To scan or not to scan - D-dimers and computed tomography pulmonary angiograms in the era of COVID-19
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Clinical Medicine Publish Ahead of Print, published on February 16, 2021 as doi:10.7861/clinmed.2020-0664
ORIGINAL RESEARCH Clinical Medicine 2021, Vol 21 No 2 March 2021
To scan or not to scan – D-dimers and computed
tomography pulmonary angiograms in the era of COVID-19
Authors: Alexander A Tuck,A* Harriet L White,A* Badr A Abdalla,B Gwendolen J Cartwright,C Katherine R
Figg,C Emily N Murphy,C Benjamin C Pyrke,A Mark A Reynolds,D Rana M TahaA and Hasan N HaboubiE
The COVID-19 pandemic has had many ramifications on fibrosis and respiratory failure. The high mortality rate of COVID-19
healthcare delivery and practice. As part of this, utilising is attributed to a number of pathological processes, including diffuse
ABSTRACT
biomarkers to risk stratify patients has become increasingly alveolar damage, venous thromboembolism (VTE), superadded
popular. During the COVID-19 pandemic the use of D-dimer has bacterial infection and heart failure.1 Due to the rapid spread of
increased due to the evidence of COVID-19 induced thrombo- COVID-19, the need for identification of prognostic factors was
embolic disease. We evaluated the use of D-dimer on all hospital apparent and a number of laboratory tests have been suggested to
admissions during the peak of the pandemic and evaluated predict mortality; one such test is D-dimer.2
its sensitivity in diagnosing pulmonary embolic disease (PE). Coagulopathy and venous thromboembolism have repeatedly
Patients without COVID-19 infection were as likely to have been described as common complications of COVID-19.1 Proposed
evidence of PE as their COVID-positive counterparts. However, aetiologies for this coagulopathy include endothelial dysfunction,
the sensitivity of a D-dimer was higher in COVID-positive increased pro-inflammatory cytokines (‘cytokine storm’) and severe
patients at a lower D-dimer level (>1,500 μg/L, sensitivity 81%, hypoxaemia. As such, D-dimer testing has dramatically increased
specificity 70%) than in those without clinical, immunological during the COVID-19 pandemic and is now an investigation used
or radiological evidence of COVID-19 infection (D-dimer >2,000 as part of the workup for suspected COVID-19 patients. This has
μg/L, sensitivity 80%, specificity 76%). These data suggest higher meant that a large group of patients with a low clinical suspicion
D-dimer thresholds should be considered for the exclusion of of pulmonary embolism (PE) have had D-dimers performed on
pulmonary emboli. admission.3 Consequently, we have observed a greater number
of computed tomography pulmonary angiograms (CTPAs)
KEYWORDS: D-dimer, CTPA, pulmonary embolism, COVID-19,
being performed. This conveys an increased risk to patients from
sensitivity
intravenous contrast and exposure to X-ray radiation,4 and also
DOI: 10.7861/clinmed.2020-0664 impacts on resource management within the NHS.
D-dimer is a biomarker of the fibrinolytic system and interpreted as
an indirect marker of thrombotic activity. In the process of thrombus
Introduction generation, fibrinogen is cleaved by thrombin, and fibrin monomers
then form polymers through the action of factor XIIIa crosslinking
In December 2019 a novel coronavirus (SARS-CoV-2) was identified adjacent D domains. D-dimer molecules are subsequently released
in Wuhan, China, which has developed into a global pandemic with during the degradation of fibrin clots by plasmin. Therefore, the
widespread repercussions. SARS-CoV-2 causes COVID-19, which presence of intravascular D-dimer molecules is highly indicative of
manifests as viral pneumonia in some patients and can lead to thrombus formation.5
overactivation of the body’s immune system, resulting in pulmonary D-dimer was first identified in the 1970s for evaluation of
disseminated intravascular coagulation. Initially, laboratory tests
were unable to distinguish between fibrinogen and products of
Authors: Asenior house officer, University Hospital Llandough, Cardiff fibrin degradation; however, the development of monoclonal
and Vale University Health Board; Bclinical fellow gastroenterology, antibody based assays allowed measurement of D-dimer alone.6
University Hospital Llandough, Cardiff and Vale University Health Board; In more recent times, a number of methods have been used to
C
foundation year 1 doctor, University Hospital Llandough, Cardiff and measure D-dimer, including enzyme-linked immunofluorescent
Vale University Health Board; Dspecialist registrar in gastroenterology, immunoassays (EIFAs), microplate enzyme-linked immunosorbent
University Hospital Llandough, Cardiff and Vale University Health Board; assays (ELISAs) and latex agglutination quantitated tests.7
E
consultant in gastroenterology, University Hospital Llandough, Cardiff The use of D-dimer in predicting venous thromboembolism has
and Vale University Health Board, and senior clinical lecturer, School of been controversial due to the difficulties in interpreting the result.
