towards a prothrombotic
lation system in older patients characterized by higher levels
of fibrinogen, factors VII, VIII, IX, and other clotting factors
[10, 11]. The analysis of a large cohort from the North
American Cardiovascular Health Study pointed out the
association between clotting and inflammatory markers and
frailty in elderly population even in the absence of clinically
relevant comorbidity . In 1995, Mari et al. reported
that baseline coagulation activity physiologically increased
in centenarians with increased thrombin concentration and
elevated level of D-dimers . These data predicted the
weak significance of D-dimers elevation in older patients.
Few elderly patients were included in the studies report-
ing procedures to rule out VTE using a decision making
process based upon D-dimers threshold. In 2001, Wells et
al. published the strategy for diagnosis of PE in patients
whose mean age was 50.5 years (18.4), ranging from 16 to
93 years . Two years later, the same authors published
an approaching strategy in patients with suspected DVT
whose mean age was 58 years . These cornerstone studies
did not specifically assess the relevance of these strategies
in older patients. Rathbun et al., in 2004, evaluated such
procedures in patients that were from 19 to 83 years .
One prospective and three retrospective studies previously
assessed the performance of D-dimers in elderly patients
visiting the emergency department with suspected PE [13–
17]. These studies used various methods for D-dimers mea-
surement. Sensitivity was almost 100% [14, 15] across all age
groups, and the negative predictive value remained clinically
relevant in elderly, ranging from 82.4% to 100%. However,
specificity decreased below 50% after 70 years, dropping to
14.3% in the very old patients. This suggested that D-dimers
Emergency Medicine International3
Table 1: Performance of the D-dimers “Vidas” assay according to age categories in 1,004 patients with suspected venous thromboembolic
events (VTE). 95%CI: 95% confidence interval.
Age categories (years) No. of patients
No. of VTE
Negative predictive value [95%CI]
should be used cautiously to rule out, diagnosis of VTE in
elderly population. Additionally, increasing D-dimers cutoff
resultedin anunacceptablelossof sensitivity witha marginal
increase of specificity [11, 13, 17].
In this paper, we have demonstrated that negative pre-
dictive value of D-dimers measurement using the reference
method efficiently ruled out the diagnosis of VTE in low-
or intermediate-risk patients across age categories whereas
specificity decreased in an age-dependent manner. The
overall sensitivity of D-dimers was relatively low—95,7%
[95%CI 0.880–0.991]—as compared to previous studies
whose sensitivity was nearly 100%. Conversely, we observed
a high overall specificity of D-dimers that dramatically
dropped in the older patients, as previously reported. A
former study reported decreased sensitivity (22% to 14%)
and specificity (31% to 22%) in patients older than 75 years
. Similar results were observed in patients older than 70
years [13, 14]. In our paper, the number of patients with D-
dimers level above the threshold increased with age, and only
3% of patients above 90 years had negative D-dimers.
Since specificity of D-dimers was poor in patients
older than 80, the European Society of Cardiology 
recommended that D-dimers are not to be used in the
latter population no matter what pretest risk category for
VTE is. However, negative D-dimers still rule out VTE
in older patients. As PE occurs most frequently and since
ultrasounds are of a minor help in this condition, our results
as well as other results point out the applicability of the
rule-out strategies for PE in the frailest elderly population.
Rule-out strategies could spare the elderly patients from
potentially detrimental investigations requiring intravenous
This study has several limitations. We conducted a single
centre study; patients were excluded if they were perceived
as a high risk for VTE after calculation of the Wells score;
the number of consecutive patients enrolled in this study was
not evaluated a priori; in addition, the number of patients is
heterogeneous across the age cohorts and some age cohorts,
are probably underrepresented.
In conclusion, we recommend the use of D-dimer testing in
elderly patients to rule out pulmonary embolism in low- and
intermediate-risk patients where its negative predictive value
and sensitivity remain 100%.
The authors wish to thank Pierre Toulon, MD, Ph.D., from
the statistical department; and Valeria RAC, M.D., Ph.D.,
(Rescu, Keenan Research Centre, Li Ka Shing Knowledge
Institute, St. Michael’s Hospital, University of Toronto,
Toronto Ontario Canada) for reviewing the paper.
