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Deep vein thrombosis in hospitalized patients with coronavirus disease 2019

Objective 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 for patients with COVID-19. We assessed our experience with deep vein thrombosis (DVT) in patients with COVID-19. Methods We performed a retrospective analysis of all patients with COVID-19 who had undergone upper or lower extremity venous duplex ultrasonography at an academic health system in New York City from March 3, 2020 to April 12, 2020 with follow-up through May 12, 2020. A cohort of hospitalized patients without COVID-19 (non–COVID-19) who had undergone venous duplex ultrasonography from December 1, 2019 to December 31, 2019 was used for comparison. The primary outcome was DVT. The secondary outcomes included pulmonary embolism, in-hospital mortality, admission to the intensive care unit, and antithrombotic therapy. Multivariable logistic regression was performed to identify the risk factors for DVT and mortality. Results Of 443 patients (COVID-19, n = 188; and non–COVID-19, n = 255) who had undergone venous duplex ultrasonography, the COVID-19 cohort had had a greater incidence of DVT (31% vs 19%; P = .005) than had the non–COVID-19 cohort. The incidence of pulmonary embolism was not significantly different statistically between the COVID-19 and non–COVID-19 cohorts (8% vs 4%; P = .105). The DVT location in the COVID-19 group was more often distal (63% vs 29%; P < .001) and bilateral (15% vs 4%; P < .001). The duplex ultrasound findings had a significant impact on the antithrombotic plan; 42 patients (72%) with COVID-19 in the DVT group had their therapy escalated and 49 (38%) and 3 (2%) had their therapy escalated and deescalated in the non-DVT group, respectively (P < .001). Within the COVID-19 cohort, the D-dimer level was significantly greater in the DVT group at admission (2746 ng/mL vs 1481 ng/mL; P = .004) and at the duplex examination (6068 ng/mL vs 3049 ng/mL; P < .01). On multivariable analysis, male sex (odds ratio [OR], 2.27; 95% confidence interval [CI], 1.06-4.87; P = .035), intensive care unit 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. Conclusions Given the high incidence of venous thromboembolic events in this population, we support the decision to empirically initiate therapeutic anticoagulation for patients with a low bleeding risk and severe COVID-19 infection. Duplex ultrasonography should be reserved for patients with a high clinical suspicion of venous thromboembolism for whom anticoagulation therapy could result in life-threatening consequences. Further study of patients with COVID-19 is warranted to elucidate the etiology of vascular thromboembolic events and guide the prophylactic and therapeutic interventions for these patients.

In late 2019 and early 2020, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global outbreak of coronavirus disease 2019 . To date, w6 million people have been affected, with an overall mortality of w7%. 1 The clinical presentation of COVID-19 ranges from asymptomatic or mild cases of pneumonia to severe acute respiratory distress syndrome, cardiomyopathy, derangements in coagulation, and death.
Although marked hypercoagulability has been observed in many patients with COVID-19, little is understood about the factors associated with deep vein thrombosis (DVT) in COVID- 19. Several recent studies have described links between COVID-19 and proinflammatory, hypercoagulable states leading to thromboembolic events. Some studies have suggested that anticoagulation therapy might lower mortality in patients with COVID-19. However, others have reported that the increased rates of venous thromboembolism (VTE) in patients with COVID-19 in the intensive care unit (ICU) persist despite prophylactic anticoagulation. [2][3][4][5] Evidence is lacking regarding which risk factors will place particular patients with COVID-19 at increased risk of VTE and which patients might benefit from prophylactic or therapeutic anticoagulation. An exploration of this issue might offer clinicians clearer guidance on the use of anticoagulation therapy as they treat patients during the COVID-19 pandemic. In the present study, we examined the incidence of DVT and associated risk factors among patients with confirmed COVID-19.

METHODS
Study population. From March 3, 2020 to April 12, 2020, all consecutive patients admitted to a single academic medical center in New York City with SARS-CoV-2 pneumonia who had undergone venous duplex ultrasonography of the upper or lower extremities were included. Duplex ultrasound studies were ordered based on the clinical judgment of the treating physicians. All studies were performed by accredited vascular technologists and reviewed and formally read by vascular surgeons with either registered vascular technologist or registered physician in vascular interpretation accreditation in a vascular laboratory accredited by the Intersociety Accreditation Commission. SARS-CoV-2 pneumonia was diagnosed clinically and confirmed by reverse transcription-polymerase chain reaction detection of COVID-19. The clinical outcomes were monitored up to May 13, 2020. A cohort of hospitalized patients admitted without COVID-19 (noneCOVID-19) who had undergone venous duplex ultrasonography from December 1, 2019 to December 31, 2019, before the pandemic, was used for comparison. The institutional review board at New York University Langone Health approved the present study before data analysis and waived the need for patient informed consent.
