key: cord-0789179-tmnkaxja
authors: Cho, Edward S.; McClelland, Paul H.; Cheng, Olivia; Kim, Yuri; Hu, James; Zenilman, Michael E.; D’Ayala, Marcus
title: Utility of D-dimer for diagnosis of deep vein thrombosis in COVID-19 infection
date: 2020-07-30
journal: J Vasc Surg Venous Lymphat Disord
DOI: 10.1016/j.jvsv.2020.07.009
sha: a3883cb3713b259c5422cf78d4c2421cd93fcf45
doc_id: 789179
cord_uid: tmnkaxja

OBJECTIVE: The objective of this study was to investigate the clinical utility of D-dimer in excluding a diagnosis of deep vein thrombosis (DVT) in patients with COVID-19 infection, potentially limiting the need for venous duplex ultrasonography (US). METHODS: We retrospectively reviewed consecutive patients admitted to our institution with confirmed COVID-19 status by PCR between March 1, 2020 and May 13, 2020 and selected those who underwent both D-dimer and venous duplex US. This cohort was divided into two groups, those with and without DVT based on duplex US. These groups were then compared to determine the value of D-dimer in establishing this diagnosis. RESULTS: A total of 1170 patients were admitted with COVID-19, of which 158 were selected as our study. Of the 158, there were 52 patients with DVT and 106 without DVT. There were no differences in gender, age, race, or ethnicity between groups. Diabetes and routine hemodialysis were less commonly seen in the group with DVT. Over 90% of patients in both groups received prophylactic anticoagulation, but the use of LMWH or subcutaneous heparin prophylaxis was not predictive of DVT. All patients had elevated acute-phase D-dimer levels using conventional criteria, and 154/158 (97.5%) had elevated levels with age-adjusted criteria (mean D-dimer 16,163 ± 5,395 ng/mL). Those with DVT had higher acute-phase D-dimer levels than those without DVT (median 13,602 [6,616-36,543 ng/mL] vs. 2,880 [1,030-9,126 ng/mL], p < 0.001). An optimal D-dimer cutoff of 6,494 ng/mL was determined to differentiate those with and without DVT (sensitivity 80.8%, specificity 68.9%, negative predictive value 88.0%). Wells DVT criteria was not found to be a significant predictor of DVT. Elevated D-dimer as defined by our optimal metric was a statistically significant predictor of DVT in both univariate and multivariable analyses when adjusting for other factors (OR 6.12, 95%CI [2.79-13.39], p <0.001). CONCLUSION: D-dimer levels are uniformly elevated in COVID-19 patients. While standard predictive criteria failed to predict DVT, our analysis showed a D-dimer of less than 6,494 ng/mL may exclude DVT, therefore potentially limiting the need for venous duplex ultrasonography.

A D-dimer level of less than 6,494 ng/mL excluded DVT in most 1 COVID-19 patients, therefore potentially limiting the need for venous duplex US. 2

A D-dimer level of less than 6,494 ng/mL had a sensitivity of 80.8% and a negative predictive 4 value of 88.0% in excluding DVT in this retrospective cohort study of 158 COVID-19 patients. elevated D-dimer level, those with DVT would have a more pronounced elevation in the acute-1 phase D-dimer level. Furthermore, we wanted to investigate the value of the Wells DVT criteria 2 in aiding the diagnosis of DVT. 3

Study Design 5 This a single-center retrospective cohort study composed of consecutive patients with 6 confirmed COVID-19 status, with positive PCR results of SARS-CoV-2 by nasopharyngeal 7 swab, between March 1, 2020 and May 13, 2020. Patients under the age of 18 were excluded 8 from analysis, as were those with a known DVT or PE prior to admission. Patients symptomatic 9

with confirmed COVID-19 status admitted to our hospital all had D-dimer levels measured, and 10 those considered at high risk for DVT based on clinical criteria underwent venous duplex US, 11 forming our study population. Venous duplex ultrasonography was performed for a variety of 12 indications including changes in clinical exam, significantly elevated D-dimer levels in critically 13 ill patients, and changes in respiratory status. Ultimately, venous duplex US were ordered based 14 on the discretion of the attending physician after discussion with a vascular surgeon. 15

All patients had at least one D-dimer measurement taken during their hospital course. D-16 dimer measurements were recorded sequentially for all patients throughout their hospital course. 17

