Clinical Review & Education

JAMA Diagnostic Test Interpretation

D-Dimer for Pulmonary Embolism

Grgoire Le Gal, MD, PhD; Marc Righini, MD; Philip S. Wells, MD, MSc

An 82-year-old woman with bladder cancer and treated hypertension was referred by
her family physician after she reported experiencing a few days history of mild fever,
cough, limited deep inspiration, and left-sided pleuritic chest pain. She had no personal
or family history of venous thrombosis and did not have any recent surgery, trauma, or
admission to hospital. Her long-term medications included fluoxetine, vitamin D, and
hydrochlorothiazide.
On examination, temperature was 38.3C (101F), blood pressure was
157/78 mm Hg, pulse rate was 82 beats per minute, and respiratory rate was 20 breaths
per minute. Oxygen saturation was 97% in room air. She had a regular heart rate with a
mild systolic murmur; her jugular venous pressure was normal; and lung auscultation
revealed reduced air entry at the left base. She had no leg swelling and no pain on calf
palpation. Laboratory testing results are reported in Table 1. The attending physician
raised the diagnosis of a pulmonary embolism (PE) among the differentials. The clinical
probability of PE was unlikely (Wells score).
Table 1. Laboratory Values for Diagnosis of Pulmonary Embolism
Laboratory Test

Patients Values

Reference Range

Hemoglobin, g/dL

12.0

14.0-17.5

White blood cell count, 103/L

7.4

4.5-11.0

Platelet count, 103/L

359

150-350

Serum creatinine, mg/dL

1.26

0.6-1.2

D-dimer, ng/mL

680

<500

HOW DO YOU INTERPRET THESE TEST

RESULTS?

A. D-dimer test result is positive.

Imaging test is required.
B. D-dimer test result is positive. The
diagnosis of PE is confirmed.
C. D-dimer test result is positive but
below her age-adjusted cutoff. PE
is ruled out.
D. D-dimer test result is positive
due to active malignancy. PE is
ruled out.

SI conversion factors: for serum creatinine (mg/dL to mol/L), multiply by 88.4.

Answer
C. D-dimer test result is positive but below the patients ageadjusted cutoff. PE is ruled out.

Test Characteristics
D-dimers result from the fibrinolysis of acute thrombi. Enzymelinked immunosorbent assay (ELISA) and immunoturbidimetric
D-dimer assays are highly sensitive for the diagnosis of PE.
The D-dimer test should be
used in combination with a
pretest clinical probability
Quiz at jama.com
assessment (Table 2). The
D-dimer is useful only in patients with a low-intermediate or
unlikely pretest clinical probability of PE, as assessed by a
validated clinical decision rule.1,2 It should not be used in patients
with a high/likely pretest clinical probability. Systematic reviews
report a sensitivity of greater than 95% and negative likelihood
ratios of 0.10 for ELISA or immuneturbidimetric assays, with a
specificity of 40% and a positive likelihood ratio of 1.64.3 Using
a cutoff value of 500 ng/mL, a negative D-dimer assay safely
rules out the diagnosis of PE in patients with a low-intermediate
or unlikely clinical probability. This was demonstrated in several
outcome studies in which patients with a low-intermediate or
unlikely pretest probability and a negative D-dimer test result
were left untreated and followed up for 3 months (ie, the3-month
risk of venous thromboembolism was 0.14% [95% CI,
1668

0.05%-0.41%], lower than the risk observed after a negative pulmonary angiography).4
Conversely, because D-dimers increase in many other clinical
situations (eg, infection, inflammation, malignancy, postsurgical
status, pregnancy), the specificity of the test is low (approximately 50%) and as a result, a positive D-dimer test is not diagnostic for PE.
The Medicare midpoint reimbursement is $18.77 for a quantitative D-dimer test.5

Application of Test Results to This Patient

The D-dimer test result for this patient was 68 ng/mL. This
result indicates a positive D-dimer test as per most commercial
assays (conventional cutoff value 500 ng/mL). Given the low
specificity of the test, a high D-dimer level never rules in the diagnosis of PE. Patients with positive D-dimer results should undergo
an imaging test, such as a computed tomography pulmonary
angiography (CTPA) or a ventilation-perfusion lung scan.6 However, D-dimer levels increase with age, and as a result, the proportion of patients in whom the diagnosis may be ruled out on the
basis of a negative D-dimer test decreases with ageonly 5% of
patients older than 80 years have a negative D-dimer, as compared with more than 50% of patients aged 40 years or
younger. 7 An age-adjusted D-dimer cutoff value was recently
derived and validated in several retrospective analyses and one
prospective management outcome study.8,9 D-dimer results are

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JAMA Diagnostic Test Interpretation Clinical Review & Education

What Are Alternative Diagnostic Testing Approaches?

