By Giovanni Russi

Deep vein thrombosis (DVT) has an annual incidence of 0.5–1.2 per thousand. When DVT or pulmonary emboloism (PE) is suspected following a clinical evaluation, D-Dimer testing is usually initiated as part of the process to exclude DVT and/or PE. Numerous publications in the past few years have reported that the use of D-Dimer, together with pretest probability (PTP) assessment, is a safe, cost-efficient management strategy for the evaluation of patients presenting to the emergency department with clinically suspected VTE.

The most cost-efficient option among those evaluated for DVT was the use of D-Dimer as the initial test, followed by a single ultrasound if the D-Dimer level was above the cutoff, followed by phlebography in patients with normal ultrasound and high clinical probability for DVT. For PE, the most cost-efficient strategy is similar to the one for DVT, but V/Q scan or helical CT are recommended in case of D-Dimer levels above the cutoff and normal ultrasound.

While there are several D-Dimer assays on the market, not all are easy to use and provide the 100% sensitivity necessary to safely exclude VTE and a high level of specificity desired to enhance the cost-efficiency of the assay by reducing the number of imaging tests required.¹

Assessing Clinical Performance and Cost-Efficiency
Several parameters are considered when assessing the clinical performance of a D-Dimer assay (Figure 1):

•  negative predictive value (NPV);
•  sensitivity;
•  specificity; and
• exclusion rate.

NPV, which represents the percentage of patients with a negative D-Dimer (< the cutoff) who are VTE-negative, is generally the most important feature to consider. The general consensus is that the NPV should be > 97%—the sensitivity of other gold standard techniques, such as venography.

In addition, sensitivity, defined as the proportion of patients with proven VTE who are D-Dimer-positive, should be > 95% to minimize false negative results. However, the specificity, and thus the positive predictive value (PPV), of all D-Dimer assays is low (25%–50%) due to numerous conditions associated with fibrin generation and degradation. Specificity reports are also affected by the prevalence of VTE in the population tested. The exclusion rate, though not widely used, defines the percentage of patients who are negative for VTE and D-Dimer and would, therefore, be safely excluded without further testing.

In general, a cost-efficient D-Dimer assay is one that minimizes costs associated with:

• incorrectly diagnosed patients, such as patients with VTE but with D-Dimer below the cutoff;
• use of one or more imaging techniques, such as lower limb venous compression ultrasonography (CUS) and venography, to assess the final diagnosis, specifically those for the false positive patients, such as patients with D-Dimer above the cutoff but with no VTE; and
• treatment of patients, in particular when the final diagnosis for VTE is not accurate.

Finally, when comparing the clinical performances and cost-efficiency of different D-Dimer assays, it is important to determine whether the total number of patients was similar, the patient enrollment was conducted with very similar criteria, and the prevalence of VTE was very similar. This is because the specificity of D-Dimer assays changes in relation to the frequency of the pathology within the population tested. More specifically, D-Dimer results increase in hospitalized patients, the elderly, pregnant women, and patients with concomitant diseases such as cancer or infection. It is also important that these types of studies involve only consecutive outpatients with a first suspected episode of DVT or PE. Furthermore, the patient outcome should be assessed with imaging techniques and a 3-month follow-up exam.

HemosIL D-Dimer HS
HemosIL D-Dimer HS (Instrumentation Laboratory, Lexington, Mass) is an automated, latex-enhanced immunoassay for the quantitative determination of D-Dimer in human citrated plasma. The assay, which runs on the ACL TOP™ Hemostasis Testing System, is cleared by the Food and Drug Administration (FDA) for use as an aid in the diagnosis of DVT and PE. This new-generation assay brings several key technical features. First, only the F(ab)2 fraction of the antibody is coated onto the microlatex particles to minimize the interference from rheumatoid factor (RF), thereby reducing the number of false-positive results requiring confirmatory investigations with imaging techniques. Second, HemosIL D-Dimer HS uses a smaller-size latex particle, for which the optimal wavelength is 671 nm, to increase analytical sensitivity and to minimize interference from hemoglobin, bilirubin, and sample turbidity. The enhanced linearity of the new assay also allows the measurement of extremely high concentrations of D-Dimer. This is a key enhancement, particularly for the management of the clotting disorder, disseminated intravascular coagulation (DIC), which requires the measurement of elevated levels of D-Dimer in the range of 10,000 to 30,000 nanograms per milliliter (ng/mL). A comprehensive overview of the HemosIL D-Dimer HS assay’s specifications can be found in Table 1.

In a recent management study conducted at an external laboratory on samples from patients suspected of VTE, HemosIL D-Dimer HS demonstrated 100% sensitivity, 100% NPV, and 46.8% specificity. Compared to traditional D-Dimer assays, the new assay showed significantly better specificity and time-to-result. These are key features to allow improved management of patients suspected of VTE and reduction of the costs associated with confirmatory procedures.

Conclusion
The D-Dimer is a key test for patients suspected of DVT or PE; and the HemosIL D-Dimer HS, a new-generation, latex-enhanced immunoassay that runs on the ACL TOP Hemostasis Testing System, is cleared by the FDA for use as an aid in the diagnosis of VTE. It offers several clinical and cost benefits, including high NPV and specificity for VTE to enhance cost-efficiency, a time to first result of only 5 minutes, very high analytical sensitivity, minimized interference from RF and hemoglobin, and an extended working range that is useful in the management of disseminated intravascular coagulation (DIC).

Giovanni Russi is group product manager, Hemostasis, Instrumentation Laboratory.

Reference
1. De Moerloose P, Bounameaux H, Wells PH. D-Dimer testing and venous thromboembolism: four viewpoints. J Thromb Haemost. 2005;3(2):380–382.

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