 R. H. White, “The epidemiology of venous thromboem-
bolism,” Circulation, vol. 107, no. 23, pp. I4–I8, 2003.
 P. S. Wells, D. R. Anderson, M. Rodger et al., “Evaluation of
D-dimer in the diagnosis of suspected deep-vein thrombosis,”
The New England Journal of Medicine, vol. 349, no. 13, pp.
 P. S. Wells, D. R. Anderson, M. Rodger 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,” Annals of Internal
Medicine, vol. 135, no. 2, pp. 98–107, 2001.
 P. S. Wells, C. Owen, S. Doucette, D. Fergusson, and H. Tran,
“Does this patient havedeepvein thrombosis?” Journal of the
American Medical Association, vol. 295, no. 2, pp. 199–207,
 R. Manfredini, “D-dimer for the diagnosis of acute venous
thromboembolism in the emergency department: a Janus-face
marker,” Internal and Emergency Medicine, vol. 1, no. 1, pp.
 D. Imberti, “D-dimer testing: advantages and limitations in
emergency medicine for managing acute venous thromboem-
 S. W. Rathbun, T. L. Whitsett, S. K. Vesely, and G. E. Raskob,
“Clinical utility of d-dimer in patients with suspected pul-
monary embolism and nondiagnostic lung scans or negative
CT findings,” Chest, vol. 125, no. 3, pp. 851–855, 2004.
 H. R. B¨ uller, G. Agnelli, R. D. Hull, T. M. Hyers, M. H.
Prins, and G. E. Raskob, “Antithrombotic therapy for venous
thromboembolic disease: the Seventh ACCP Conference on
Antithrombotic and Thrombolytic Therapy: evidence-based
guidelines,” Chest, vol. 126, supplement 3, pp. 401–428, 2004.
4Emergency Medicine International
 S. M. Opal and C. T. Esmon, “Functional relationships
between coagulation and the innate immune response and
their respective roles in the pathogenesis of sepsis,” Critical
Care, vol. 7, no. 1, pp. 23–38, 2003.
 D. Mari, P. M. Mannucci, R.Coppola, B. Bottasso, K. A. Bauer,
and R. D. Rosenberg, “Hypercoagulability in centenarians:the
paradox of successful aging,” Blood, vol. 85, no. 11, pp. 3144–
 A. Sagripanti and A. Carpi, “Natural anticoagulants, aging,
and thromboembolism,” Experimental Gerontology, vol. 33,
no. 7-8, pp. 891–896, 1998.
 H. J. Cohen, T. Harris, and C. F. Pieper, “Coagulation and
activation of inflammatory pathways in the development of
functional decline and mortality in the elderly,” American
Journal of Medicine, vol. 114, no. 3, pp. 180–187, 2003.
 B. Tardy, B. Tardy-Poncet, A. Viallon et al., “Evaluation of D-
 M. Righini, C. Goehring, H. Bounameaux, and A. Perrier,
for pulmonary embolism,” American Journal of Medicine, vol.
109, no. 5, pp. 357–361, 2000.
 M. Righini, P. de Moerloose, G. Reber, A. Perrier, and H.
Bounameaux, “Should the D-dimer cut-off value be increased
in elderly patients suspected of pulmonary embolism ?”
Thrombosis and Haemostasis, vol. 85, no. 4, p. 744, 2001.
 M. S¨ ohne, P. W. Kamphuisen, P. J. W. B. Van Mierlo, and H. R.
B¨ uller, “Diagnostic strategy using a modified clinical decision
rule and D-dimer test to rule out pulmonary embolism in
elderly in- and outpatients,” Thrombosis and Haemostasis, vol.
94, no. 1, pp. 206–210, 2005.
 P. L. Harper, E. Theakston, J. Ahmed, and P. Ockelford, “D-
dimer concentration increases with age reducing the clinical
value of the D-dimer assay in the elderly,” Internal Medicine
Journal, vol. 37, no. 9, pp. 607–613, 2007.
 M. L. Levin, “Acute renal failure in the elderly: strategies
for prevention. How the physiologic effects of aging increase
nephrotoxic risk,” The Journal of Critical Illness, vol. 10, no.
11, pp. 783–793, 1995.