key: cord-0799228-p4p2ci02
authors: Koleilat, Issam; Galen, Benjamin; Choinski, Krystina; Hatch, Ayesha Nzeribe; Jones, Davis Brent; Billett, Henny; Indes, Jeff; Lipsitz, Evan
title: Clinical Characteristics of Acute Lower Extremity Deep Venous Thrombosis Diagnosed by Duplex in Patients Hospitalized for Coronavirus Disease (COVID-19)
date: 2020-06-25
journal: J Vasc Surg Venous Lymphat Disord
DOI: 10.1016/j.jvsv.2020.06.012
sha: 03e25dea284a8f5382c203bf0da786d92aa5f521
doc_id: 799228
cord_uid: p4p2ci02

OBJECTIVE: Little is known about coronavirus disease (COVID-19)-associated hypercoagulability. We sought to characterize patients with deep venous thrombosis (DVT) identified after admission for COVID-19. METHODS: All adult patients admitted to Montefiore Medical Center (MMC) from March 1, 2020 to April 10, 2020 and undergoing lower extremity venous duplex for DVT evaluation were included. Patients admitted with suspicion of COVID-19 were divided into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive and SARS-CoV-2 negative groups based on in-hospital test results. Patients without clinical suspicion for COVID-19 were not tested. A retrospective case-control study design was used to identify potential risk factors for DVT in patients with COVID-19. Demographic, radiographic and laboratory values were abstracted and analyzed. RESULTS: During the study period, 3,404 patients with confirmed COVID-19 were admitted to the hospital. Of the 135 SARS-CoV-2 patients who underwent duplex scanning, there were 18 (13.3%) noted to have DVT compared to 72 of the 711 patients (10.1%) who were either SARS-CoV-2 negative or untested. The odds ratio for DVT in COVID-19 was 1.35 (95% CI 0.78 – 2.34, p=0.289). Baseline characteristics for COVID-19 patients with and without DVT were overall similar. COVID-19 patients with DVT had an elevated median first D-dimer (18.88 mcg/mL [IQR 7.79, 20.00] versus 2.55 mcg/mL [IQR 1.45, 6.28], p=0.002, reference range <0.5 mcg/mL), average in-hospital D-dimer (median 11.93 mcg/mL [IQR 8.25, 16.97] versus 3.54 mcg/mL [IQR 2.05, 8.53] , p<0.001) and median fibrinogen level (501.0 (IQR 440.0, 629.0) versus 654.5 (IQR 535.8, 780.0), p= 0.002, reference range 187-502 mg/dL). There was a trend to significance for COVID-19 patients with DVT compared to without DVT in median D-dimer levels at the time of the duplex (13.61 mcg/mL [IQR 4.04, 19.97] versus 3.58 mcg/mL [IQR 2.51, 9.62], p=0.055) and median ferritin levels (1,679.0 ng/mL [IQR 1,168.0, 2,577.0] versus 1,103.0 ng/mL [IQR 703.5, 2,076.5], p=0.055, reference 25-270 ng/mL). Twelve of the 18 patients with COVID who developed DVT did so despite chemical thromboprophylaxis, and two developed DVT in spite of therapeutic anticoagulation CONCLUSIONS: We found only a modestly increased risk of DVT in patients with COVID-19, likely underestimated due to limitations in duplex testing early in the epidemic. Elevated D-dimer and a less elevated fibrinogen are associated with DVT in patients with COVID-19 who appear to form thrombus despite conventional chemical thromboprophylaxis. Additionally, an increasing D-dimer over time may be a reflection of the development of DVT in patients with COVID-19.

