key: cord-0972394-x4l9svow
authors: Wu, Ting; Zuo, Zhihong; Yang, Deyi; Luo, Xuan; Jiang, Liping; Xia, Zanxian; Xiao, Xiaojuan; Liu, Jing; Ye, Mao; Deng, Meichun
title: Venous thromboembolic events in patients with COVID-19: A systematic review and meta-analysis
date: 2020-11-17
journal: Age Ageing
DOI: 10.1093/ageing/afaa259
sha: 8ec6a4051c95033a2aed8464225e0f22be22bcaa
doc_id: 972394
cord_uid: x4l9svow

BACKGROUND: High incidence of venous thromboembolic complications in COVID-19 patients was noted recently. OBJECTIVE: This study aimed to explore the factors associated with prevalence of venous thromboembolism (VTE) in COVID-19 patients. METHODS: A literature search was conducted in several online databases. Fixed effects meta-analysis was performed for the factors associated with prevalence of VTE in COVID-19 patients. RESULTS: A total of 39 studies were analyzed in this analysis. The incidence of pulmonary embolism and VTE in severe COVID-19 patients were 17% (95% CI, 13–21%) and 42% (95% CI, 25–60%), respectively. VTE were more common among individuals with COVID-19 of advance age. Male COVID-19 patients are more likely to experience VTE. Higher levels of white blood cell (WBC; WMD = 1.34×10(9)/L; 95% CI, 0.84–1.84×10(9)/L), D-dimer (WMD = 4.21 ug/mL; 95% CI, 3.77–4.66 ug/mL), activated partial thromboplastin time (APTT; WMD = 2.03 s; 95% CI, 0.83–3.24 s), fibrinogen (WMD = 0.49 ug/mL; 95% CI, 0.18–0.79 g/L) and C-reactive protein (CRP; WMD = 21.89 mg/L; 95% CI, 11.44–32.34 mg/L) were commonly noted in COVID-19 patients with VTE. Patients with lower level of lymphocyte (WMD = −0.15×10(9)/L; 95% CI, −0.23—0.07×10(9)/L) was at high risk of developing VTE. The incidence of severe condition (OR = 2.66; 95% CI, 1.95–3.62) was more likely to occur among COVID-19 patients who developed VTE. CONCLUSION: VTE is a common complication in severe COVID-19 patients and thromboembolic events are also associated with adverse outcomes.

Up to September 23rd, 2020, 30 million COVID-19 cases and more than 970 thousand deaths were reported globally. The virus that causes COVID-19 is a new type of highly diverse enveloped positive single-stranded RNA virus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] . The clinical manifestations of COVID-19 are varied, ranging from asymptomatic to severe, including acute respiratory distress syndrome and multi-organ failure [2, 3] , of which some severe cases developed into death due to hyperinflammation and respiratory dysfunction [4] . Histopathology of COVID-19 patients indicated diffuse alveolar damage and inflammatory infiltrates in lungs and pathological changes in extra-pulmonary sites, such as gastrointestinal and cardiovascular organs [5] [6] [7] . Even though the pathogenesis of COVID-19 was not fully uncovered, direct viral damage [8] , systemic hyperinflammation [9] , dysregulation of immune system [10] and ACE2-related pathway [11] were believed to participate in the process [12] . In term of therapeutics, remdesivir, a promising anti-viral agent, gives the potential reduction in time to clinical improvement [13] . Patients treated with remdesivir got better clinical status than the standard group [14] . Corticosteroid also plays its role in reducing escalation of care and improving clinical outcomes [15, 16] .

Besides, convalescent plasma therapy was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases [17, 18] .

Currently, several vaccines also have gone through different stages of clinical trials [19, 20] . Although both treatment and vaccination are encouraging, large clinical trials are needed for next validation.

Coagulation function in patients with COVID-19 is significantly deranged compared with healthy people [21] . Hyperinflammation caused by SARS-CoV-2 infection elevated level of many pro-inflammatory cytokines [22, 23] , which triggers multiple procoagulant pathways and disrupts anticoagulant system, leading to thrombotic microangiopathy [24] . IL-6 is reported to be the most important mediator for cytokine-induced coagulation activation [25] . It is well-known that endothelial cell injury caused by SARS-CoV-2 can strongly activates the coagulation system via exposure of tissue factor (TF). Moreover, the spike protein of the virus downregulates the expression of ACE2 by mediating its engagement, resulting in activation of the renin-angiotensin system, followed by facilitating platelet adhesion and aggregation [26] . In addition, completement system activation partly functions in the disordered coagulant network, founded on the observation of terminal complement components deposit in lungs [27] .

