D-dimer Unreliable for Ruling Out Pulmonary Embolism in COVID-19

Fran Lowry

October 13, 2021

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

The plasma D-dimer assay has been used, along with clinical prediction scores, to rule out pulmonary embolism (PE) in critically ill patients for decades, but a new study suggests it may not be the right test to use in hospitalized COVID-19 patients.

The results showed that all hospitalized patients with COVID-19 and radiographic evidence of PE had plasma D-dimer levels of 0.05 μg/mL or greater, the cutoff point for the diagnosis.

"If using D-dimer to exclude patients with PE, the increased values we found among 92.3% of patients suggest that this assay would be less useful than in the populations in which it was originally validated, among which a minority of patients had increased D-dimer values," the authors write. "Setting higher D-dimer thresholds was associated with improved specificity at the cost of an increased false-negative rate that could be associated with an unacceptable patient safety risk."

The inclusion of patients with D-dimer and computed tomography pulmonary angiography (CTPA) was necessary to estimate diagnostic performance, they note, but "this may have introduced selection bias by excluding patients unable to undergo CTPA."

"Nonetheless, given the high pre-test probability of PE and low specificity observed in this and other studies, these results suggest that use of D-dimer levels to exclude PE among patients hospitalized with COVID-19 may be inappropriate and have limited clinical utility," they conclude.

Led by Constantine N. Logothetis, MD, from Morsani College of Medicine, University of South Florida, Tampa, the study was published online October 8 as a Research Letter in JAMA Network Open.

Uncertain Utility

The authors note that the availability of D-dimer samples routinely collected from hospitalized COVID-19 patients — as well as the heterogeneity of early, smaller studies — generated uncertainty about the utility of this assay.

This uncertainty prompted them to test the diagnostic accuracy of the D-dimer assay among a sample of 1541 patients who were hospitalized with COVID-19 at their institution between January 2020 and February 2021 for a possible PE.

They compared plasma D-dimer concentrations with CTPA, the criterion standard for diagnosing PE, in 287 of those patients.

Overall, 118 patients (41.1%) required care in the ICU, and 27 patients (9.4%) died during hospitalization.

The investigators looked at the ability of plasma D-dimer levels collected on the same day as CTPA to diagnose PE.

Thirty-seven patients (12.9%) had radiographic evidence of PE, and 250 patients (87.1%) did not.

Overall, the vast majority of patients (92.3%; n = 265 patients) had plasma D-dimer levels of 0.05 μg/mL or more, including all patients with PE and 225 of 250 patients without PE (91.2%).

The median D-dimer values were 1.0 μg/mL for 250 patients without PE, and 6.1 μg/mL for 37 patients with PE.

D-dimer values ranged from 0.2 μg/mL to 128 μg/mL among patients without PE, and from 0.5 μg/mL to more than 10,000 μg/mL among patients with PE. Patients without PE had statistically significantly decreased mean D-dimer values (8.7 μg/mL vs 1.2 μg/mL; P < .001).

A D-dimer concentration of 0.05 μg/mL was associated with a sensitivity of 100%, specificity of 8.8%, negative predictive value (NPV) of 100%, positive predictive value (PPV) of 13.9%, and a negative likelihood ratio (NLR) of less than 0.1.

The age-adjusted threshold was associated with a sensitivity of 94.6%, specificity of 22.8%, NPV of 96.6%, PPV of 13.9%, and NLR of 0.24.

The authors note that all hospitalized patients with COVID-19 and radiographic evidence of PE had plasma D-dimer levels of 0.05 μg/mL or greater.

D-Dimer in VTE May Not Extrapolate to COVID-19

"The D-dimer test, which is a measure of circulating byproducts of blood clot dissolution, has long been incorporated into diagnostic algorithms for venous thromboembolic [VTE] disease, including deep vein thrombosis and pulmonary embolism. It is uncertain whether this diagnostic use of D-dimer testing can be extrapolated to the context of COVID-19 — an illness we now understand to be associated itself with intravascular thrombosis and fibrinolysis," Matthew Tomey, MD, a cardiologist at Mount Sinai Morningside, New York City, told theheart.org | Medscape Cardiology.

"The authors of this study sought to evaluate the test characteristics of the D-dimer assay for diagnosis of pulmonary embolism in a consecutive series of 287 hospitalized patients with COVID-19 who underwent computed tomography pulmonary angiography (CTPA). This was a selected group of patients representing less than 20% of the 1541 patients screened. Exclusion of data on the more than 80% of screened patients who did not undergo CTPA is a significant limitation of the study," Tomey said.

"In the highly selected, small cohort studied, representing a group of patients at high pretest probability of pulmonary embolism, there was no patient with pulmonary embolism who had a D-dimer value less than 0.5 μg/mL. Yet broad ranges of D-dimer values were observed in COVID-19 patients with (0.5 to >10,000 μg/mL) and without (0.2 to 128 μg/mL) pulmonary embolism," he added.

Based on the presented data, it is likely true that very low levels of D-dimer decrease the likelihood of finding a pulmonary embolus on a CTPA, if it is performed, Tomey noted.

"Yet the data confirm that a wide range of D-dimer values can be observed in COVID-19 patients with or without pulmonary embolism. It is not clear at this time that D-dimer levels should be used as gatekeepers to diagnostic imaging studies such as CTPA when pretest suspicion of pulmonary embolism is high," he said.

"This issue becomes relevant as we consider evolving data on use of anticoagulation in treatment of hospitalized patients with COVID-19. We learned this year that in critically ill patients hospitalized with COVID-19, routine therapeutic anticoagulation (with heparin) was not beneficial and potentially harmful when compared with usual thromboprophylaxis," he concluded.

"As we strive to balance competing risks of bleeding and thrombosis, accurate diagnosis of pulmonary embolism is important to guide decision-making about therapeutic anticoagulation, including in COVID-19."

Logothetis and Tomey have disclosed no relevant financial relationships.

JAMA Netw Open. 2021;4(10):e2128802. Abstract

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