Data collection. The electronic medical records were retrospectively reviewed from hospital admission to the time of discharge, death, or the end of data monitoring period (May 13, 2020). Data, including demographic characteristics, medical history, laboratory and imaging data, antithrombotic therapy, in-hospital mortality, DVT, and pulmonary embolism (PE), were collected for analysis. DVT was classified as proximal if localized to the iliac, femoral, or popliteal vein and distal if in the tibial, gastrocnemius, or soleal vein. Upper extremity DVT was defined as thrombosis of the radial, ulnar, brachial, axillary, subclavian, or internal jugular vein. Patients were categorized as non-ICU or ICU patients. Non-ICU patients were defined as those not in the ICU for their entire hospital stay. All ICU patients had required mechanical ventilation and/or were hemodynamically unstable, requiring a titrating dose of vasoactive infusion in an intensive care setting at some point during their hospitalization. Prophylactic antithrombotic therapy was a part of the standard care for all admitted patients with COVID-19, unless clinically contraindicated and consisted of 5000 U of subcutaneous unfractionated heparin three times daily, 40 mg of subcutaneous low-molecularweight heparin (LMWH; enoxaparin sodium) daily, or 30 mg LMWH twice daily. Persistent elevation of D-dimer levels after initiation of anticoagulation was defined as an increasing D-dimer value after $5 days of anticoagulation compared with the level before the initiation of anticoagulation.
Outcomes. The primary outcome was DVT. The secondary outcomes included PE, in-hospital mortality, admission to the ICU, and antithrombotic therapy.  , with a greater proportion of distal (63% vs 29%; P < .001) and bilateral (15% vs 4%; P < .001) DVTs compared with those without COVID-19. Male sex and markers of a severe inflammatory process such as intensive care unit admission and extracorporeal membrane oxygenation support were independently associated with DVT. d Take Home Message: Given the high incidence of venous thromboembolic events in patients with COVID-19, we support the decision to empirically initiate therapeutic anticoagulation for patients with severe COVID-19 infection. Duplex ultrasonography should be reserved for patients with a high clinical suspicion of venous thromboembolism for whom anticoagulation therapy could result in lifethreatening consequences.
In-hospital outcomes and thromboembolic characteristics. The results from a comparison of in-hospital outcomes are detailed in Table II. The COVID-19 cohort had a greater incidence of DVT (31% vs 19%; P ¼ .005) compared with the noneCOVID-19 cohort. However, the incidence of PE was not significantly different statistically between the COVID-19 and noneCOVID-19 cohorts (8% vs 4%, respectively; P ¼ .105). The distribution of DVTs stratified by COVID-19 status is summarized in Table III. The DVTs in the COVID-19 cohort tended to be distal (63% vs 29%; P < .001) and bilateral (15% vs 4%; P < .001). In contrast, those in the noneCOVID-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 than in the none COVID-19 cohort (22% vs 7%; P < .001).
VTE characteristics in the COVID-19 cohort. The VTE characteristics are shown in Table III. Of the 58 cases of DVT, 36 (63%) were distal (soleal, tibial, or gastrocnemius vein), 7 (13%) were proximal (iliac, femoral, or popliteal vein), 10 (18%) were both, and 4 (7%) were in the upper extremity (brachial, internal jugular, or radial vein). Of the 15 cases of PE in the COVID-19 cohort, 11 (73%) had occurred in the setting of concomitant DVT and 4 (27%) without demonstrable DVT. Four patients with DVT underwent inferior vena cava filter placement because of extensive bilateral DVTs with PE in three patients and a contraindication for systemic anticoagulation in one patient.
Antithrombotic regimen in the COVID-19 cohort. A comparison of various antithrombotic therapies before and after duplex ultrasonography in the COVID-19 cohort is detailed in Table IV. Of the 188 patients, 20 (11%) had not received any antithrombotic therapy until duplex ultrasonography had been performed, 12 because of recent or remote gastrointestinal bleeding and 8 because of active intracranial malignancy, recent neurosurgery, or intracranial hemorrhage. Of 37 patients (20%) receiving therapeutic dose anticoagulation at duplex ultrasonography, 21 had received a therapeutic dose since admission and 16 had had the therapy escalated to the therapeutic dose because of a progressive increase in D-dimer before the duplex ultrasound examination. Of the 188 patients, 152 (81%) had received a prophylactic dose on admission to the hospital (unfractionated heparin, n ¼ 39; LMWH, n ¼ 113). Of the 113 patients receiving a prophylactic dose of LMWH, 16 had their does escalated to the therapeutic level, as stated previously. Patients receiving the therapeutic dose before duplex ultrasonography had had a significantly greater mean D-dimer level at admission and duplex ultrasound examination compared with those not receiving a therapeutic dose (3527 ng/mL vs 1467 ng/mL; P < .001; and 5823 ng/mL vs 3528 ng/mL; P ¼ .008, respectively).