In late 2019, the first reports of human infection with a novel coronavirus named severe acute 8 respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed a highly transmissible, significantly 9 morbid and potentially fatal disease. [1] [2] [3] In addition to the pulmonary impact of this infection, 10 cardiac, renal and hematologic manifestations have been identified. There have been multiple 11 reports of an increased risk of deep venous thrombosis (DVT) in patients hospitalized with 12 SARS-CoV-2 infection or coronavirus disease 2019 . 4, 5 Interestingly, the rapid and 13 sudden demise, particularly of younger patients, is concerning for undiagnosed massive 14 pulmonary embolism. A recent study found the incidence of a thrombotic complication (arterial 15 or venous) at 31% in intensive care unit (ICU) patients with This may also explain including hemoglobin, blood cell counts, coagulation parameters, cardiac biomarkers, and 1 creatinine; radiologic studies; and any operative variables if patients underwent surgery related to 2 the DVT. D-dimers were recorded throughout the hospitalization and the average D-dimer for 3 the admission was calculated. D-dimers obtained the day of the ultrasound were analyzed 4 independently, as were the first d-dimer levels obtained during the hospitalization. Acute kidney 5 injury (AKI) was defined using the Acute Kidney Injury Network criteria: increase in serum 6 creatinine of 0.3 mg/dL in 48 hours, increase in serum creatinine 50% over baseline, or oliguria 7 of less than 0.5 mL/kg/hour for greater than six hours. The fraction of inspired oxygen (FiO 2 ) for 8 non-intubated patients receiving supplemental oxygen by nasal cannula was estimated by 9 assuming 4% of inspired oxygen per every liter as described previously. 7 Sequential Organ 10 Failure Assessment (SOFA) score was calculated for each patient from data from the day of the 11 duplex test.

Duplex testing for acute DVT was obtained at the provider's discretion for patients with 14 significant clinical concern for DVT or in those in whom the results were deemed to impact 15 management (for example, patients who were mechanically ventilated and placed prone for 16 persistently poor oxygenation were deemed too unstable, and those already on anticoagulation 17 for other reasons such as cardiac arrhythmias or prior history of thrombotic episodes requiring 18 lifelong anticoagulation were unlikely to undergo venous duplex testing). The majority of studies 19 were conducted as portable studies at bedside. These targeted vascular laboratory and ultrasound 20 testing protocols were implemented hospital-wide to address the increased clinical need, reduce 21 hospital staff exposure and to reduce inadvertent viral transmission of SARS-CoV-2 to non-7 infected patients. Findings of isolated chronic DVT identified on duplex were classified as 1 negative to reflect the absence of an acute thrombosis. The odds ratio for acute DVT in COVID-19 was evaluated with a two-tailed Fisher's exact test.

Univariate analysis of risk factors was conducted with t-tests for continuous and chi square tests 5 for categorical variables with nonparametric testing as appropriate. Multivariable analysis was 6 not performed due to small sample sizes. Values for D-dimer, AST, ALT, ferritin, aPTT, CPK, 7 CRP and serum creatinine beyond the limit of detection for the assay were imputed at the 8 threshold value. All analysis was conducted in RStudio (version 1.2.1335) and Microsoft Excel 9 (version 16.0) with alpha set at 0.05. Missing data was assumed to be missing at random and 10 excluded from the analysis for that variable. This study was approved by the Institutional Review 11 Board of MMC with a waiver of informed consent for this observational review (#2020-11411). 8 SARS-CoV-2 negative or not tested. DVT was found in 72 of these patients (10.1%) (Figure 1 ).

The odds ratio for DVT in COVID-19 was 1.35 (95% CI 0.78 -2.34, p=0.289). Table I with laboratory and treatment characteristics shown in Table   5 II. Of these, eighteen (13.3%) were ultimately found to have acute DVT by duplex examination.

Overall baseline demographics and characteristics were similar to patients with COVID-19 7 without ultrasound evidence of acute DVT, notably including BMI and CHF. There was a trend 8 in patients ultimately diagnosed with DVT to have presented with fever (81 (69.2%) versus 17 9 (94.4%), p=0.051). Importantly, there was no difference noted in the C-reactive protein (CRP), 10 absolute neutrophil count (ANC), neutrophil-to-lymphocyte ratio, SOFA score, need for 11 mechanical ventilation, ratio of arterial partial pressure of oxygen to the fraction of inspired 12 oxygen (P:F ratio), or anticoagulant use at the time of the duplex between groups. There were 13 also no significant differences in the rates of AKI, pulmonary embolism (PE), death or length of 14 stay, although many were still actively hospitalized and undergoing medical care at the time of 15 data analysis.

