High Incidence of Venous Thromboembolism in Patients with Coronavirus Disease 2019: A Call for Improved Awareness and Prevention


 Background: An increased risk of venous thromboembolism (VTE) in patients with coronavirus disease 2019 (COVID-19) has been reported. We performed a meta-analysis to evaluate the prevalence of VTE in COVID-19 patients.Methods: The PubMed and Embase databases were searched for studies reporting VTE in COVID-19 patients up to June 27, 2020. The selected studies were predefined into the “suspected screening group” and the “routine screening group.” The VTE prevalence was calculated using random-effect models.Results: We selected 20 studies including a total of 2763 COVID-19 patients. In 2203 COVID-19 patients from the suspected screening group, the pool VTE incidence was 15.2% (95% confidence interval [CI]: 10.5–21.6%). In 560 COVID-19 patients from the routine screening group, the VTE prevalence was 40.8% (95% CI: 20.6–64.7%). Furthermore, the VTE incidence of critically ill COVID-19 patients from the two groups was 19.6% and 61.4%, respectively, which indicates that critically ill COVID-19 patients were more susceptible to VTE.Conclusions: A high incidence of VTE was observed in COVID-19 patients, especially in severe cases. The incidence of VTE in COVID-19 patients from the routine screening group was higher than that in patients from the suspected screening group. This indicates that a lower threshold of suspicion to perform VTE imaging tests may be reasonable and there is an urgent need to adapt a regular screening strategy for VTE.


Introduction
Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has led to a global health crisis. Emerging evidence shows that patients with COVID-19, especially those who are severely ill, have a variety of risk factors for venous thromboembolism (VTE), including infection, immobilization, and mechanical ventilation [1]. The high mortality of COVID-19 patients has been presumed to be partly due to unrecognized pulmonary embolism (PE) and pulmonary in situ thrombosis [2]. Several studies have reported the incidence of VTE in COVID-19 patients [1,[3][4][5][6]. Accurate knowledge of the incidence of VTE in COVID-19 patients is important for decision making with respect to anticoagulation treatment. However, to our knowledge, no previous meta-analysis has estimated the global prevalence of VTE in COVID-19 patients. We therefore performed a meta-analysis and systematic review of studies investigating the prevalence of VTE in patients with COVID-19.

Search strategy
To nd relevant studies, the international databases PubMed and Embase were searched for articles published until June 27, 2020. We performed our search with a search string focusing on "pulmonary embolism," "venous thromboembolism," "pulmonary thromboembolism," "deep venous thrombosis," "2019 novel coronavirus," "COVID 19," "COVID-19," "SARS-CoV-2," "2019 novel coronavirus," "novel coronavirus pneumonia" or "2019-nCoV," and "coronavirus disease-19." These key words were translated speci cally for each database. We additionally performed a manual search of references of the identi ed relevant original and review articles. The reporting of this meta-analysis was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement [7].

Inclusion and exclusion criteria
Studies were included if they met the following criteria: (1) studies that included laboratory-proven COVID-19 patients or clinically con rmed COVID-19 patients screened by a multidisciplinary team, (2) cohort, casecontrol and cross-sectional studies reporting the incidence of image-proven VTE in COVID-19 patients, and (3) articles published in the English language. Conversely, the exclusion criteria were as follows: (1) abstracts, reviews, expert opinion articles, conference proceedings, and books; (2) studies with insu cient data for the calculation of incidence; (3) low-quality studies according to the Newcastle-Ottawa Scale (NOS) criteria or Agency for healthcare Research and Quality (AHRQ) criteria; and (4) studies that only chose the patients examined by computer tomography pulmonary angiography (CTPA) as the subjects.

Data extraction and quality assessment
Two reviewers independently screened and evaluated the literature. Any disagreements were resolved through a discussion. The quality of the included papers was assessed using the NOS, with the scores ranging from 0 to 9. Cohort studies or case-control studies with a score of≥5 were considered high-quality studies. Cohort studies or case-control studies with a score of 5 were considered low-quality studies and excluded from the meta-analysis. Cross-sectional studies with a score of ≥7 were considered high-quality studies. Studies with a score of 7 were considered low-quality studies and excluded from the metaanalysis. The following information was extracted: name of the rst author, sample size, study type, diagnostic method for VTE, incidence of VTE in COVID-19 patients, and anticoagulant therapy.