In clinical practice, approximately 20% of COVID-19 patients, and almost all patients with

severe and critical COVID-19, had severe coagulation abnormalities [28, 29] . Patients with COVID-19 and coagulopathy were characterized by increased D-dimer levels, a modest decrease in platelet count, and a prolongation of the prothrombin time, some of which are positively associated with disease severity [30, 31] 

This study was registered in PROSPERO, with registration No. CRD42020189157.

A literature search was conducted in the EMBASE, PubMed, Web of Science, MedRxiv, and Biorxiv databases using the following search terms: "SARS-CoV-2," "coronavirus," "COVID-19," "2019-nCoV," "thrombus," "thrombosis," and "embolism,"

alone or in combination, without language restrictions. Included articles were published before and on September 11th, 2020.

The following inclusion criteria were used: (1) type of participants: patients (≥18-years-old) who were infected with SARS-CoV-2 and (2) type of study; and studies that provide information with respect to medical history, laboratory results, and clinical outcomes of COVID-19 patients who developed VTE, which was defined as a composite of PE (pulmonary embolism) and DVT (deep vein thrombosis). Studies that included venous thromboembolic and non-venous thromboembolic groups were analyzed to explore the factors associated with the prevalence of venous thromboembolic events.

Criteria in this analysis for severe COVID-19 patients included severe and/or critical cases, which were defined by the World Health Organization (Clinical management of COVID-19: interim guidance). Adults with clinical signs of pneumonia (fever, cough, dyspnea, fast breathing) plus one of the following: (1) respiratory rate > 30 breaths/min;

(2) severe respiratory distress; or (3) SpO 2 <90% on room air were regarded as severe COVID-19. Patients needing respiratory support or presenting with or presenting with sepsis or developing multiple organ dysfunction were classified as critical cases. The following exclusion criteria were used: (1) study design: case reports, reviews, comments, letters, and abstracts, (2) type of participants: patients <18-years-old, pregnant women, and animals, and (3) insufficient information concerning evaluation rates.

All studies from the electronic search were uploaded into Endnote X9 and duplicates were removed. Two independent investigators reviewed remaining identified trials to confirm that they fulfilled the inclusion criteria. Finally, reference lists of included studies were screened to assess other potentially relevant studies. All disagreements were discussed and solved after rechecking the source data with a third investigator; in all cases one person recognized an error.

Two reviewers extracted data by using a predefined data extraction form. The extracted data included: last name of the first author, geographical region, event (thrombosis and/or embolism, N), sample size (N), minimum, mean and maximum age (years), percentage of male patients (%), subtypes of thromboembolic events, and study design. We employed the Newcastle-Ottawa scale (NOS) for quality assessment of included trials. NOS scores of at least six were considered high quality studies. All disagreements were resolved through discussion.

The odds ratio (OR) and weighted mean difference (WMD) were employed to compare dichotomous and continuous variables, respectively. All results are reported with 95% confidence intervals (CIs). Data presented as median (range) or median (interquartile range [IQR]) were transferred to the form of mean (standard deviation [SD])

[38]. The effect estimates of outcomes were pooled by using fixed-effects models. A random-effects model was applied when significant heterogeneity was detected.

Heterogeneity was estimated by using the I 2 value, and I 2 > 50% was considered significant. The sensitivity analyses were performed by excluding one study at a time to observe the changes in outcome. The publication bias was assessed by Egger's test and Begg's test (P < 0.10). All statistical analyses were performed with Stata 12.0 statistical software (Stata Corporation, College Station, Texas, USA).

A total of 1562 relevant articles were identified by searching several online databases. Figure 1 presented the screening and selection process of the eligible trials. This meta-analysis included 39 studies [39-77], of which 30 articles were retrospective studies and 9 were prospective studies. Among these studies, 7 were from China, 13 from France, 3 from Netherlands, 6 from The United States, 4 from The United Kingdom, 3 from Spain, 2 from Switzerland and 1 from Russia. The characteristics of the included trials were listed in Table 1 . The results of the quality assessments were presented in Table 1 .