Only fibrinogen and the average D-dimer were found to be significantly different between the 18 two groups. A sensitivity analysis was conducted to further characterize the D-dimer results using an analysis 9 of the variable as categorical. Categories included D-dimer <0.5, 0.5 -3, 3 -10, 10 -15, 15 -20, 10 and >20 mcg/mL. While the D-dimer on the day of the duplex was not found to be significantly 11 different using this method, the average D-dimer and the first D-dimer obtained on 12 hospitalization were both significant (p = 0.004 and p < 0.001, respectively). This was consistent Three patients without evidence of acute DVT on lower extremity ultrasound developed 20 pulmonary embolism (PE) as identified on chart review. Since our study data was derived from 21 patients undergoing lower extremity duplex for DVT, these patients were analyzed as no DVT 22 and we did not specifically review the imaging that may have confirmed PE for all COVID-19 23 admissions. Sensitivity analysis performed evaluating any DVT or PE compared to no DVT or 1 PE did not reveal any difference in results.

Details regarding the patients with COVID-19 who were diagnosed by venous duplex with acute 4 DVT are displayed in Table III . In patients with a DVT, the median time from symptoms, SARS-5 CoV-2 testing and admission to DVT diagnosis was 7.6, 7.3 and 7.6 days, respectively. No 6 patient required thrombolysis or surgical management of DVT. Only two patients (11.1%) had 7 isolated below-the-knee acute DVT. When patients found to have DVT or PE on presentation We herein describe our early experience with DVT in patients with COVID-19. Development of 3 DVT can severely impact the outcomes of critically ill patients with increased mechanical 4 ventilation time, increased hospital and ICU length of stay, and mortality. 8 Known risk factors 5 for DVT include prior venous thromboembolic event (VTE), malignancy, genetic or acquired 6 hypercoagulable states, pregnancy, smoking, long-distance travel, immobility, inflammation, 7 obesity, and importantly critical illness. 9-11 Infection with novel SARS-CoV-2 appears to induce 8 a hypercoagulable state that may not be completely explained by critical illness alone when 9 present. A retrospective analysis of 81 patients admitted to the ICU with COVID-19 suggested a 10 risk of VTE as high as 25% with the authors highlighting that "no preventive anticoagulant was 11 administered." 5 Importantly, they describe elevated D-dimer levels as a marker of risk and 12 suggest a cutoff value of 1.5 mcg/mL for VTE prediction. Others have found increased risk of 13 mortality with elevated D-dimers and fibrinogen levels. 12

In this study, there was evidence of an increased risk of acute lower extremity DVT in patients 16 with COVID-19 compared to those without COVID-19 although this increase did not reach 17 statistical significance. Acute DVT in patients with COVID-19 was significantly associated with 18 an elevated first D-dimer level, an average D-dimer throughout hospitalization, and a less 19 elevated fibrinogen level. When comparing patients who had confirmed COVID-19 with and 20 without acute DVT, there were no significant differences in inflammatory markers such as CRP 21 or neutrophil-to-lymphocyte ratio. The severity of illness at the time of data abstraction and 22 analysis was similar as well including SOFA score, AKI, and mortality (Table II) . We did not identify differences in BMI, rates of a history of CHF or pulmonary status at the time of duplex 1 (as measured by arterial partial pressure of oxygen, fraction of inspired oxygen, the P:F ratio and 2 mechanical ventilation at the time of the duplex). There was a statistically non-significant trend towards elevated ferritin levels in patients with 5 COVID-19 with ultrasound evidence of acute DVT compared to those without. While likely not 6 statistically significant due to study sample size, we suspect that this difference could be 7 clinically significant. Ferritin may be a marker of hyperinflammation with COVID-19. 13 A recent 8 metanalysis suggested that serum ferritin may serve to discriminate severe disease. 14 Further 9 study should aim to characterize this relationship, especially as it relates to the development of 10 acute DVT with COVID-19.

