D-dimer

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Editor(s)-In-Chief: C. Michael Gibson, M.S., M.D. [1], The APEX Trial Investigators; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2] The APEX Trial Investigators; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [3]

Overview

D-dimer is a fibrin degradation product. D-dimer levels are elevated in the plasma after the acute formation of a blood clot. The majority of patients with pulmonary embolism have some degree of endogenous fibrinolysis with an elevation in D-dimer levels, therefore there is a high negative predictive value in ruling out a pulmonary embolism when D-dimer levels are low. However a wide range of diseases are associated with mild degree of fibrinolysis which elevate D-dimer levels and contribute towards a reduced specificity and a poor positive predictive value of a high D-dimer level. This means that it is more likely that one can rule out a PE with a low D-dimer level, but cannot necessarily confirm the diagnosis of a PE based on a high D-dimer level. Other disease states that can also have a high d-dimer level include pneumonia, congestive heart failure (CHF), myocardial infarction (MI) and malignancy. False-negative values may occur in patients with prolonged symptoms of venous thromboembolism (≥14 days), patients on therapeutic heparin therapy, and patients with suspected deep venous thrombosis on oral anticoagulation, as these patients have will have low D-dimer levels in the presence of a PE.[1][2]

Historical Perspective

D-dimer testing was originally developed in the diagnosis of disseminated intravascular coagulation. In the 1990s, they turned out to be useful in diagnosing thromboembolic process.

Physiology

Fibrin degradation products (FDPs) are formed whenever fibrin is broken down by enzymes (e.g. plasmin). Determining FDPs is not considered useful, as this does not indicate whether the fibrin is part of a blood clot (or being generated as part of inflammation).

D-dimers are unique in that they are the breakdown products of a fibrin mesh that has been stabilized by Factor XIII. This factor crosslinks the E-element to two D-elements. This is the final step in the generation of a thrombus.

Plasmin is a fibrinolytic enzyme that organizes clots and breaks down the fibrin mesh. It cannot, however, break down the bonds between one E and two D units. The protein fragment thus left over is a D-dimer.

Principles of D-dimer testing


D-Dimer Test

D-dimer assays rely on monoclonal antibodies to bind to this specific protein fragment. The first patented MoAb of the kind was D Dimer-3B6/22, although others have been developed.

Indications

D-dimer testing is of clinical use when there is a suspicion of deep venous thrombosis (DVT) or pulmonary embolism (PE). In patients suspected of disseminated intravascular coagulation (DIC), D-dimers may aid in the diagnosis.

For DVT and PE, there are various scoring systems that are used to determine the a priori clinical probability of these diseases; the best-known were introduced by Wells et al (2003).

  • For a very high score, or pretest probability, a D-dimer will make little difference and anticoagulant therapy will be initiated regardless of test results, and additional testing for DVT or pulmonary embolism may be performed.
  • For a moderate or low score, or pretest probability:[3]
    • A negative D-dimer test will virtually rule out thromboembolism: the degree to which the d-dimer reduces the probability of thrombotic disease is dependent on the test properties of the specific test used in your clinical setting: most available d-dimer tests with a negative result will reduce the probability of thromboembolic disease to less than 1% if the pretest probability is less than 15-20%
    • If the D-dimer reads high, then further testing (ultrasound of the leg veins or lung scintigraphy or CT scanning) is required to confirm the presence of thrombus. Anticoagulant therapy may be started at this point or withheld until further tests confirm the diagnosis, depending on the clinical situation.

In some hospitals, they are measured by laboratories after a form is completed showing the probability score and only if the probability score is low or intermediate. This would reduce the need for unnecessary tests in those who are high-probability.[4]

Reference Range

Most sampling kits have 0-300 ng/ml as normal range. Values exceeding 250, 300 or 500 ng/ml (different for various kits) are considered positive.

