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D-Dimer for Pulmonary EmbolismGrégoire 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 byher 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 personalor family history of venous thrombosis and did not have any recent surgery, trauma, oradmission to hospital. Her long-term medications included fluoxetine, vitamin D, andhydrochlorothiazide.

On examination, temperature was 38.3°C (101°F ), blood pressure was157/78 mm Hg, pulse rate was 82 beats per minute, and respiratory rate was 20 breathsper minute. Oxygen saturation was 97% in room air. She had a regular heart rate with amild systolic murmur; her jugular venous pressure was normal; and lung auscultationrevealed reduced air entry at the left base. She had no leg swelling and no pain on calfpalpation. Laboratory testing results are reported in Table 1. The attending physicianraised the diagnosis of a pulmonary embolism (PE) among the differentials. The clinicalprobability of PE was unlikely (Wells score).

AnswerC. D-dimer test result is positive but below the patient’s age-adjusted cutoff. PE is ruled out.

Test CharacteristicsD-dimers result from the fibrinolysis of acute thrombi. Enzyme-linked immunosorbent assay (ELISA) and immunoturbidimetricD-dimer assays are highly sensitive for the diagnosis of PE.

The D-dimer test should beused in combination with apretest clinical probabilityassessment (Table 2). The

D-dimer is useful only in patients with a low-intermediate orunlikely pretest clinical probability of PE, as assessed by avalidated clinical decision rule.1,2 It should not be used in patientswith a high/likely pretest clinical probability. Systematic reviewsreport a sensitivity of greater than 95% and negative likelihoodratios of 0.10 for ELISA or immuneturbidimetric assays, with aspecificity of 40% and a positive likelihood ratio of 1.64.3 Usinga cutoff value of 500 ng/mL, a negative D-dimer assay safelyrules out the diagnosis of PE in patients with a low-intermediateor unlikely clinical probability. This was demonstrated in severaloutcome studies in which patients with a low-intermediate orunlikely pretest probability and a negative D-dimer test resultwere left untreated and followed up for 3 months (ie, the3-monthr i s k o f ve n o u s t h r o m b o e m b o l i s m wa s 0.1 4% [ 9 5% C I ,

0.05%-0.41%], lower than the risk observed after a negative pul-monary angiography).4

Conversely, because D-dimers increase in many other clinicalsituations (eg, infection, inflammation, malignancy, postsurgicalstatus, pregnancy), the specificity of the test is low (approxi-mately 50%) and as a result, a positive D-dimer test is not diag-nostic for PE.

The Medicare midpoint reimbursement is $18.77 for a quanti-tative D-dimer test.5

Application of Test Results to This PatientThe D-dimer test result for this patient was 68 ng/mL. Thisresult indicates a positive D-dimer test as per most commercialassays (conventional cutoff value 500 ng/mL). Given the lowspecificity of the test, a high D-dimer level never rules in the diag-nosis of PE. Patients with positive D-dimer results should undergoan imaging test, such as a computed tomography pulmonaryangiography (CTPA) or a ventilation-perfusion lung scan.6 How-ever, D-dimer levels increase with age, and as a result, the propor-tion of patients in whom the diagnosis may be ruled out on thebasis of a negative D-dimer test decreases with age—only 5% ofpatients older than 80 years have a negative D-dimer, as com-pared with more than 50% of patients aged 40 years oryounger.7 An age-adjusted D-dimer cutoff value was recentlyderived and validated in several retrospective analyses and oneprospective management outcome study.8,9 D-dimer results are

Quiz at jama.com

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. Thediagnosis of PE is confirmed.

C. D-dimer test result is positive butbelow her age-adjusted cutoff. PEis ruled out.

D. D-dimer test result is positivedue to active malignancy. PE isruled out.

Table 1. Laboratory Values for Diagnosis of Pulmonary Embolism

Laboratory Test Patient’s Values Reference Range

Hemoglobin, g/dL 12.0 14.0-17.5

White blood cell count, × 103/μL 7.4 4.5-11.0

Platelet count, × 103/μL 359 150-350

Serum creatinine, mg/dL 1.26 0.6-1.2

D-dimer, ng/mL 680 <500

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

Clinical Review & Education

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typically reported without providing the age-adjusted upper limitof normal. However, the age-adjusted cutoff value is easy to com-pute: in patients aged 50 years or more, a D-dimer level belowtheproduct of their age multiplied by 10 (eg, 820 ng/mL in this82-year-old patient) appears to safely rule out PE without anyimaging test.

What Are Alternative Diagnostic Testing Approaches?In some centers, most patients with suspected PE are directly re-ferred for a CTPA without prior use of pretest probability assess-ment and D-dimer. The combination of a D-dimer test with a clini-cal probability assessment allows ruling out PE without undergoingan imaging test in approximately one-third of outpatients.4 The costeffectiveness of this approach has been demonstrated.7 Moreover,there is an increasing concern about the risk of cancer in patientsexposed to radiation from medical imaging.10 The D-dimer test rep-resents a safe and reliable option to avoid the use of CTPA in an im-portant proportion of patients with clinically suspected PE.

