key: cord-0986790-i3zg6nyl
authors: Chang, Heepeel; Rockman, Caron B.; Jacobowitz, Glenn R.; Speranza, Giancarlo; Johnson, William S.; Horowitz, James M.; Garg, Karan; Maldonado, Thomas S.; Sadek, Mikel; Barfield, Michael E.
title: Deep Venous Thrombosis in Hospitalized Patients with Coronavirus Disease 2019
date: 2020-10-08
journal: J Vasc Surg Venous Lymphat Disord
DOI: 10.1016/j.jvsv.2020.09.010
sha: 173d94c8e2da93a4e171cb2c7108339feb2cfcc0
doc_id: 986790
cord_uid: i3zg6nyl

OBJECTIVES: The pandemic of Coronavirus disease 2019 (COVID-19) has caused devastating morbidity and mortality worldwide. In particular, thromboembolic complications have emerged as a key threat in COVID-19. We assessed our experience with deep venous thrombosis (DVT) in patients with COVID-19. METHODS: We performed a retrospective analysis of all patients with COVID-19 undergoing upper or lower extremity venous duplex ultrasonography at an academic health system in New York City between March 3 2020 and April 12 2020 with follow-up through May 12 2020. A cohort of hospitalized patients without COVID-19 (non-COVID-19) undergoing venous duplex ultrasonography from December 1 2019 to December 31 2019 was used for comparison. The primary outcome was DVT. Secondary outcomes included pulmonary embolism (PE), in-hospital mortality, admission to intensive care unit, and antithrombotic therapy. Multivariable logistic regression was performed to identify risk factors for DVT and mortality. RESULTS: Of 443 patients (188 COVID-19 and 255 non-COVID-19) undergoing venous duplex ultrasonography, patients with COVID-19 had higher incidence of DVT (31% vs. 19%; P=0.005), compared to the non-COVID-19 cohort. The incidence of PE was not statistically different between the COVID-19 and non-COVID-19 cohorts (8% vs. 4%; P=.105). The DVTs in the COVID-19 group were more distal (63% vs. 29%; P<.001) and bilateral (15% vs. 4%; P<.001). The result of duplex ultrasonography had a significant impact on the antithrombotic plan; 42 (72%) patients with COVID-19 in the DVT group had their therapies escalated while 49 (38%) and 3 (2%) patients had their therapies escalated and de-escalated in the non-DVT group, respectively (P<.001). Within the COVID-19 cohort, the D-dimer was significantly higher in the DVT group at the time of admission (2,746 ng/mL vs 1,481 ng/mL; P=.004) and at the time of the duplex exam (6,068 ng/mL vs. 3,049 ng/mL; P<0.01). At multivariable analysis, male sex (odd ratio (OR) 2.27; 95% confidence interval (CI), 1.06-4.87; P=.035), ICU admission (OR 3.42; 95% CI, 1.02-11.44; P=.046) and extracorporeal membrane oxygenation (OR 5.5; 95% CI, 1.01-30.13; P=.049) were independently associated with DVT. CONCLUSION: Given the high incidence of venous thromboembolic events in this population, we support the decision to empirically initiate therapeutic anticoagulation in patients with low bleeding risk and severe COVID-19 infection, with duplex ultrasonography reserved for patients with high clinical suspicion of VTE in which anticoagulation may pose a life-threatening consequence. Further study is warranted in patients with COVID-19 to elucidate the etiology of vascular thromboembolic events and guide prophylactic and therapeutic interventions in these patients.

