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]

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.

D-Dimer and Non Thromboembolism Conditions

D-dimer levels physiologically increase with age, making the usefulness of D-dimer among the elderly less significant. The exact mechanism of D-dimer increase with age is poorly understood. It is thought to be related to the expected increase in patient co-morbidities and thrombotic events that occur with age, and that also happen to elevate D-dimer levels. The use of D-dimer in elderly nonetheless remains helpful in diagnosing VTE in low and intermediate risk patients. Age-adjusted D-dimer levels are thought to be useful, especially for the elderly. However, specific age-adjusted values have not been released yet.

Aortic Dissection

Elevated levels of D-dimer lab test has been used to rapidly rule out emergencies such as acute aortic dissection (AAD). More than 15 studies that enrolled more than 400 patients have evaluated the use of D-dimer in AAD. With the absence of specific biomarkers, the clinical diagnosis of AAD remains a challenge for clinicians based on clinical suspicion alone. A meta analysis for D-dimer testing in AAD revealed that D-dimer has 97% sensitivity and 59% specificity in diagnosis of AAD. The diagnostic cut-off D-dimer value for patients with AAD ranges between 0.1 and 0.9 µg/mL., with sensitivities ranging between 100% and 86% respectively. Using D-dimer cut-off value similar to that for PE at a level of 0.5 µg/mL is considered an appropriate level that has a negative predictive value that approximately reaches 100%.

Renal Disease

D-dimer levels is correlated with nephrotic syndrome and other renal diseases. While some postulate that D-dimer elevation is associated with renal clearance, data is conflicting as to whether D-dimer elevation may be less likely correlated with renal clearance as much as it is associated with proteinuria. Nevertheless, the increase of hemostatic markers, such as D-dimer in renal disease, are considered risk factors for VTE in patients with renal disease.

Nephrotic syndrome is considered a hypercoagulable state that is notoriously associated with DVT and PE. Among 100 patients with proteinuria, 53% had elevated D-dimer levels. When proteinuria was more than 1g/24 hours, elevation of D-dimer levels was seen in 69% of patients with proteinuria. D-dimer is believed to be related to the heavy proteinuria in nephrotic syndrome and subsequent hepatic synthesis of fibrinogen, where strong association between D-dimer elevation and hypoalbuminemia is found. It is also suggested that elevated serum fibrinopeptide A, thrombin-antithrombin III complex, along with products of thrombin and prothrombin, and the state of activated hemostasis in nephrotic syndrome causes the elevation of D-dimer with no evidence of clinical thrombosis.

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) "