Statistical analysis
Heterogeneity was evaluated using Cochran's Q test and I 2 statistics. On the basis of the Q test, a randomeffect model was used when the P value was < 0.1. I 2 statistics were utilized to measure the extent of the overall variation due to heterogeneity. I 2 statistics of 25%, 50%, and 75% represented low, medium, and high heterogeneity, respectively. When substantial heterogeneity was observed (I 2 > 50%), the sources of the heterogeneity was investigated using subgroup analyses. We investigated the possibility of publication bias using Egger and Begg tests for asymmetry. All statistical analyses were performed using the meta package in R software (3.3.2).

Characteristics of the included studies
The initial search yielded 558 articles from the different databases. All papers were screened by reading the abstracts, and 173 articles were eliminated for being duplicates found in different databases. After evaluating the full texts, studies presenting data that were irrelevant to our aim were excluded. This left 20 original research articles for inclusion in the meta-analysis and systematic review (Fig. 1). The characteristics of the included studies are provided in Table 1. Thirteen studies used lower-extremity venous ultrasound scanning or CTPA to con rm the diagnosis of VTE only in the presence of a clinical suspicion, and we prede ned this study group as the "suspected screening group." [1,[3][4][5][6][8][9][10][11][12][13][14][15] Seven studies routinely screened VTE in every patient using lower-extremity venous ultrasound scanning, and this study group was prede ned as the "routine screening group." [16][17][18][19][20][21][22] Our primary aim was to determine the incidence of VTE in COVID-19 patients in two prede ned cohort subtypes: (1) suspected screening group and (2) routine screening group.
3.2. Prevalence of VTE in COVID-19 patients from the suspected screening group Figure 2 shows the incidence of VTE in COVID-19 patients when screening for VTE was performed only in the presence of a clinical suspicion. The incidence ranged from 4.1-33.7%, with a pooled incidence of 15.2% (95% con dence interval [CI]: 10.5-21.6%) (Fig. 2). The highest pooled incidence was observed in France (33.7%), and the lowest incidence was seen in Italy (4.1%). A substantial amount of heterogeneity was found among the studies (I 2 = 91.0%, P < 0.01) (Fig. 2). However, there was no indication of publication bias, as evidenced by nonsigni cant results in Egger and Begg tests (P = 0.388 and 0.329, respectively).
We performed subgroup analyses to investigate the sources of heterogeneity. The subgroup analyses were conducted across various clinically relevant subgroups and methodological factors, including population source, geographic location, study quality, and number of cases. Statistically signi cant heterogeneity was observed in all subgroups (I 2 > 50%, P < 0.001). Although we did not nd clear sources of heterogeneity, the subgroup analyses provided additional insights. The intensive care unit (ICU) subgroup tended to yield a higher incidence (21.1%, 95% CI: 16.5-26.5%) than the ICU plus general ward subgroup (7.6%, 95% CI: 3.4-16.1%) (Online Figure I).
To further clarify the incidence of VTE in ICU-admitted COVID-19 patients from the suspected screening group, we extracted detailed information on the study population and recalculated the pooled incidence. Of the 2203 admitted COVID-19 patients, 1223 were admitted to the ICU. The recalculated incidence of VTE was 19.6% (95% CI: 14.3-26.4%) (Fig. 4), which indicates that ICU-admitted COVID-19 patients were more susceptible to VTE. Figure 5 shows the incidence of VTE in COVID-19 patients when routine screening of VTE was performed in all patients. The incidence ranged from 7.3-85.4%, with a pooled incidence of 40.8% (95% CI: 20.6-64.7%).