Take home Message: Given the high incidence of venous thromboembolic events in patients 11 with COVID-19, we support the decision to empirically initiate therapeutic anticoagulation in 12 patients with severe COVID-19 infection, with duplex ultrasonography reserved for patients with 13 high clinical suspicion of VTE in which anticoagulation may pose a life-threatening consequence. 14 15 Table of Contents Summary 16 Incidence of DVT in hospitalized patients with COVID-19 is higher than a general pre-pandemic 17 hospitalized inpatient cohort. We support the decision to empirically initiate therapeutic 18 anticoagulation in patients with severe COVID-19 infection, with duplex ultrasonography (38%) and 3 (2%) patients had their therapies escalated and de-escalated in the non-DVT group, 1 respectively (P<.001). Within the COVID-19 cohort, the D-dimer was significantly higher in the 2 DVT group at the time of admission (2,746 ng/mL vs 1,481 ng/mL; P=.004) and at the time of 3 the duplex exam (6,068 ng/mL vs. 3,049 ng/mL; P<0.01). At multivariable analysis, male sex 4 (odd ratio (OR) 2.27; 95% confidence interval (CI), 1.06-4.87; P=.035), ICU admission (OR 5 3.42; 95% CI, 1.02-11.44; P=.046) and extracorporeal membrane oxygenation (OR 5.5; 95% CI, 6 1.01-30. 13 ; P=.049) were independently associated with DVT. While marked hypercoagulability has been observed in many patients with COVID-19, 8 little is understood about factors associated with DVT in COVID-19. Several recent studies have 9 described links between COVID-19 and pro-inflammatory, hypercoagulable states leading to 10 thromboembolic events. Some studies have suggested that anticoagulation may lower mortality 11 in patients with COVID-19, while others have noted that increased rates of venous There is a lack of evidence as to which risk factors place particular patients with COVID-15 19 at increased risk for VTE and which patients may benefit from prophylactic or therapeutic 16 anticoagulation. An exploration of this issue may offer clinicians clearer guidance on 17 anticoagulation therapy as they face the COVID-19 pandemic. In this study, we examine the December 1, 2019 to December 31, 2019, pre-pandemic, was used for comparison. This study 13 was approved by the institutional review board at New York University Langone Health prior to 14 data analysis, and the need for informed consent was waived.

Data collection 16 Electronic medical records were retrospectively reviewed from hospital admission to the 17 time of discharge, death or end of data monitor period on May 13, 2020. Data including 18 demographic characteristics, medical history, laboratory and imaging data, antithrombotic 19 therapy, in-hospital mortality, DVT, and pulmonary embolism (PE) were collected for analysis. 20 DVT was classified as proximal if localized to the iliac, femoral or popliteal vein, and distal if in The primary outcome was DVT. Secondary outcomes included PE, in-hospital mortality, 12 admission to ICU, and antithrombotic therapy. 13 Statistical analysis 14 Statistical analysis was performed using SPSS 25.0 software (IBM Inc., Armonk, NY).

Chi-square test of independence and Mann-Whitney U test were used for data analysis where 16 applicable, and the Student's t-test was used to compare normally distributed continuous 17 variables. Continuous variables were presented as mean value with standard deviation (SD). 18 Discrete variables were presented as absolute numbers with population percentage. Based on 19 univariate screening of variables with a P < .2, logistic regression models for risk of DVT and in- 20 hospital mortality were created. The effect was expressed by odd ratios (ORs) with 21 corresponding 95% confidence intervals (CIs). Statistical significance was accepted with a P Table I . The COVID-19 cohort were more likely to be male (65% vs. 53%; P = .015) and have 6 higher body-mass index (BMI; 30.2 kg/m 2 vs. 28.1 kg/m 2 ; P = .0002), with higher proportions of 7 diabetes mellitus (DM; 35% vs. 25%; P = .027). Coronary artery disease (CAD; 23% vs. 13%; P 8 = .008), congestive heart failure (CHF; 14% vs. 5%; P = .002), atrial fibrillation (14% vs. 7%; P 9 = .015), hypercoagulable state (10% vs. 4%; P = .018) and prior history of DVT (18% vs. 4%; P 10 < .001) were more common in the non-COVID-19 cohort. The COVID-19 cohort had higher 11 proportions of patients requiring ICU admission (52% vs. 18%; P < .001), ventilatory support 12 (45% vs. 12%; P < .001) and dialysis (12% vs. 2%; P < .001). The mean age was similar, 64 ± 15 13 year in the COVID-19 and 63 ± 18 years in the non-COVID-19 cohorts (P = .513). The mean 14 time from admission to duplex ultrasound in the COVID-19 cohort was 7 ± 6 days (range, 0-29 15 days). The mean length of stay was 21 ± 15 days (range, 1-60 days) among 162 (86%) patients 16 with COVID-19, and 22 (14%) patients remained hospitalized by the end of the follow-up 17 period.