Acute-phase D-dimer values, defined as the highest D-dimer level prior to obtaining venous 18 duplex US, were used to compare with the presence of confirmed DVT. During the study, 19 venous duplex US protocols differed from our usual standard. All venous duplex US were 20 performed at bedside rather than in our vascular laboratory due to the contact and droplet 21 isolation precautions of each patient with COVID-19. Venous duplex US was limited to the 22 femoral and popliteal veins and did not include the tibial veins. Also, once a diagnosis of DVT 23 was made, the study was terminated, such that not all studies included bilateral extremities. 1 These changes were implemented to limit COVID-19 exposure among our sonographers. Distal 2 DVT and tibial vein DVT were not included in this analysis. All venous duplex studies were 3 done by a registered vascular technologist. 4

Internal institutional review board approval was obtained prior to collection of patient 6 data (ID# 1595707). Patient consent was not required for our study by our institutional review 7 board as this was a retrospective study and data was de-identified. Variables collected fell into 8 three major categories: patient demographics, prehospital medical conditions active on 9 presentation, and variables associated with a diagnosis of DVT. All data was manually extracted 10 utilizing the hospital electronic medical record, de-identified and aggregated within spreadsheet 11 software (LibreOffice Calc, v6.4.1.2, The Document Foundation, Berlin, Germany) on a 12 password-protected computer with an encrypted hard drive. 13

Patient demographic factors recorded for study included sex, age, race, ethnicity, height, 14 weight, as well as date of admission. Patient medical history variables active on presentation that 15 were extracted from the electronic medical record were diabetes mellitus, smoking history 16 (within 30 days), functional status on presentation (independent, partially dependent, or 17 completely dependent), history of chronic obstructive pulmonary diseases (COPD), ascites, 18 congestive heart failure (CHF), hypertension (HTN) requiring medication, acute kidney injury 19 (AKI), history of requiring dialysis, active malignancy, metastatic cancer, wound infection or 20 chronic steroid use, active pregnancy, active DVT, PE or disseminated intravascular 21 coagulopathy (DIC), any recent trauma (<30 days), any recent surgeries (<30 days), history of 22 coagulopathic or hypercoagulable disorders (such as factor V Leiden, systemic lupus 23 erythematosus, antithrombin III deficiency, prothrombin deficiency, etc), and sepsis or septic 1 shock on presentation (based on systemic inflammatory response syndrome (SIRS) criteria). The 2 use of anticoagulation, either as prophylaxis or therapeutic, was recorded, as was patient 3 intubation during hospital admission. Wells criteria for DVT was calculated for all patients. 4

Patients who received a venous duplex US positive for DVT subsequently were initiated 5 on therapeutic anticoagulation with either a parenteral unfractionated heparin infusion with a 6 goal partial thromboplastin time of 60-90 seconds or low molecular weight heparin dosed at 7 1mg/kg unless a contraindication was present. Those with negative venous duplex US continued 8 to receive DVT thromboprophylaxis as long as no contraindications to do so were observed. 9

None of the patients in our study received thromboprophylaxis higher than the standard dose. 10

Continuous variables were described as means (standard deviation, SD) or medians 12 (interquartile range, IQR). Categorical values were described as proportions (percentages). 13

Associations between continuous variables were determined using two-sided t-tests or Wilcoxon 14 rank-sum tests where appropriate. Comparisons between categorical variables were made via 15

Pearson chi-square test. Univariate logistic regression analysis was performed on all of our 16 variables. Statistically significant variables with a p < 0.05 on our univariate analysis 17 subsequently underwent multivariable analysis. Optimal cutoff values for diagnostic tests were 18 determined by receiver operating characteristic curves (ROC) and Youden index calculation. A 19 p-value ≤ 0.05 was considered significant. R statistical programming language (v3.6.3, R

A total of 158 patients with COVID-19 positive status who had both a D-dimer level and 2 venous duplex US during their admission were included in the study. Patients with DVT were 3 more commonly male, although this finding was not significant (61.5% vs. 50.0%, p = 0.17). 4

There were no significant differences in race and ethnicity between patients with and without 5 DVT. Similarly, comorbidities were roughly equally distributed between the two cohorts (see 6   Table I ). Notable exceptions included diabetes mellitus and routine hemodialysis, which were 7 more common in patients without DVT (49.1% vs. 30.8%, p = 0.03; and 8.5% vs. 0.0%, p = 8 0.031, respectively). DVT thromboprophylaxis (either unfractionated subcutaneous heparin 9 5,000 units every 8 hours or low molecular weight heparin 40mg per day) was given to 144/158 10 patients (90.1%), with proportionally fewer patients in the DVT cohort receiving low molecular 11 weight heparin (21.2% vs. 50.0%, p = 0.002). Patients who presented with acute kidney injury 12 and without a contraindication to thromboprophylaxis were placed on unfractionated 13 subcutaneous heparin, while patients without acute kidney injury and a contraindication to 14 thromboprophylaxis were placed on low molecular weight heparin. Moreover, patients with 15 DVT were more likely to be intubated during their hospitalization than those without (73.1% vs. 16 51.4%, p = 0.01). 17