For patients over age 50 a value of ageX10 may be abnormal.[5][6][7]

Types of Assays

  • ELISA (e.g. Vidas)
  • Latex turbidimetric assay (automated immunoassay, e.g. Roche Tina-quant, MDA D-dimer)
  • Enhanced microlatex
  • Latex-enhanced photometric
  • Whole Blood Agglutination (e.g. SimpliRED)
  • Rapid Lateral Flow (e.g. Clearview Simplify)

Test Properties

Various kits have a 93-95% sensitivity and about 50% specificity in the diagnosis of thrombotic disease.[8]

  • False positive readings can be due to various causes: liver disease, high rheumatoid factor, inflammation, malignancy, trauma, pregnancy, recent surgery as well as advanced age
  • False negative readings can occur if the sample is taken either too early after thrombus formation or if testing is delayed for several days. Additionally, the presence of anti-coagulation can render the test negative because it prevents thrombus extension.
  • Likelihood ratios are derived from sensitivity and specificity to adjust pretest probability.

D-dimer and Thromboembolism

Abnormal Levels

Plasma D-dimer levels > 500 ng/mL are abnormal.[9]

Sensitivity and Specificity

Sensitivity[9]

ELISA (p=0.020), quantitative rapid ELISA (p=0.016) and semi-quantitative ELISA (p=0.047) are shown to be statistically superior to whole-blood agglutination.

Specificity[9]

Qualitative rapid ELISA has shown to be statistically superior to ELISA (p=0.004), quantitative rapid ELISA (p=0.002), semi-quantitative rapid ELISA (p=0.001), quantitative (p=0.005) and semi-quantitative latex agglutination assays (p=0.019).


Method Sensitivity (95% CI) Specificity (95% CI) Positive Likelihood Ratio (95% CI) Negative Likelihood Ratio (95% CI) Time to obtain Results
Enzyme-linked immunosorbent assay (ELISA) 0.95 (0.85 to 1.00) NS NS 0.13 (0.03 to 0.58) ≥ 8 hours
Quantitative rapid ELISA 0.95 (0.83 to 1.00) NS NS 0.13 (0.02 to 0.84) 30 mins
Semi-Quantitative rapid ELISA 0.93 (0.79 to 1.00) NS NS 0.20 (0.04 to 0.96) 10 mins
Qualitative rapid ELISA NS 0.68 (0.50 to 0.87) NS 0.11 (0.01 to 0.93) 10 mins
Quantitative Latex Agglutination NS NS NS NS 10-15 mins
Semi-quantitative Latex Agglutination NS NS NS 0.17 (0.04 to 0.78) 5 mins
Whole-Blood Agglutination NS 0.74 (0.60 to 0.88) NS NS 2 mins

Hemodynamically Stable Patients

Incidence of Thromboembolic Events in Hemodynamically Stable Patients

Condition Incidence of thromboembolic event (%)
Patients not receiving anticoagulation with negative CT findings. 1.5%[10][11]
Patients with a high d-dimer level 1.5%
Patients with a normal d-dimer level 0.5%[10]
  • Multidetector CT is indicated in hemodynamically stable patients with a high clinical probability of PE and/or patients with elevated plasma d-dimer levels secondary to the lack of specificity.[11][12]
  • In patients with low-to-moderate suspicion of PE, a normal D-dimer level is considered sufficient to exclude the possibility of pulmonary embolism.[13]

Flowchart Summarizing the Role of D-dimer in the Diagnosis of PE

 
 
 
Patients with suspection of Pulmonary embolism
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinically Low or Moderate
 
 
 
 
Clinically High
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D-Dimer Positive
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D-Dimer Negative
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No treatment
 
Further Tests
 
Further Tests


A new D-Dimer (DDMR) analyzer has shown to be more accurate in excluding patients with a low clinical pre-test probability.[14]

ESC 2008 Guideline Recommendations [15]

Suspected Non High-risk PE Patients (DO NOT EDIT)[15]

Class I
"1. Plasma D-dimer measurement is recommended in emergency department patients to reduce the need for unnecessary imaging and irradiation, preferably with the use of a highly sensitive assay. (Level of Evidence: A) "

Low Clinical Probability (DO NOT EDIT)[15]

Class I
"1. Normal D-dimer level using either a highly or moderately sensitive assay excludes pulmonary embolism. (Level of Evidence: A) "

Intermediate Clinical Probability (DO NOT EDIT)[15]

Class I
"1. Normal D-dimer level using a highly sensitive assay excludes pulmonary embolism. (Level of Evidence: A) "
Class IIa
"1. Further testing should be considered if D-dimer level is normal when using a less sensitive assay. (Level of Evidence: B) "

High Clinical Probability (DO NOT EDIT)[15]

