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Int J Clin Pract. 2021;00:e14910. wileyonlinelibrary.com/journal/ijcp
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1 of 8
https://doi.org/10.1111/ijcp.14910
© 2021 John Wiley & Sons Ltd
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Coronavirus disease- 2019 (COVID- 19), a viral illness caused by se-
vere acute respiratory syndrome- coronavirus- 2 (SARS- CoV- 2), can
lead to coagulation dysfunction in patients with severe COVID- 19
infection.1 Venous thromboembolism (VTE) is a recurrent com-
plication in COVID- 19 patients2 and results in a poor prognosis.1
COVID- 19 may predispose to both venous and arterial throm-
boembolic disease because of excessive inflammation, hypoxia,
immobilisation and diffuse intravascular coagulation.3- 6 Many of the
hospitalised COVID- 19 patients are elderly people, suffering from
severe infectious illness and are immobile in an intensive care unit
(ICU) setting. Therefore, a relatively high incidence of VTE amongst
patients diagnosed with COVID- 19 is expected bec ause of the se-
verity of their disease and distinctive risk factors.7
However, so far, there have been only a few studies describing
VTE either deep vein thrombosis or pulmonary embolism in patients
with COVID- 19 infection.8- 1 1 A high incidence of VTE in COVID- 19
Received:15August2020
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Accepted :19Septembe r2021
DOI : 10.1111 /ij cp.14910
1|1|1|1|2|
1
1Centre for Translation al and Clinical
Research, Scho ol of Chemi cal & Life
Science s, Jamia Hamdard , New Delhi, India
2School of Primar y, Community and Social
Care, Keele University, Staffordshine, UK
Nidhi Bharal Ag arwal, Centre for
Translational and Clinical Research, School
of Chemic al & Life Sciences , Jamia Hamdard,
New Delhi 110062, India.
Email: nidhi.bharal@gmail.com;
nidhiagarwal@jamiahamdard.ac.in
Coronavirus disease- 2019 (COVID- 19) may predispose to venous thrombo-
embolism (VTE) and arterial thromboembolism because of excessive inflammation,
hypoxia, immobilisation and diffuse intravascular coagulation. The understanding of
the association might be helpful in early vigilant monitoring and better management
of COVID- 19 patients at high risk. Thus, in this meta- analysis, we aim to assess the
association of V TE with the severity of COVID- 19 disease.
A literature search was conducted on PubMed and Cochrane Central
Register of Controlled Trials using the keywords “COVID- 19 and thromboembolism”
and “COVID- 19 and embolism,” till 20 February 2021. Thirteen studies including
6648 COVID- 19 patients were incorporated in this systematic review and explora-
tory meta- analysis.
The analysis revealed nearly three times more risk than intensive care unit
(ICU) care in patients with V TE compared to non- VTE patients (RR: 2.78; 95% CI:
1.75- 4.39; P < .001; I2: 65.1%). Patients with pulmonary embolism and deep vein
thrombosis are at increased risk of being admitted to ICU (RR: 2.21; 95% CI: 1.86-
2. 61; P < .001; I2: 41.2%) and (RR: 2.69; 95% CI: 2.37- 3.06; P < .001; I2: 0.0%), respec-
tively. The quality assessment indicated that the included studies were of fair quality.
Our findings suggest that VTE either deep vein thrombosis or pulmo-
nary embolism may have a negative effect on the health status of COVID- 19 patients.
This study highlights the need to consider measures for reducing thromboembolism
risk amongst COVID- 19 patients.
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S RIVASTAVA eT Al.
patients has been reported in various studies.1,12- 14 A retrospective
study reported a high prevalence of deep vein thrombosis and as-
sociated adverse outcomes in COVID- 19 patients.15 Another pro-
spective study demonstrated a ver y high incidence of deep vein
thrombosis in COVID- 19 patients requiring ICU admission.16 A co-
hort study observed a high risk for VTE in COVID- 19 patients re-
quiring ICU care.14
Several studies have demonstrated a higher incidence of VTE
in COVID- 19 patients,1,14,17,18 however, the effec t of the incidence
of VTE on the prognosis of the disease needs further exploration.
Precise knowledge of the incidence of thrombotic complications in
COVID- 19 patients is impor tant for decision- making with regards to
the intensity of thromboprophylaxis.13 The understanding of the as-
sociation might be helpful for clinicians in early vigilant monitoring
and better management of COVID- 19 patients at high risk. Thus, in
the present exploratory meta- analysis, we aimed to assess the as-
sociation of VTE with the severity of disease in COVID- 19 patients.