Table 2. The Wells Score for Pulmonary Embolisma

Clinical Variable

Points

Clinical signs of DVT

3.0

Recent surgery or immobilization (<1 mo)

1.5

Heart rate >100/min

1.5

Previous history of PE or DVT

1.5

Hemoptysis

1.0

Malignancy

1.0

An alternative diagnosis is less likely than PE

Pretest Probability Assessment

3.0
Score

PE Prevalence,
% (95% CI)b

3 Categories
Low

<2

Intermediate

6 (4-8)

2-6

High

>6

23 (18-28)
49 (42-56)

2 Categories
Unlikely

8 (6-11)

Likely

>4

34 (29-40)

Abbreviations: DVT, deep venous thrombosis; PE, pulmonary embolism.

a

Data are from Wells et al.2

Data are from Ceriani et al.10

typically reported without providing the age-adjusted upper limit

of normal. However, the age-adjusted cutoff value is easy to compute: in patients aged 50 years or more, a D-dimer level belowthe
product of their age multiplied by 10 (eg, 820 ng/mL in this
82-year-old patient) appears to safely rule out PE without any
imaging test.
ARTICLE INFORMATION
Author Affiliations: Thrombosis Program,
University of Ottawa, Ottawa, Ontario, Canada
(Le Gal, Wells); Division of Hematology, University
of Ottawa, Ottawa, Ontario, Canada (Le Gal, Wells);
Department of Medicine, University of Ottawa,
Ottawa, Ontario, Canada (Le Gal, Wells); Clinical
Epidemiology Unit, Ottawa Health Research
Institute, Ottawa, Ontario, Canada (Le Gal, Wells);
The Ottawa Hospital, Ottawa, Ontario, Canada
(Le Gal, Wells); Division of Angiology and
Hemostasis, Geneva University Hospital, Geneva,
Switzerland (Righini).
Corresponding Author: Philip S. Wells, MD, MSc,
The Ottawa Hospital, General Campus, 501 Smyth
Rd, PO Box 206, Ottawa, Ontario K1H 8L6, Canada
(pwells@toh.on.ca).
Section Editor: Mary McGrae McDermott, MD,
Senior Editor.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Wells reports receipt of personal fees for serving as
a speaker for Bayer Healthcare, Boehringer
Ingelheim, Biomerieux, and BMS/Pfizer, all of which
were outside the submitted work. and none were
reported. Drs Le Gal and Righini report no
disclosures.

In some centers, most patients with suspected PE are directly referred for a CTPA without prior use of pretest probability assessment and D-dimer. The combination of a D-dimer test with a clinical probability assessment allows ruling out PE without undergoing
an imaging test in approximately one-third of outpatients.4 The cost
effectiveness of this approach has been demonstrated.7 Moreover,
there is an increasing concern about the risk of cancer in patients
exposed to radiation from medical imaging.10 The D-dimer test represents a safe and reliable option to avoid the use of CTPA in an important proportion of patients with clinically suspected PE.

Patient Outcome
A chest x-ray film revealed a left inferior lobar consolidation. The patient was treated with antibiotics, discharged home on the same day,
and asked to follow up with her general practitioner. She had a good
and uneventful recovery.

Clinical Bottom Line

In combination with a validated clinical decision rule, a negative
D-dimer assay allows the physician to safely rule out the diagnosis of PE in approximately one-third of outpatients.
A positive D-dimer is not diagnostic for PE. Patients with clinically
suspected PE and positive D-dimer should undergo imaging tests
for PE.
According to recent studies, PE might be ruled out in patients with
a low-intermediate or unlikely pretest probability and D-dimer level
that is less than their age-adjusted cutoff (ie, patients age 10 in
patients aged 50 years or older).

REFERENCES

6. Anderson DR, Kahn SR, Rodger MA, et al.

Computed tomographic pulmonary angiography vs
ventilation-perfusion lung scanning in patients with
suspected pulmonary embolism: a randomized
controlled trial. JAMA. 2007;298(23):2743-2753.

1. Le Gal G, Righini M, Roy P-M, et al. Prediction of

pulmonary embolism in the emergency
department: the revised Geneva score. Ann Intern
Med. 2006;144(3):165-171.

7. Righini M, Nendaz M, Le Gal G, Bounameaux H,

Perrier A. Influence of age on the cost-effectiveness
of diagnostic strategies for suspected pulmonary
embolism. J Thromb Haemost. 2007;5(9):1869-1877.

2. Wells PS, Anderson DR, Rodger M, et al.

Derivation of a simple clinical model to categorize
patients probability of pulmonary embolism:
increasing the models utility with the SimpliRED
D-dimer. Thromb Haemost. 2000;83(3):416-420.

8. Andro M, Righini M, Le Gal G. Adapting the

D-dimer cutoff for thrombosis detection in elderly
outpatients. Expert Rev Cardiovasc Ther. 2013;11(6):
751-759.

Additional Contribution: We thank the patient for

sharing her experience and for granting permission
to publish it.

3. Di Nisio M, Squizzato A, Rutjes AW, Bller HR,

Zwinderman AH, Bossuyt PM. Diagnostic accuracy
of D-dimer test for exclusion of venous
thromboembolism: a systematic review. J Thromb
Haemost. 2007;5(2):296-304.
4. Carrier M, Righini M, Djurabi RK, et al. VIDAS
D-dimer in combination with clinical pre-test
probability to rule out pulmonary embolism:
a systematic review of management outcome
studies. Thromb Haemost. 2009;101(5):886-892.

9. Righini M, Van Es J, Den Exter PL, et al.

Age-adjusted D-dimer cutoff levels to rule out
pulmonary embolism: the ADJUST-PE study. JAMA.
2014;311(11):1117-1124.
10. Ceriani E, Combescure C, Le Gal G, et al. Clinical
prediction rules for pulmonary embolism:
a systematic review and meta-analysis. J Thromb
Haemost. 2010;8(5):957-970.

5. Centers for Medicare & Medicaid Services.

Clinical Laboratory Fee Schedule. http://www
.cms.gov/Medicare/Medicare-Fee-for-Service
-Payment/ClinicalLabFeeSched/index.html. Accessed
June 27, 2014.

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