In-hospital outcomes and thromboembolic characteristics 19 Comparison of in-hospital outcomes are detailed in Table II . The COVID-19 cohort had a 20 higher incidence of DVT (31% vs. 19%; P = .005), compared to the non-COVID-19 cohort.

However, the incidence of PE was not statistically different between the COVID-19 and non- Table III . The DVTs in the COVID-19 cohort tended to be 1 distal (63% vs. 29%; P < .001) and bilateral (15% vs. 4%; P < .001) whereas those in the non-2 COVID-19 cohort were more likely to occur in the upper extremities (20% vs. 7%; P < .001).

The overall in-hospital mortality was significantly higher in the COVID-19 cohort as compared 4 to the non-COVID-19 cohort (22% vs. 7%; P < .001). Table I . The DVT group was more likely to be male (77% vs. 60%; P = .026) and need 8 extracorporeal membrane oxygenation (ECMO; 11% vs. 2%; P = .004), compared to the non-9 DVT group. There was higher prevalence of patient taking anticoagulants as home medications 10 in the non-DVT group (16% vs. 0%; P < .001). The rates of in-hospital mortality (19% vs. 24%; 11 P = .7), ICU admissions (61% vs. 49%; P = .49), ventilatory support (48% vs. 44%; P = .573) 12 and dialysis (12% vs. 12%; P = .963) did not differ significantly between the DVT and non-DVT 13 groups, respectively. 14 VTE characteristics in the COVID-19 cohort 15 VTE characteristics are shown in Table III 1,467 ng/mL; P < .001, and 5,823 ng/mL vs. 3,528 ng/mL; P = .008, respectively). 13 Before duplex ultrasound, the proportions of prophylactic (62% vs. 74%) and therapeutic As compared to the pre-pandemic hospitalized cohorts, the severity of acute inflammatory 7 response and the prevalence of organ failure were significantly higher in patients with COVID-8 19, as evidenced by higher rates of ICU admission, ventilatory support, renal failure requiring 9 hemodialysis and death. Furthermore, the risk profile associated with COVID-19 appeared to 10 supersede previously known risk factors for DVT such as prior VTE, advanced age, obesity, 11 cancer and baseline hypercoagulable disorder. As such, patients with COVID-19 may benefit 12 from empiric therapy instead of awaiting duplex ultrasonography, which can delay appropriate 13 therapy and potentially subject vascular laboratory technicians to unnecessary exposure. Emerging evidence points toward intense vasodilation and endothelial dysfunction as the 3 mechanism leading to severe acute respiratory syndrome in COVID-19. 15 Reports of increased 4 respiratory dead space suggest pulmonary vascular thrombosis from thrombotic 5 microangiopathy. 16 We found that ECMO and ICU status were independently associated with There are several limitations to this study. There was a limited number of patients 10 undergoing venous duplex ultrasonography, largely related to the lack of available resources to 11 scan all patients with elevated D-dimers and competing risk of death; however, this is the largest 12 series to date specifically tailored to characterize DVT and evaluate the incidence of DVT in 13 patients with COVID-19 undergoing venous duplex. Another limitation of the study is that it is 14 retrospective in nature, and we were unable to control for such confounders as multiple 15 investigational drugs (i.e. clazakizumab, remdesivir, and sarilumab). J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

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