Before duplex ultrasonography, the proportion of prophylactic (62% vs 74%) and therapeutic (26% vs 16%) doses did not differ between the DVT and non-DVT groups, respectively (P ¼ .231). However, the results of duplex ultrasonography had a significant effect on the antithrombotic plan; 42 patients (72%) in the DVT group had had their therapy escalated and 49 (38%) and 3 (2%) had had their therapy escalated and deescalated in the non-DVT group, respectively (P < .001). Of the 20 patients who had not been receiving any antithrombotic therapy, 7 (35%) were diagnosed with DVT. In contrast, 36 of 132 patients receiving a prophylactic dose had developed DVT. Of 36 patients receiving a therapeutic dose, 15 (42%) had developed DVT. None of the 21 patients receiving a therapeutic dose of antithrombotic therapy because of their comorbidities (atrial fibrillation or history of DVT) had developed DVT.
D-dimer level and association with DVT in the COVID-19 cohort. The comparison of the plasma D-dimer levels at different stages of the hospital stay between the DVT and non-DVT cohorts is summarized in Table II. The Ddimer level was significantly higher in the DVT cohort at hospital presentation (2746 ng/mL vs 1481 ng/mL; P ¼ .004) and at the duplex ultrasound examination (6068 ng/mL vs 3049 ng/mL; P < .001). The peak D-dimer level was also higher in the DVT cohort (6927 ng/mL vs 4293 ng/mL; P < .001). The initiation of therapeutic anticoagulation in the DVT cohort was associated with a significant reduction in the D-dimer level compared with that of the non-DVT cohort (2241 ng/mL vs 2028 ng/mL; P ¼ .58). However, 9 patients (16%) in the DVT cohort and 39 (30%) in the non-DVT cohort exhibited persistently elevated D-dimer levels refractory to systemic anticoagulation therapy. This subset of patients was associated with increased in-hospital mortality (46% vs 12%; P < .001). The location and extent of DVT did not have a significant effect on the degree of D-dimer elevation (data not shown).

DISCUSSION
COVID-19 has been associated with hemostatic abnormalities, including mild thrombocytopenia, increased D-dimer levels, and derangement in coagulation. [6][7][8] However, only a few studies have described the association between DVT and COVID-19. Although thrombosis was observed in other acute infections such as the influenza pandemic in 2009, we observed an unusually high rate (31%) of DVT in patients admitted with SARS-CoV-2 pneumonia. Compared with the prepandemic hospitalized cohorts, the severity of the acute inflammatory response and the prevalence of organ failure were significantly greater in patients with COVID-19, as evidenced by the higher rates of ICU admission, ventilatory support, renal failure requiring hemodialysis, and death. Furthermore, the risk profile associated with COVID-19 appeared to supersede previously known risk factors for DVT such as previous VTE, advanced age, obesity, cancer, and a baseline hypercoagulable disorder. As such, patients with COVID-19 might benefit from empiric therapy, instead of waiting for duplex ultrasonography, which can delay appropriate therapy and, potentially, subject vascular laboratory technicians to unnecessary exposure to COVID-19.
Thromboembolic complications have emerged as a key threat in patients with COVID-19. Although largely unknown, several mechanisms have been proposed to explain the potential cascades by which COVID-19 might promote thrombosis. A metallopeptidase, angiotensinconverting enzyme 2, has been identified as a functional receptor of SARS-CoV-2. 9 Because these receptors are expressed in endothelial cells, COVID-19 might cause hemostatic derangement through direct endothelial involvement. 10   and found extensive endotheliitis, suggesting direct viral infection of the endothelial cells. This direct endothelial involvement might explain why D-dimer elevations has been one of the most consistent findings in COVID-19.
