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D-dimer assays have been Food and Drug Administration (FDA)–approved or cleared for results below a manufacturer-defined cutoff in conjunction with low or intermediate pretest clinical probability to rule out venous thromboembolism.1 Given apparent overall increase of D-dimer level with age, clinical guidelines have recommended application of an age-adjusted D-dimer–level cutoff to exclude suspected pulmonary embolus specifically in patients with low or intermediate pretest clinical probability.2,3 Despite additional studies and literature availble, these guidelines themselves rest solely on the Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism: The ADJUST-PE Study,4 applying an age-adjusted D-dimer–level cutoff defined as age×10 in patients aged 50 years or older to elderly patients presenting to the emergency department with low or intermediate pretest clinical probability of pulmonary embolus. Theoretically, by using this strategy to exclude pulmonary embolus in more patients, health systems could reduce cost and improve diagnostic efficiency without sacrificing sensitivity for identifying patients at risk for pulmonary embolus.

Numerous D-dimer assays (≈30) with various sensitivities and specificities are used worldwide, with no international standard available for harmonization. Expression of results is not standardized and uses different magnitudes (ie, nanograms per milliliter or milligrams per liter) and different nonequivalent units, including fibrinogen equivalent units (FEU) and D-dimer units (DDU) (DDU at 1 ng/mL are ≈FEU at 2 ng/mL). Guidelines from the Clinical and Laboratory Standards Institute for adequate evaluation of quantitative D-dimer to exclude venous thromboembolism in clinical studies are strict, with only a handful of assays meeting this criterion for age-adjusted D-dimer–level cutoff in suspected pulmonary embolus.5 Currently, no manufacturer has obtained FDA approval or clearance for use of age-adjusted D-dimer–level cutoffs. Assuming that all currently commercially available assays will correctly perform with the provided age-adjusted D-dimer–level cutoff is misguided, and, as recommended previously, these parameters (with harmonization of standards and appropriate units added) should be clarified in research studies, trials, and clinical guidelines.3,5

Many laboratories now use FDA-approved or -cleared D-dimer assays as an “aid in diagnosis” or for “exclusion” in venous thromboembolism evaluation. However, adding any postanalytic modification of assay, including manipulations of units or magnitude, or adding comment text not approved by the FDA, changes this FDA-approved or -cleared assay into a laboratory-developed test. Laboratory regulations require that a laboratory-developed test be fully validated by the specific laboratory before it is implemented into patient care, a challenging undertaking for most institutions; this is especially true for age-adjusted D-dimer–level cutoffs in patients older than 75 years, a largely uncharacterized population. In the absence of a validated laboratory-developed test at their institution, laboratories should refrain from broadly accepting the postanalytic modification of the age-adjusted D-dimer–level cutoff. Pathologists should work with clinical colleagues to explain the limitations of the age-adjusted D-dimer–level cutoffs and highlight the importance of properly validating a specific D-dimer assay before calculating an age-adjusted D-dimer–level cutoff.