key: cord-1031550-q7ae4dyf
authors: Brosnahan, Shari B.; Smilowitz, Nathaniel R.; Amoroso, Nancy E.; Barfield, Michael; Berger, Jeffery S.; Goldenberg, Ronald; Ishida, Koto; Talmor, Nina; Torres, Jose; Yaghi, Shadi; Yuriditsky, Eugene; Maldonado, Thomas
title: Thrombosis at Hospital Presentation in Patients with and without COVID-19
date: 2020-11-10
journal: J Vasc Surg Venous Lymphat Disord
DOI: 10.1016/j.jvsv.2020.11.004
sha: d4486eff7108da2c50466f7c8dec09e298c88bff
doc_id: 1031550
cord_uid: q7ae4dyf

OBJECTIVE: To better characterize COVID-19 patients most at risk for severe, outpatient thrombosis by defining patients hospitalized with COVID-19 with an arterial or venous thrombosis diagnosed at admission METHODS AND RESULTS: We conducted a single center retrospective analysis of COVID-19 patients. There was a shift in the proportions of thrombosis subtypes from 2019 to 2020, with declines in STEMI (from 22.0% to 10.1% of thrombotic events) and stroke (from 48.6% to 37.2%), and an increase in the proportion of patients with VTE (29.4% to 52.7%). COVID-associated thrombosis were younger (58 years vs. 64 years, p=0.043), trended to be less frequently female (31.3% vs. 43.9%, p =0.16), but there was no difference body mass index or major comorbidities between those with and without COVID-19. COVID-19-associted thrombosis was correlated with a higher mortality (15.2% vs. 4.3%, p=0.016). The biometric profile of patients admitted with COVID-associated thrombosis compared to regular thrombosis had significant changes in the complete blood count, liver function tests, d-dimer, c-related protein, ferritin, and coagulation panels. CONCLUSIONS: Outpatients with COVID-19 who developed thrombosis requiring hospitalization have an increased mortality over non-COVID-19 outpatients who develop thrombosis requiring hospitalization. Given the significantly higher inflammatory markers, it is possible this is related to different mechanisms of thrombotic disease in these patients. The inflammation may be a target to reduce the risk of or aid in the treatment of thrombosis. We call for more studies elucidating the role immunothrombosis maybe playing in COVID.

1 the first 48 hours of hospital admission in March and April of 2020 (44 per 1,000 admissions), 2 compared to 109 patients with thrombosis during the same time period in 2019 (37 per 1,000 3 admissions). There was a shift in the relative proportions of thrombosis subtypes, with declines 4 in STEMI (from 22.0% to 10.1% of thrombotic events) and stroke (from 48.6% to 37.2%), and 5 an increase in the proportion of patients with VTE (29.4% to 52.7%). COVID-associated 6 thrombosis were younger (58 years vs. 64 years, p=0.043), trended to be less frequently female 7 (31.3% vs. 43.9%, p =0.16), but there was no difference body mass index or major comorbidities 8 between those with and without COVID-19. COVID-19-associted thrombosis was correlated 9 with a higher mortality (15.2% vs. 4.3%, p=0.016).

10 11 Take home Message: In patients infected with COVID-19, the development of thrombosis as 12 an outpatient portends a higher mortality than others who develop outpatient thrombosis. The 13 mechanism of thrombosis has not been completely understood, given the variations in biometric 14 profiles there is questions of immunothrombosis being the major driver. This may mean that 15 treatment and prevention strategies should vary. between those with and without COVID-19. Given the variation in biometric profiles in those 1 with COVID clot, there could be a role of immunothrombosis. patients. There was a shift in the proportions of thrombosis subtypes from 2019 to 2020, with 6 declines in STEMI (from 22.0% to 10.1% of thrombotic events) and stroke (from 48.6% to 7 37.2%), and an increase in the proportion of patients with VTE (29.4% to 52.7%). COVID-8 associated thrombosis were younger (58 years vs. 64 years, p=0.043), trended to be less 9 frequently female (31.3% vs. 43.9%, p =0.16), but there was no difference body mass index or 10 major comorbidities between those with and without COVID-19. COVID-19-associted 11 thrombosis was correlated with a higher mortality (15.2% vs. 4.3%, p=0.016). The biometric 12 profile of patients admitted with COVID-associated thrombosis compared to regular thrombosis 13 had significant changes in the complete blood count, liver function tests, d-dimer, c-related 14 protein, ferritin, and coagulation panels.

