key: cord-313243-pwmi765q authors: Middeldorp, Saskia; Coppens, Michiel; van Haaps, Thijs F.; Foppen, Merijn; Vlaar, Alexander P.; Müller, Marcella C. A.; Bouman, Catherine C. S.; Beenen, Ludo F. M.; Kootte, Ruud S.; Heijmans, Jarom; Smits, Loek P.; Bonta, Peter I.; van Es, Nick title: Incidence of venous thromboembolism in hospitalized patients with COVID‐19 date: 2020-07-27 journal: J Thromb Haemost DOI: 10.1111/jth.14888 sha: doc_id: 313243 cord_uid: pwmi765q BACKGROUND: Coronavirus disease 2019 (COVID‐19) can lead to systemic coagulation activation and thrombotic complications. OBJECTIVES: To investigate the incidence of objectively confirmed venous thromboembolism (VTE) in hospitalized patients with COVID‐19. METHODS: Single‐center cohort study of 198 hospitalized patients with COVID‐19. RESULTS: Seventy‐five patients (38%) were admitted to the intensive care unit (ICU). At time of data collection, 16 (8%) were still hospitalized and 19% had died. During a median follow‐up of 7 days (IQR, 3‐13), 39 patients (20%) were diagnosed with VTE of whom 25 (13%) had symptomatic VTE, despite routine thrombosis prophylaxis. The cumulative incidences of VTE at 7, 14 and 21 days were 16% (95% CI, 10‐22), 33% (95% CI, 23‐43) and 42% (95% CI 30‐54) respectively. For symptomatic VTE, these were 10% (95% CI, 5.8‐16), 21% (95% CI, 14‐30) and 25% (95% CI 16‐36). VTE appeared to be associated with death (adjusted HR, 2.4; 95% CI, 1.02‐5.5). The cumulative incidence of VTE was higher in the ICU (26% (95% CI, 17‐37), 47% (95% CI, 34‐58), and 59% (95% CI, 42‐72) at 7, 14 and 21 days) than on the wards (any VTE and symptomatic VTE 5.8% (95% CI, 1.4‐15), 9.2% (95% CI, 2.6‐21), and 9.2% (2.6‐21) at 7, 14, and 21 days). CONCLUSIONS: The observed risk for VTE in COVID‐19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE. Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival. Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and can lead to systemic coagulation activation. Initial studies from China report increased D-dimers (0.5 mg/L or higher) in 46% to 63% of patients, as well as other signs of coagulation activation including mild thrombocytopenia and a moderately prolonged prothrombin time. 1, 2 Additionally, more pronounced coagulation activation seems to be correlated with a severe disease course, including admission to the intensive care unit (ICU) and death. For example, patients who died of COVID-19 had higher D-dimers on admission compared with those who survived, whereas D-dimer levels increased further during hospital stay in patients who died, but not in survivors. 3 In another study, patients with D-dimer levels of 1.0 µg/L or higher had an 18-fold increased risk of death. 2 One study used the International Society on Thrombosis and Haemostasis definition of disseminated intravascular coagulation and found that a score of ≥5 points was present in 71% of those who died compared with 0.6% in survivors. 4 None of these studies reported on the number of patients with thrombotic complications. Since the pandemic spread of SARS-CoV-2, there have been several anecdotal reports from colleagues on a high incidence of thrombotic complications, including thrombosis of extracorporeal The primary outcome was an objectively confirmed diagnosis of distal or proximal DVT, PE, or venous thrombosis at other sites including catheter-related thrombosis. The secondary outcome was symptomatic VTE, excluding events detected by bilateral leg ultrasound screening. All outcomes were adjudicated by two of the authors (M.C. and N.v.E.). We did not adjudicate deaths to identify fatal PE because almost all deaths were due to hypoxemic respiratory failure, which can be indistinguishable from fatal PE, whereas autopsies were rarely performed in COVID-19 patients. Patient data were retrospectively reviewed from the day of admission to our hospital (also in case a patient was transferred from another hospital) until death, hospital discharge, transfer to another hospital, or end of data collection on April 30, 2020. We collected data on demographics and blood tests on admission. D-dimer levels were included if measured on or within 72 hours of admis- Patient characteristics were compared between ICU and ward patients using standard descriptive statistics. Between March 2 and April 12, 2020, 199 patients who were hospitalized because of COVID-19 were identified. One patient was ex- Patient characteristics are shown in Table 1 Median follow-up duration was 15 days in ICU patients (IQR, 9, 20) and 4 days in ward patients (IQR, 2, 7 Besides ICU stay, other risk factors associated with VTE in univariable regression analyses were a higher white blood cell count (SHR, 1.9 for every log-transformed unit increase; 95% CI, 1.1-3.2), higher neutrophil-to-lymphocyte ratio (SHR, 2.0 for every log-transformed unit increase; 95% CI, 1.3-3.1), and a higher D-dimer level (SHR, 1.6 for every log-transformed unit increase; 95% CI, 1.2-2.1) ( Table 3) . These associations remained materially unchanged when adjusted for age, sex, and ICU stay (Table 3) We observed a very high risk of VTE in patients with COVID-19. Although the profound coagulopathy associated with COVID-19 has been described soon after start of the pandemic, few data on clinical VTE have been reported. In a cohort of 81 ICU patients in China, in which routine thromboprophylaxis was not the standard of care, the proportion of patients who were diagnosed with DVT was 25%; a follow-up duration or cumulative incidence was not reported. 8 patients suggested that thrombosis prophylaxis was associated with a 56% to 63% reduction in mortality in patients with sepsis-induced coagulopathy, but not in other patients. 12 Only 22% of COVID-19 patients received thrombosis prophylaxis, which is much less than expected according to guidelines on thrombosis prophylaxis in medical patients. 13 Currently, several randomized controlled trials are being planned or have started in which the optimal dose of thrombosis prophylaxis will be investigated. Some of these trials use an pneumonia, although VTE during the course of disease appeared to be associated with mortality in an exploratory analysis in our cohort. Interestingly, none of the patients who were receiving therapeutic anticoagulation at admission (for other indications) developed VTE. The 3% risk of VTE among patients who were not admitted to ICU is considerable, despite the standard use of thrombosis prophylaxis. In an Italian single-center retrospective cohort study, the proportion of COVID-19 patients with VTE was 6% in ward patients, corresponding to a cumulative incidence of 7%. 11 These reported risks appear to be higher than expected in medical hospitalized patients who are not critically ill. 13 Based on the present findings, we believe the threshold of sus- Anticoagulant use at admission 0 (0) 19 (12) SD, standard deviation; SHR, subdistribution hazard ratio; VTE, venous thromboembolism Variables with a non-normal distribution (ie, body weight, white blood cell count, neutrophil count, lymphocyte count, neutrophil-to-lymphocyte ratio, and D-dimer) were analyzed log-transformed Multivariable analysis were adjusted for age, sex, and intensive care unit admission Clinical characteristics of coronavirus disease 2019 in China Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Detection of SARS-CoV-2 in different types of clinical specimens Correlation of chest CT and RT-PCR testing in coronavirus disease CO-RADS -a categorical CT assessment scheme for patients with suspected COVID-19: definition and evaluation Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan. Italy Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients How to cite this article Incidence of venous thromboembolism in hospitalized patients with COVID-19