COVID-19 and D-dimer: Frequently Asked Questions

(Version 1.0; last updated April 20, 2020)

Input from Drs. Morayma Reyes Gil, Aggie Lee, Nigel Key, Dan Sabath, Cindy Leissinger, Oksana Volod, Geoff Wool , Lisa Baumann Kreuziger

Note: Please review ASH's disclaimer regarding the use of the following information.

What is D-dimer and how is it measured?

D-dimer is a degradation product of crosslinked fibrin resulting from plasmin cleavage. During fibrinolysis plasmin may degrade fibrin monomers, crosslinked fibrin polymers and possibly fibrinogen during systemic fibrinolysis following alpha2 depletion. All these fragments are collectively called fibrin degradation products (FDPs). D-dimer constitutes two adjacent fibrin ‘D’ domains (ends) that are cross-linked and released as an intact fragment, hence the name D-dimer.

There are two main types of D-dimer assays, each reporting different D-dimer units (see Table 1). The Fibrinogen Equivalent Unit (FEU) reports D-dimer levels based on the molecular weight of fibrinogen (340kDa), whereas the D-Dimer Unit (DDU) reports D-dimer levels based on its own molecular weight (195kDa), which is about half that of fibrinogen. Also, the reporting of the unit is different depending on the manufacturer, resulting in up to 9 different depictions of results, including mg/L, mg/dL, ng/dL, ng/mL, μg/L, μg/mL, μg/dL, mg/mL, and ng/L. It is relevant to acknowledge that some laboratories do not follow manufacturer recommendations regarding reporting or cut-offs.¹

We recommend that clinicians become familiarized with their laboratory methodology, reporting units and cut offs, and those used in COVID-19 papers they are basing treatment decisions on, since direct extrapolation may not be straightforward. We also recommend against conversion of DDU into FEU and vice versa, as these conversions may add more confusion and should first be validated.

What does an elevated D-dimer in COVID-19 patients mean?

Several studies from Wuhan have shown elevated D-dimer in COVID-19 patients is associated with higher mortality, although prophylactic anticoagulation in ICU patients in China was not common when these studies were performed. These studies provided little information on assays/unit types utilized. Although it is not clear what effect anticoagulation has on D-dimer levels in the setting of COVID-19, very low D-dimer levels are usually observed in patients receiving anticoagulation.

Because D-dimer is a product of cross-linked fibrin, it is considered a sensitive biomarker to rule out venous thromboembolism. However, D-dimer has low specificity as there are many other conditions with ongoing activation of the hemostatic system in which D-dimer can be elevated such pregnancy, inflammation, malignancy, trauma, liver disease (decreased clearance), heart disease, sepsis or as a result of hemodialysis, CPR or recent surgery.

When and how often should D-dimer be measured?

There is not yet a consensus as to how D-dimer levels should be used for management and/or monitoring of COVID-19 patients. Checking D-dimer on initial presentation in the emergency department, urgent care facility or outpatient clinic is appropriate. Based on available COVID-19 experience (see Table 2) a cut off of >1 μg/mL may stratify patients at higher risk of poor outcomes. For hospitalized patients, there is no consensus regarding how often D-dimer should be measured, or how results should be acted upon with respect to anticoagulation.

Are D-dimer result accurate in COVID-19 patients or are there confounding laboratory issues?

The most common pre-analytical errors include inappropriate drawing techniques and inadequate transportation and/or storage. Slow blood collection may cause hemolysis; therefore, a needle size of at least 19 to 22 gauge is necessary. Collection tubes should be maintained in a vertical position during transportation, although studies have shown that transportation via pneumatic tubes is acceptable. Stability for most assays is 24 hrs. at room temperature but we recommend clinicians to adhere to individual lab policies. In the laboratory, we have experienced an increased frequency of clogged needles during D-dimer testing (needle 1, STA-R Max system) likely due to samples with very high D-dimer and fibrinogen concentrations. We recommend increasing the frequency of instrument maintenance and needle cleaning to at least once every shift to avoid this issue.

The most common substances resulting in analytical interference with D-Dimer levels are paraproteins, bilirubin, lipids and hemolysis. Post-analytical errors are less common but as mentioned above there is great confusion surrounding the use of different unit types and different magnitudes of units. Recent evidence for the utility of age-adjusted cut offs has been published. Specific pregnancy and pediatric ranges have also been proposed. We recommend careful attention to these issues for proper interpretation of patient results and published studies, particularly if D-dimer levels will be used to guide changes in therapy.

For additional information, see:

• D-Dimer assays and units (only FDA-approved assays for VTE exclusion) — see Table 1
• Available studies on D-dimer levels, assays and association with outcomes — see Table 2

References

1. Arch Pathol Lab Med. 2013;137:1030–1038; doi: 10.5858/arpa.2012-0296-CP

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