Prevalence of VTE in COVID-19 patients from the routine screening group
A substantial amount of heterogeneity was found among the studies (I 2 = 95.0%, P < 0.01) (Fig. 5).
We performed subgroup analyses using a number of moderators (population source, geographic location, study quality, and number of cases) to assess whether they can explain some of the heterogeneity. These factors did not explain the heterogeneity. In addition, consistent with the prevalence in the routine screening group, our subgroup analyses indicated that patients in the ICU subgroup had a higher incidence of DVT (74.7%, 95% CI: 52.9-88.6%) than those in the ICU plus general ward subgroup (21.6%, 95% CI: 6.9-50.3%) and those in the general ward subgroup (14.7%, 95% CI: 10.0-21.2%) (Online Figure II).
A total of 216 ICU-admitted patients from six studies in the routine screening group were evaluated to prospectively determine the incidence of VTE among ICU patients. The incidence of VTE in ICU-admitted COVID-19 patients was 61.4% (95% CI: 40.3-78.9%) (Fig. 6), which demonstrates a high incidence rate of VTE in ICU patients from the routine screening group. This nding supports considering routine screening for VTE in ICU-admitted COVID-19 patients in the pandemic context.

Discussion
This timely rapid meta-analysis provides a comprehensive synthesis of the existing evidence highlighting the high prevalence rates of VTE in COVID-19 patients. Our main ndings were the VTE incidences of 15.2% and 40.8% in two prede ned groups: suspected screening group and routine screening group, respectively.
Furthermore, our analysis revealed that COVID-19 patients admitted to the ICU ward had a higher VTE prevalence.
To our knowledge, this is the rst meta-analysis study to assess the incidence of VTE in patients with COVID-19. Our meta-analysis reported that the incidence of VTE in COVID-19 patients from the suspected screening group was 15.2% (95% CI: 10.5-21.6%) and that in COVID-19 patients from the routine screening group was 40.8% (95% CI: 20.6-64.7%). Our ndings indicate a high prevalence of VTE in COVID-19 patients, which is consistent with previous clinical and post-mortem reports. Histologic analysis of pulmonary vessels in patients with COVID-19 showed widespread thrombosis with microangiopathy.
Alveolar capillary microthrombi were nine times as prevalent in patients with COVID-19 as in patients with in uenza (P < 0.001) [23]. This con rms that VTE is an important complication in COVID-19 patients. Physicians need to recognize the signi cant possibility of VTE in COVID-19 patients and should maintain a low threshold for investigating this complication in all patients. The concrete mechanisms underlying the increased risk of VTE in COVID-19 patients are not yet identi ed. Several mechanisms may explain the hypercoagulability in COVID-19 patients, which may involve multiple pathogenetic mechanisms. Endothelial cells are known to play an important role in regulating hemostasis, brinolysis, and vessel wall integrity.
Profound hypoxemia in the pulmonary capillaries may induce endothelial dysfunction and platelet dysfunction [24]. Endothelial cell injury activates a large number of pro-in ammatory cytokines, contributing to microvascular thrombosis including plugging of the pulmonary microvasculature and the occurrence of VTE [25,26]. A better knowledge of the pathogenesis of abnormal coagulation in COVID-19 patients is urgently needed to provide the potential basis of targeted treatments.
VTE is a common complication in the ICU. Critically ill patients are prone to developing VTE as they are susceptible to both general risk factors of VTE and risk factors speci c to ICU patients, such as sedation, immobilization, and vasopressor use [27]. As mentioned in Sect. 3, COVID-19 patients in the ICU were more susceptible to VTE than non-ICU patients, which is in agreement with the previous study. However, the prevalence of VTE in COVID-19 patients in the ICU seemed to be in the higher range than that in published reports on ICU patients admitted for other disease conditions [28][29][30]. In a meta-analysis of seven studies including 1783 ICU patients, the mean rate of VTE diagnosis was 12.7% (95% CI: 8.7-17.5%) [31]. In our meta-analysis, the incidence of VTE in ICU-admitted COVID-19 patients was 19.6% (95% CI: 14.3-26.4%). A previous study identi ed that abnormal coagulation in critically ill COVID-19 patients is associated with a poorer outcome, indicating that VTE may in uence the outcome of critically ill patients with COVID-19 [32].
However, the relationship between VTE and the prognosis of COVID-19 patients needs further studies.
The clinical value of ultrasound screening of the lower extremities in ICU patients with COVID-19 is a matter of debate. Our meta-analysis revealed that the VTE incidence was 40.8% (95% CI: 20.6-64.7%) in the routine screening group, which was much higher than that in the suspected screening group. In addition, the

Conclusions
In conclusion, our meta-analysis and systematic review found a high incidence of VTE in COVID- 19