The pooled meta-analysis results indicated that the overall incidences of PE and VTE in patients with severe COVID-19 were 17% (95% CI, 13%-21%) and 42% (95% CI, 25%-60%), respectively. The average age of COVID-19 patients with venous thromboembolic events was 64.5 (95% CI, 63.23-65.76) and the body mass index (BMI) was 27.22 kg/m 2 (95% CI, 25.70-28.75 kg/m 2 ), which was significantly higher than the normal range. The proportion of male patients was 69% (95% CI, 61%-77%). The laboratory results revealed that neutrophil counts (7.62×10 9 /L; 95% CI, 6.57-8.68×10 9 /L), fibrinogen levels (6.01 g/L; 95% CI, 5.29-6.72 g/L), D-dimer levels (7.47 μg/mL; 95% CI, 6.34-8.60 μg/mL), and C-reactive protein (CRP) levels (136.99 mg/L; 95% CI, 103.60-170.37 mg/L) were significantly higher in COVID-19 patients with thromboembolic events than in control COVID-19 patients. In addition, decreased lymphocyte counts (0.77×10 9 /L; 95% CI, 0.70-0.84×10 9 /L) were observed. These results demonstrated that 45% (95% CI, 24%-67%) of COVID-19 patients who developed VTE developed severe or critical condition ( Table 2) . 

to 16.62×10 9 /L), neutrophil counts (WMD = 1.03×10 9 /L; 95% CI, -0.06 to 2.12×10 9 /L were not significant predictors of thromboembolic events in COVID-19 patients (Appendix 3). In addition, COVID-19 patients who developed thromboembolic events were more likely (OR = 2.66; 95% CI, 1.95-3.62) to develop severe condition or need critical care (Figure 3 ).

Our result suggested no possible publication bias in the pooled result of the outcomes (Appendix 1). Our sensitivity analysis revealed no significant differences in the outcomes except for the pooled results of fibrinogen and netrophil (Appendix 4).

A total of 39 studies were analyzed and the following conclusions were drawn. Venous thromboembolic event was a common complication in severe COVID-19 patients.

Advanced age, gender and levels of WBC and lymphocyte might be closely associated with prevalence of venous thromboembolic events. Inflammatory factors, such as CRP, may be involved in the occurrence of venous thromboembolic events. D-dimer, APTT and fibrinogen can be served as significant predictors of venous thromboembolic events in patients with COVID-19 infections. In addition, venous thromboembolic events were associated with adverse outcomes.

Individuals at any age can be infected with SARS-CoV-2, however, older individuals are the most vulnerable to experiencing an aggressive form of COVID-19. It was reported that viral load was associated with advanced age [78]. Furthermore, there was a strong age gradient in the risk of death among patients with COVID-19. According to the analysis including 72,314 cases, an overall case fatality rate (CFR) was 2.3%, while CFR was 8% in patients aged 70 to 79 years and 14.5% in patients aging 80 and older [79] .Unsurprisingly, there was a similar pattern, regardless of the geographic region. In another analysis in Korea, the overall CFR was much higher in older people compared with 11,344 confirmed cases [80] . In France, an average death rate was 0.0001% in young patients and 8.3% in patients older than age 80 [81]. In Asia, Europe and North America, 10% mortality rate was observed in those 65 years of age or older, which was much higher than patients who were younger [82] . In this scenario, the dynamical remodeling of immune response with aging could be essential explanation. As age advances, reduced production of native T and B cells and dysfunction of innate immune cells were observed. This series of changes associated with age affecting the immune system was denominated as immunosenescence [83] . Innate immunity serves as the first line to against pathogen invasion and successful mounting of type I interferons (IFN) secreted by infected cells should be able to induce an antimicrobial state to limit viral Our meta-analysis had several limitations. First, most of the included studies were retrospective studies with a low level of evidence. However, the quality of the majority of studies included in the meta-analysis was moderate or high. Second, due to the limited number of studies, we didn't compare mortality rate of patients with and without VTE and evaluate the effectiveness of anticoagulants for patients developing VTE.

In the present study we successfully and systematically evaluated the incidence and 

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