We also observed an increasing D-dimer level that peaked the day prior to the duplex was 13 performed and declined thereafter. Not all patients had D-dimer levels drawn daily precluding 14 our ability to ascertain whether this overall trend was observed at the individual patient level. We elucidated. This is especially true given that it appears that the majority of DVT in these patients 7 with COVID-19 occurs despite conventionally adequate DVT chemical prophylaxis. Twenty-one patients (19.9%) of the DVT negative group were also prescribed therapeutic instances of DVT. Lastly, inpatient treatment is ongoing for many patients in this study with 1 some data not reflecting a complete hospital course.

This study is limited by the false negative rate of the PCR test for SARS-CoV-2 as well. While 4 the exact false positive rate is not known, it is conceivable that many of the patients who tested recommendation which refers to a study by Reynolds, et. al that found no difference in q12 and 18 q8 hour dosing. 24 Our institution practice, however, is to use q8 hours dosing for patients with 19 BMI greater than 30. Additionally, the decision to initiate therapeutic anticoagulation evolved 20 during the study period. With increasing anecdotal reports of thrombotic events worldwide, our 21 center moved to establishing a threshold d-dimer value of 3 mg/dL to initiate anticoagulation, as the risks of not doing so were deemed potentially too great. These issues may also have impacted 1 the likelihood of developing DVT in our patient sample.

Issues surrounding infection containment and patient stability for transportation and testing may 4 have impacted the diagnosis of PE as well. It is for this reason that PE was not included in the 5 outcome definition in this study given concerns of significant underestimation. In this study, we 6 elected to focus solely on lower extremity acute DVT as one of the most common manifestations 7 of venous thromboembolic disease. Additionally, DVT is easily evaluated with duplex which can 8 be a portable bedside study. Other manifestations of hypercoagulability are also possible, such as 9 arterial thrombosis or mesenteric venous thrombosis. This is of special interest given reports 10 documenting the early and severe occurrence of in situ pulmonary thrombosis and evidence of 11 damage to the pulmonary alveoli and the vascular endothelium in the lungs. 15 However, to 12 decrease heterogeneity in the sample we elected not to include patients with these conditions. It 13 was our goal that the current study provide an early confirmation of the anecdotal findings of 14 physicians globally that there is a potentially increased likelihood of acute DVT with COVID-19 15 and that D-dimer testing is indispensable.

the COVID-19 patients with acute DVT were increased at the upper limit of normal. The clinical 1 utility of these laboratory trends in guiding the workup and treatment of patients with COVID-19 2 requires further study. These early data describe the clinical characteristics of acute DVT in 3 COVID-19 patients and may provide a framework for further study. elevations in the first D-dimer level obtained, the average D-dimer throughout hospitalization, 6 and a less elevated fibrinogen level. There were no significant differences in inflammatory 7 markers such as CRP or neutrophil-to-lymphocyte ratio. The severity of illness at the time of 8 data abstraction and analysis was similar including SOFA score, AKI, and subsequent mortality.

There was a suggestion of an association with ferritin levels and d-dimer levels at the time of the D-Dimer (mcg/mL)

Acute DVT in patients with COVID-19 was associated with elevations in the first D-dimer level obtained, the average D-dimer throughout hospitalization, and a less elevated fibrinogen level. There were no significant differences in inflammatory markers such as CRP or neutrophil-to-lymphocyte ratio. The severity of illness at the time of data abstraction and analysis was similar including SOFA score, AKI, and subsequent mortality

LOS, length of stay. SOFA, sequential organ failure assessment. CPK, creatine phosphokinase. UH, unfractionated heparin. DOAC, direct oral anticoagulant. P:F, ratio of arterial partial pressure of oxygen to the fraction of inspired oxygen. CT, computed tomography. VQ, ventilation-perfusion scan