Other mechanisms include cytokine storm, hypoxic injury, increased platelet activity, complement cascade activation, and a transient increase in antiphospholipid antibodies, leading to prothrombotic state. [12][13][14] Emerging evidence has pointed toward intense vasodilation and endothelial dysfunction as the mechanism leading to severe acute respiratory syndrome in patients with COVID-19. 15 Reports of increased respiratory dead space have suggested the presence of pulmonary vascular thrombosis from thrombotic microangiopathy. 16 We found that ECMO and ICU status were independently associated with DVT among patients undergoing venous duplex ultrasonography. These findings might indicate that the severity of intrapulmonary shunting and microvascular thrombosis could reflect the severity of global endothelial inflammation, predisposing patients to venous thromboembolic events. A few studies have demonstrated a high incidence of VTE in patients with COVID-19. However, these studies were limited by the small numbers of patients undergoing duplex ultrasonography to confirm and characterize DVT (ie, location, extent, and unilateral vs bilateral). 4,[17][18][19][20][21] Of 34 patients with COVID-19 receiving antithrombotic therapy in the ICU, Nahum et al 17 demonstrated a DVT rate of 65%, predominantly bilateral (53%) and proximal (26%) in distribution. In 81 ICU patients in China, Cui et al 18 showed that 25% of patients were diagnosed with DVT. However, the study was biased by patients not having received routine antithrombotic therapy. In European studies of patients receiving prophylactic antithrombotic therapy, the incidence VTE ranged from 18% to 31% and was predominantly PE. 4,[19][20][21] In contrast to our unusually high rate of DVT, the incidence of DVT in these studies was reported at 2% to 13%. This observed difference could also have results from the diagnostic challenges among patients with COVID-19, because the imaging studies used to diagnose DVT might not be pursued owing to the risk of transmitting infection to other patients or healthcare workers and, potentially, because of patient instability. Moreover, the use of duplex ultrasonography could have been limited by patient positioning, because many patients with acute respiratory distress syndrome will require prone positioning, and the prognosis of patients might be grave enough that the diagnosis of an underlying VTE might not alter the course of treatment. Unlike previous studies, we included only patients who had undergone venous duplex ultrasonography. As such, our study had the largest number of positive duplex studies to date, allowing for the most accurate characterization of DVT in patients with COVID-19. The COVID-19 cohort exhibited more distal (63% vs 29%; P < .001) and bilateral (15% vs 4%; P < .001) DVTs. These findings are consistent with previous studies demonstrating the effect of COVID-19 on small blood vessels, which might explain the unusually high proportion of distal DVTs seen in our study.
At present, the role of empiric therapeutic anticoagulation without a diagnosis of VTE has been controversial. A few single-center studies have suggested the potential benefit of intermediate and therapeutic doses of anticoagulation to prevent microvascular thrombosis. 4 anticoagulation. Because of the difficulty in performing duplex ultrasonography owing to the limited workforce and personal protective equipment and difficulty in completely disinfecting the machine between patients, the clinical practice at our institution changed toward the end of the study period. Duplex ultrasonography was performed more selectively for patients with a high bleeding risk and a high clinical suspicion of PE and/or DVT. In addition, with the increased awareness of VTE developing in patients with COVID-19, therapeutic anticoagulation was pre-emptively initiated without a confirmed diagnosis of VTE in the ICU patients with a low bleeding risk and suspected VTE and/or a high level of serum acute phase reactants reflective of a severe inflammatory process (ie, elevated D-dimer >2000 mg/dL).
Additional studies might be needed to further define the additional risk factors for VTE to help identify those at most risk of VTE. A prospective randomized controlled trial (ClinicalTrials.gov identifier, NCT04359277) is ongoing to compare a lower dose against a higher dose of antithrombotic therapy to reduce the complications of DVT formation in patients hospitalized for COVID-19 infection.
The present study had several limitations. A limited number of patients had undergone venous duplex ultrasonography, largely related to the lack of available resources to scan all patients with elevated D-dimer levels and the competing risk of death. However, to the best of our knowledge, the present study is the largest series to date specifically tailored to characterize DVT and evaluate the incidence of DVT in patients with COVID-19 undergoing venous duplex ultrasonography. Another limitation of the present study was that it was  retrospective in nature, and we were unable to control for such confounders as multiple investigational drugs (ie, clazakizumab, remdesivir, sarilumab).

CONCLUSIONS
Our study has provided the characteristics and incidence of DVT in patients with confirmed COVID-19. Given the high incidence of venous thromboembolic events in this population, we support the decision to empirically initiate therapeutic anticoagulation for patients with a low bleeding risk and severe COVID-19 infection. Duplex ultrasonography should be reserved for patients with a high clinical suspicion of VTE for whom therapeutic anticoagulation could result in lifethreatening consequences. Further studies are needed to elucidate the mechanisms leading to venous thromboembolic events to better guide treatment in the COVID-19 cohort.