Class III
"1. D-dimer measurement is not recommended in high clinical probability patients as a normal result does not safely exclude pulmonary embolism even when using a highly sensitive assay. (Level of Evidence: C) "

References

  1. Bruinstroop E, van de Ree MA, Huisman MV (2009). "The use of D-dimer in specific clinical conditions: a narrative review". Eur J Intern Med. 20 (5): 441–6. doi:10.1016/j.ejim.2008.12.004. PMID 19712840.
  2. Agnelli G, Becattini C (2010). "Acute pulmonary embolism". N Engl J Med. 363 (3): 266–74. doi:10.1056/NEJMra0907731. PMID 20592294.
  3. Wells PS, Anderson DR, Rodger M; et al. (2003). "Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis". N. Engl. J. Med. 349 (13): 1227–35. doi:10.1056/NEJMoa023153. PMID 14507948.
  4. Rathbun, SW (2004). "Clinical utility of D-dimer in patients with suspected pulmonary embolism and nondiagnostic lung scans or negative CT findings". Chest (125): 851. Unknown parameter |coauthors= ignored (help); |access-date= requires |url= (help)
  5. Schouten HJ, Geersing GJ, Koek HL, Zuithoff NP, Janssen KJ, Douma RA; et al. (2013). "Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis". BMJ. 346: f2492. doi:10.1136/bmj.f2492. PMC 3643284. PMID 23645857.
  6. van Es J, Mos I, Douma R, Erkens P, Durian M, Nizet T; et al. (2012). "The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded". Thromb Haemost. 107 (1): 167–71. doi:10.1160/TH11-08-0587. PMID 22072293.
  7. Douma RA, le Gal G, Söhne M, Righini M, Kamphuisen PW, Perrier A; et al. (2010). "Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts". BMJ. 340: c1475. doi:10.1136/bmj.c1475. PMID 20354012.
  8. Schrecengost JE, LeGallo RD, Boyd JC, Moons KG, Gonias SL, Rose CE Jr, Bruns DE. Comparison of diagnostic accuracies in outpatients and hospitalized patients of D-dimer testing for the evaluation of suspected pulmonary embolism. Clin Chem 2003;49:1483-90. PMID 12928229.
  9. 9.0 9.1 9.2 Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, Biel RK, Bharadia V, Kalra NK (2004). "D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review". Annals of Internal Medicine. 140 (8): 589–602. PMID 15096330. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  10. 10.0 10.1 Perrier A, Roy PM, Sanchez O, Le Gal G, Meyer G, Gourdier AL; et al. (2005). "Multidetector-row computed tomography in suspected pulmonary embolism". N Engl J Med. 352 (17): 1760–8. doi:10.1056/NEJMoa042905. PMID 15858185. in: J Fam Pract. 2005 Aug;54(8):653, 657
  11. 11.0 11.1 van Belle A, Büller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW; et al. (2006). "Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography". JAMA. 295 (2): 172–9. doi:10.1001/jama.295.2.172. PMID 16403929.
  12. Gupta RT, Kakarla RK, Kirshenbaum KJ, Tapson VF (2009). "D-dimers and efficacy of clinical risk estimation algorithms: sensitivity in evaluation of acute pulmonary embolism". AJR Am J Roentgenol. 193 (2): 425–30. doi:10.2214/AJR.08.2186. PMID 19620439.
  13. Bounameaux H, de Moerloose P, Perrier A, Reber G (1994). "Plasma measurement of D-dimer as diagnostic aid in suspected venous thromboembolism: an overview". Thromb. Haemost. 71 (1): 1–6. PMID 8165626.
  14. Gosselin RC, Wu JR, Kottke-Marchant K, Peetz D, Christie DJ, Muth H; et al. (2012). "Evaluation of the Stratus® CS Acute Care™ D-dimer assay (DDMR) using the Stratus® CS STAT Fluorometric Analyzer: A prospective multisite study for exclusion of pulmonary embolism and deep vein thrombosis". Thromb Res. doi:10.1016/j.thromres.2011.12.015. PMID 22245223.
  15. 15.0 15.1 15.2 15.3 15.4 Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP (2008). "Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)". Eur. Heart J. 29 (18): 2276–315. doi:10.1093/eurheartj/ehn310. PMID 18757870. Retrieved 2011-12-07. Unknown parameter |month= ignored (help)

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