Medicine, Swansea University; *joint first authors. Results were previously reported as ‘positive’ or ‘negative’, which
1 © Royal College of Physicians 2021. All rights reserved.
Copyright 2021 by Royal College of Physicians.D-dimers and CTPAs in the era of COVID-19
SYNAPSE, we obtained chest X-ray and CTPA reports and collected
Table 1. Demographics and biochemical measured variables
data on PE diagnosis, COVID-19 diagnosis and reported COVID-19
of study participants
severity. From WCP we cross-referenced results for COVID-19
Gender Male 260/544 (47.8) polymerase chain reaction (PCR) swabs, D-dimer, C-reactive protein
Female 284/544 (52.2) (CRP), procalcitonin and troponin-I from the initial bloods of the
admission pertaining to the CTPA in question.
Age Total 60.30 (95% CI 58.33–61.25) Assays used are shown in supplementary material S1. The study
Males 61.45 (95% CI 58.14–62.24) was registered on the Clinical Audit Database (9524).
Females 58.40 (95% CI 57.34–61.49)
Data analysis
COVID-19 Total diagnosed 198/544 (36.4)
status with COVID-19 Analyses were performed using the Statistical Package for the
Suspected 261/544 (48.0) Social Sciences (SPSS v.23.0), IBM Corp, Amrok, New York, USA with
COVID-19 significance set at pOriginal research
Table 2. Risk factors for pulmonary embolism: univariate and multivariate analysis
PE diagnosed (n=86) (%) Univariate analysis Multivariate analysis
Total 86/544 (15.8%)
Gender (male) 49/86 (57%) 0.055
Median age (95% confidence interval) 60.05 (47.49–63.31)D-dimers and CTPAs in the era of COVID-19
60
Non-Covid Covid Total
Percentage (%) patients with positive CTPA
50
40
30
20
10
0
2,000 >20,000
(2,001–19,999) (Unrecordably high)
D-Dimer range
Fig 1. Percentage of patients with positive CTPA at different ranges of D-dimer.
the cut off could be extended to 2,000 μg/L while still maintaining (98.5%) but an unacceptably low specificity in all patients (12.0%).
sensitivity and improving specificity. Associated ROC curves for all This is similar to sensitivities and specificities of previous studies
three groups of data can be found in supplementary material S3. into D-dimer;8,9 however we support the argument that a higher
Hence, a slightly lower D-dimer cut off should be considered in uniform cut-off is now needed. Numerous studies have attempted
COVID-19 as there are greater numbers of PEs diagnosed in the to balance the differences in sensitivity and specificity10 that exist
1,501–2,000 group in patients with COVID-19 compared to the with D-dimer measurement. Recent studies have reported that
non-COVID-19 cohort (Fig 1). lowering the target sensitivity can lead to a higher cut-off. As
such, cut-offs of 900 and 1,200 have been suggested.18,19 A more
Patient mortality recent 2019 latex agglutination-based study of 370 patients has
reported that a significantly higher cut-off of 2,152 μg/L led to a
Male gender was associated with an increased risk of death sensitivity of 75.4% with a specificity of 62.7% for PE with a ROC
(p=0.022), with a relative risk increase of 1.5. Having a diagnosis AUC of 0.69 (95% CI 0.64–0.74; pOriginal research >2,000 μg/L was associated with a higher incidence of mortality We have demonstrated higher cut-offs of D-dimer can be used (P
D-dimers and CTPAs in the era of COVID-19
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to D-dimer levels. Radiology 2020;296:E189–E191. Email: hasanhaboubi@doctors.org.uk
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