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.

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:
  • 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.

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.

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.

• 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.

Sensitivity and Specificity

Sensitivity

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

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%
Patients with a high d-dimer level	1.5%
Patients with a normal d-dimer level	0.5%

• 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.

• In patients with low-to-moderate suspicion of PE, a normal D-dimer level is considered sufficient to exclude the possibility of pulmonary embolism.

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.

ESC 2008 Guideline Recommendations

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

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)

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)

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)

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) "