All patients had elevated acute-phase D-dimer levels using the conventional reference 19 range of ≤ 230 ng/mL D-dimer unit (DDU). Similarly, when adjusting for age, all patients 20 except 4 (2.5%) had elevated acute-phase D-dimer levels. Patients with DVT had significantly 21 higher acute-phase D-dimer levels than those who did not (median 13,602 [6,616-36,543 ng/mL] 22

vs. 2,879 [1,030-9,126 ng/mL], p < 0.001, see Figure 1 ). A Wells DVT Criteria score > 2 23 ("likely DVT") was more common among patients with confirmed DVT, although this was not 1 significant (44.2% vs. 31.1%, p = 0.106). 2

Using Youden index calculation, an optimal cutoff of 6,494 ng/mL DDU was calculated 3 to differentiate between those with and without DVT. By this new metric, 42/52 (80.8%) of 4 patients with DVT had a D-dimer above this level, whereas 33/106 (31.1%) of patients without 5

DVT had elevated D-dimer (p < 0.001, see Table II ). Calculated sensitivity and specificity for 6 this new cutoff were 80.8% and 68.9%, respectively. Negative predictive value was 88.0%. C-7 statistic (area under curve) was 0.802 (see Figure 2 ). 8

Predictors of DVT 9 In univariate logistic regression analysis, patients with diabetes mellitus were found to duplex US has previously been a readily available resource, its use has become increasingly 23 limited due to the current COVID-19 pandemic. Logistic constraints such as the availability of 1 registered vascular technologists (RVT) and US machines, or the need for routine 2 decontamination following exposure to COVID-19 positive environments has restricted the 3 ability to obtain venous duplex US on a regular basis. In addition, limiting the exposure of our 4

RVTs has become increasingly important, thus creating the need to determine which patients 5 should be prioritized when obtaining venous duplex US. 6

When associated with a low clinical probability for VTE, age-adjusted D-dimer cutoff 7 has been shown to be associated with a decreased incidence of VTE. 11 All patients in our study 8 had an increased D-dimer according to the conventional cutoff of 230ng/mL, along with 97.5% 9 of patients when an age-adjusted D-dimer cutoff was used. Our results correspond to Zhou et. al, 10 which showed that D-dimer levels were generally elevated in patients with COVID-19 11 infection. 12 Due to an elevated D-dimer level according to both conventional and age-adjusted 12 cutoffs in almost all patients, D-dimer would lose its predictive value according to such cutoffs. 13

Although D-dimer has previously been seen as a relatively nonspecific test, our analysis showed 14 D-dimer levels were significantly elevated in patients who were confirmed to have a DVT on 15 venous duplex US. An optimal D-dimer cutoff of 6,494 ng/mL was determined to differentiate 16 those with and without DVT with a sensitivity of 80.8%, a specificity of 68.9%, and a negative 17 predictive value of 88.0%. This new cutoff was validated with good predictive merit in both our 18 univariate and multivariate logistic regression. 19

As venous duplex US becomes increasingly difficult to obtain due to increasing demand 20 and limited resources, the need for D-dimer in ruling out DVT increases. Due to the universally 21 This study has several important limitations. First this study was performed 18 retrospectively, which created difficulty in obtaining important clinical data including the Wells 19 score. This data was primarily obtained through assessing clinical notes that led up to the 20 decision to perform a venous duplex US and relied upon accurate documentation of the patient's 21 clinical condition and medical decision making. Second, due to the recent onset of the COVID-22

19 pandemic, our sample size is relatively small compared to prior studies regarding D-dimer 23 and DVT. 3, 5, 11, 17 As the pandemic progresses, additional patients may also be evaluated. 1

Prospective studies with a larger patient population may help validate our results. Also, we did 2 not include patients with a diagnosis of pulmonary embolus, and the use of D-dimer in this 3 patient population remains questionable. 4

Imaging with the use of noninvasive vascular studies has been limited during the current 6 COVID-19 pandemic. With an increasing scarcity of resources despite a growing demand, 7 utilization of additional tools to aid in diagnosis are necessary. Since D-dimer levels are 8 universally elevated in COVID-19 patients, conventional and age-adjusted use of this marker has 9 become impractical. In our analysis, a D-dimer level of less than 6,494 ng/mL excluded DVT, 10 therefore limiting the need for duplex ultrasonography. the IQR appended to these quartiles. Extraneous points represent outliers. 10 Acute-phase D-dimer, mean (SD)

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