Conclusions: Outpatients with COVID-19 who developed thrombosis requiring hospitalization 16 have an increased mortality over non-COVID-19 outpatients who develop thrombosis requiring 17 hospitalization. Given the significantly higher inflammatory markers, it is possible this is related 18 to different mechanisms of thrombotic disease in these patients. The inflammation may be a

J o u r n a l P r e -p r o o f Thrombosis is a frequent complication during hospitalization for the novel 2019 coronavirus 1 disease (COVID-19) and occurs in up to 31% of cases. 1 Even in patients without overt 2 thrombosis, COVID-19 is frequently characterized by abnormal coagulation parameters, 3 including elevated D-dimer, which are associated with an adverse prognosis. [2] [3] [4] [5] anticoagulation in patients with COVID-19 may be beneficial. In an observational study, patients 5 with severe COVID-19 and an elevated D-dimer or evidence of coagulopathy who received 6 thromboprophylaxis during hospitalization had decreased in-hospital mortality, 6 supporting 7 associations between thrombosis and outcomes. Autopsy studies also note fatal thromboses in 8 -19. 7 Consequently, current society recommendations support chemical 9 thromboprophylaxis to mitigate thrombotic risk among inpatients with 8, 9 10 Catastrophic thrombotic events, including pulmonary embolism, stroke, and myocardial 11 infarction have been also reported in COVID-19 at the time of hospital presentation, suggesting 12 pre-hospital initiation of thrombus. 7, 10-12 Excess out-of-hospital deaths observed during the Demographics of patients with thrombosis with and without COVID-19 are shown in Table 1 . 5 Patients with COVID-associated thrombosis were younger (58 years vs. 64 years, p=0.043) and In-hospital mortality or discharge to hospice care was significantly more common in patients 9 with COVID-19-associted thrombosis than patients with thrombosis in the absence of COVID-10 19 (15.2% vs. 4.3%, p=0.016). COVID-19 status was significantly associated with in-hospital 11 all-cause mortality after adjustment for age, sex, and subtype of thrombosis (aOR 35.7, 95% CI 2.0 (0-6), p=0.031 than those without (n=71). COVID-19 patients who presented with stroke 15 were as likely to have a pre-morbid modified Rankin score ≥1 as patients without COIVD-19 16 (12.5% with COVID vs. 32.4% without COVID, p=0.424). Among 80 strokes included in the 17 final analysis, in-hospital mortality in patients with COVID-19 was numerically higher than 18 those without COVID-19 (33.3% vs. 6.8%, p=0.084). In this study of patients with thrombosis before and after the COVID-19 pandemic, we observed 1 that the number of STEMI activations decreased, 18, 19 severe strokes in younger patients 2 increased, 20, 21 and incidence of deep vein thrombosis and pulmonary embolism increased, 22, 23 as 3 previously described in other cohorts. However, unlike prior studies, our data demonstrate that 4 this occurred among patients with thrombosis in the outpatient setting. Although patients with 5 thrombosis and COVID-19 were younger than those without COVID-19, we observed few other 6 differences in demographics and clinical characteristics between the two groups. These data 7 suggest that patients at risk before COVID-19 remain at increased risk with COVID-19 with the 8 notable exception of those with malignancy. There was a large reduction in proportion of 9 patients with clots requiring hospitalization with malignancy who had COVID compared to those 10 who did not have COVID Thrombi were identified within 21 days of COVID-19 symptom onset, 11 and most were within 14 days. This may inform the optimal duration of thromboprophylaxis in 12 those that might derive benefit.

Changes in thrombosis epidemiology during the COVID-19 era is also complicated by home 14 quarantine orders in the New York City area. This city mandate increased the time that residents 15 were indoors and limited their mobility. Home quarantine might increase the risk of thrombosis, 16 but this has not been proven and the degree to which quarantine increases risk is not known. 17 We showed increased mortality in COVID-19 patients who develop outpatient thrombosis as Respiratory infections, and pneumonia specifically, have shown to increase incidence of venous 4 thromboembolism. 24 In the Sirius study, mobility changes, cancer, and infectious disease were 5 identifies as risk factors for increased thrombosis. 25 The degree to which COVID-19 confers 6 thrombotic risk relative to other infections is not known but is an area of ongoing interest.