Patient OutcomeA chest x-ray film revealed a left inferior lobar consolidation. The pa-tient was treated with antibiotics, discharged home on the same day,and asked to follow up with her general practitioner. She had a goodand 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 diagno-sis of PE in approximately one-third of outpatients.

• A positive D-dimer is not diagnostic for PE. Patients with clinicallysuspected PE and positive D-dimer should undergo imaging testsfor PE.

• According to recent studies, PE might be ruled out in patients witha low-intermediate or unlikely pretest probability and D-dimer levelthat is less than their age-adjusted cutoff (ie, patient’s age × 10 inpatients aged 50 years or older).

ARTICLE INFORMATION

Author Affiliations: Thrombosis Program,University of Ottawa, Ottawa, Ontario, Canada(Le Gal, Wells); Division of Hematology, Universityof Ottawa, Ottawa, Ontario, Canada (Le Gal, Wells);Department of Medicine, University of Ottawa,Ottawa, Ontario, Canada (Le Gal, Wells); ClinicalEpidemiology Unit, Ottawa Health ResearchInstitute, Ottawa, Ontario, Canada (Le Gal, Wells);The Ottawa Hospital, Ottawa, Ontario, Canada(Le Gal, Wells); Division of Angiology andHemostasis, Geneva University Hospital, Geneva,Switzerland (Righini).

Corresponding Author: Philip S. Wells, MD, MSc,The Ottawa Hospital, General Campus, 501 SmythRd, 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 havecompleted and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest. DrWells reports receipt of personal fees for serving asa speaker for Bayer Healthcare, BoehringerIngelheim, Biomerieux, and BMS/Pfizer, all of whichwere outside the submitted work. and none werereported. Drs Le Gal and Righini report nodisclosures.

Additional Contribution: We thank the patient forsharing her experience and for granting permissionto publish it.

REFERENCES

1. Le Gal G, Righini M, Roy P-M, et al. Prediction ofpulmonary embolism in the emergencydepartment: the revised Geneva score. Ann InternMed. 2006;144(3):165-171.

2. Wells PS, Anderson DR, Rodger M, et al.Derivation of a simple clinical model to categorizepatients probability of pulmonary embolism:increasing the models utility with the SimpliREDD-dimer. Thromb Haemost. 2000;83(3):416-420.

3. Di Nisio M, Squizzato A, Rutjes AW, Büller HR,Zwinderman AH, Bossuyt PM. Diagnostic accuracyof D-dimer test for exclusion of venousthromboembolism: a systematic review. J ThrombHaemost. 2007;5(2):296-304.

4. Carrier M, Righini M, Djurabi RK, et al. VIDASD-dimer in combination with clinical pre-testprobability to rule out pulmonary embolism:a systematic review of management outcomestudies. Thromb Haemost. 2009;101(5):886-892.

5. Centers for Medicare & Medicaid Services.Clinical Laboratory Fee Schedule. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/ClinicalLabFeeSched/index.html. AccessedJune 27, 2014.

6. Anderson DR, Kahn SR, Rodger MA, et al.Computed tomographic pulmonary angiography vsventilation-perfusion lung scanning in patients withsuspected pulmonary embolism: a randomizedcontrolled trial. JAMA. 2007;298(23):2743-2753.

7. Righini M, Nendaz M, Le Gal G, Bounameaux H,Perrier A. Influence of age on the cost-effectivenessof diagnostic strategies for suspected pulmonaryembolism. J Thromb Haemost. 2007;5(9):1869-1877.

8. Andro M, Righini M, Le Gal G. Adapting theD-dimer cutoff for thrombosis detection in elderlyoutpatients. Expert Rev Cardiovasc Ther. 2013;11(6):751-759.

9. Righini M, Van Es J, Den Exter PL, et al.Age-adjusted D-dimer cutoff levels to rule outpulmonary embolism: the ADJUST-PE study. JAMA.2014;311(11):1117-1124.

10. Ceriani E, Combescure C, Le Gal G, et al. Clinicalprediction rules for pulmonary embolism:a systematic review and meta-analysis. J ThrombHaemost. 2010;8(5):957-970.

Table 2. The Wells Score for Pulmonary Embolisma

Clinical Variable PointsClinical 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 3.0

Pretest Probability Assessment Score PE Prevalence,% (95% CI)b

3 Categories

Low <2 6 (4-8)

Intermediate 2-6 23 (18-28)

High >6 49 (42-56)

2 Categories

Unlikely ≤4 8 (6-11)

Likely >4 34 (29-40)

Abbreviations: DVT, deep venous thrombosis; PE, pulmonary embolism.a Data are from Wells et al.2

b Data are from Ceriani et al.10

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