Although thromboprophylaxis may yield clinical benefit in COVID-19, the optimal 8 antithrombotic therapy is unknown, and bleeding complications the use of anticoagulation in 9 COVID-19 have been reported. 26, 27 In order to determine which patients should receive 10 anticoagulation, risks and benefits need to be well-established. Understanding the clinical 11 characteristics of outpatients who develop thrombosis in the setting of COVID-19 will be 12 imperative to this effort and this paper is one of the first steps in generating this data.

Our study has several important limitations. It is a retrospective, observational analysis of a 14 single large academic hospital center in the epicenter of the early COVID-19 pandemic in the 15 United States. Data were acquired during the surge of cases in New York City, prior to 16 understanding the complex pathophysiology of disease. The concern of infectious spread may particularly if patients allowed symptoms to persist for longer, and outpatient providers were 21 unable to establish the diagnosis via telemedicine. While we are not able to quantify the 22 reluctance, our data shows evidence of this as there was a trend toward increase in the time from symptoms onset to presentation for myocardial infarct. Even with these limitations, this paper 1 highlights the risks of outpatient thrombosis in patients with COVID-19 and demonstrates that 2 the thrombosis risk appears to be highest within 3 weeks of COVID-19 symptoms. This 3 highlights the need to identify which patients may derive the greatest benefit from outpatient 4 thromboprophylaxis. 

Confirmation of the high cumulative incidence of 3 thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis

Venous and arterial thromboembolic complications in COVID-19 7 patients admitted to an academic hospital in

Abnormal coagulation parameters are associated with poor 9 prognosis in patients with novel coronavirus pneumonia

Medical Treatment Expert Group for C. Clinical Characteristics of Coronavirus 15 Disease 2019 in China

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Anticoagulant treatment is associated with 21 decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Autopsy Findings and Venous 27

Thromboembolism in Patients With COVID-19: A Prospective Cohort Study. Annals of internal medicine

ISTH interim 30 guidance on recognition and management of coagulopathy in COVID-19

Thromboembolism and anticoagulant therapy during the 34 COVID-19 pandemic: interim clinical guidance from the anticoagulation forum

Pulmonary and Cardiac 37 Pathology in Covid-19: The First Autopsy Series from New Orleans; 2020. 38 11

Pulmonary Arterial Thrombosis in COVID-19 With Fatal Outcome: Results From a 40

Clinicopathologic Case Series

Large-Vessel 43 Stroke as a Presenting Feature of Covid-19 in the Young

Death Reach 6 Times the Normal Level, Far More Than Coronavirus 1 Count Suggest. The New York Times

There's Been a Spike in People Dying at Home in Several Cities. That 3 Suggests Coronavirus Deaths Are Higher Than Reported

Characteristics Associated With Out-of-Hospital Cardiac Arrests and Resuscitations During the Novel 6

Coronavirus Disease

COVID-19 and hypercoagulability in the outpatient setting. 8 Thrombosis research

Clinical 10 characteristics and outcome of inpatients versus outpatients with venous thromboembolism: Findings 11 from the RIETE Registry

Reduced Rate of Hospital Admissions for ACS 18 during Covid-19 Outbreak in Northern Italy

The Covid-19 Pandemic and the Incidence of Acute Myocardial Infarction

Large-Vessel 24 Stroke as a Presenting Feature of Covid-19 in the Young

Lord A 28 and Frontera J. SARS2-CoV-2 and Stroke in a New York Healthcare System

Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased 32 Prevalence

Confirmation of the high cumulative incidence of 35 thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis

Pneumonia 38 and risk of venous thrombosis: results from the MEGA study

An epidemiologic study of risk factors for deep vein thrombosis in medical 41 outpatients: the Sirius study

Hemorrhagic stroke and anticoagulation in COVID-19

Bleeding in COVID-19 severe pneumonia: 46 The other side of abnormal coagulation pattern?

COPD-Chronic Obstructive Pulmonary Disease, CKD-Chronic kidney disease, ESRD-End-Stage Renal Disease , HIV-Human Immunodeficiency Virus, MI-Myocardial Infarction, NSAIDs-Nonsteroidal Anti-inflammatory Drugs, STEMI-ST-segment Myocardial Infarction

J o u r n a l P r e -p r o o f