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Preferred Reporting Items for Systematic Review and Meta- Analysis
(PRISMA) guidelines extension for scoping reviews19 was followed
for designing and reporting this systematic literature review.
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We searched PubMed and Cochrane Central Register of Controlled
Trials until 20 February 2021 using the keywords “COVID- 19 and
thromboembolism” and “COVID- 19 and embolism.” Grey literature
was searched on Clinical Trial Registry of India, Clinicaltrials.gov,
Google Scholar and reference list of eligible articles.
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Studies describing the incidence of thromboembolism according to
disease severity were included. We excluded duplicate publications,
reviews, editorials, case reports, letters, meta- analyses, protocols,
studies in a language other than English and studies not reporting
the required data. The first author (RS) searched data and screened
articles for eligibility. Senior author (RP) double checked all the in-
cluded ar ticles and any dispute was resolved by consensus.
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Two reviewers (RS and RP) assessed the quality of data included in
this study using the National Institute of Health (NIH) quality as-
sessment tools developed by the National Heart, Lung, and Blood
Institute.20 We preferred the NIH tool because it is comprehen-
sive and widely accepted for an exhaustive assessment of data
quality. We rated the general qualit y of included studies nearly as
good, fair and poor and incorporated them within the result of the
meta- analysis.
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Data were inputted into a standardised data extraction table (Excel)
and independently checked by a second reviewer (RP) for accuracy.
The following variables were ex tracted: name of the first author,
year of publication, study design, age, gender, number of patients
in ICU and non- ICU care with comorbidities as well as prognosis.
The disease was considered severe if the patient with COVID- 19 re-
quired ICU care.
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We performed an explorator y meta- analysis to understand the mag-
nitude and direction of the ef fect estimate. Relative risk (RR) was cal-
culated an d presented with r espective 95% confi dence interva ls (CIs).
Mantel- Haenszel random effects meta- analysis using DerSimonian
and Laird method was used to pool RR.21 Heterogeneity between
studies was assessed using the χ2- based Cochran’s Q statistic (P < .1
• We conducted a systematic review and meta- analysis of
the studies describing the incidence of venous thrombo-
embolism in COVID- 19 patients requiring intensive care
unit care.
• We searched PUBMED and Cochrane Central Register
of Controlled Trials using the keywords “COVID- 19 and
thromboembolism” and “COVID- 19 and embolism” till
20 February 2021.
• We pooled dichotomous outcomes as risk ratios and
continuous outcomes as mean differences with 95%
confidence intervals, both under the random or fixed ef-
fects model.
• This study highlights the need to consider measures for
reducing thromboembolism risk amongst COVID- 19
patients.
• Precise knowledge of the incidence of thrombotic
complications in COVID- 19 patients is important
for decision- making with regards to the intensity of
thromboprophylaxis.
• The understanding of the association might be helpful
in early vigilant monitoring and better management of
COVID- 19 patients at high risk.
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SRIVASTAVA eT Al.
considered as the presence of heterogeneity) and I2 statistics (>50%
representing moderate heterogeneity).21 Forest plot was produced,
and subgroup analysis was conducted according to the study design.
The 95% prediction interval (PI) was calculated, which estimates the
uncertainty bounds for a new study evaluating that the same as-
sociation by considering between- study heterogeneity. Publication
bias was not assessed as a total number of studies were <10 for a
given outcome.21 P value < .05 was set as statistical significance for
comparing study level effects.
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The systematic search yielded a total of 1607 publications. Out of
1607 studie s, 920 studies were f ound using the key words “COVID- 19
and thromboembolism,” and 686 studies with keywords “COVID- 19
and embolism.” One study was found from another source. After
removing duplicates, 1200 articles were found to be potential pub-
lications for screening. After the application of predefined inclusion
and exclusion criteria, a total of 13 studies were included for the
meta- analysis (Figure 1).
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The incidence of VTE either deep vein thrombosis or pulmo-
nary embolism was reported in ICU care and non- ICU care in 12
studies,12,14 - 17,22- 28 and one study reported the incidence of VTE
either deep vein thrombosis or pulmonar y embolism in survivors
and non- survivors group.1 Among the 13 included studies, a total
of 6648 patients were enrolled, including 3973 males and 2675 fe-
males. The baseline characteristics of the subjects included in these
studies are provided in Table 1.
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We assessed the qualit y of data in the included studies using the
NIH qualit y assessment tools. The quality assessment indicated
that most of the included studies were of fair quality. All the stud-
ies clearly stated the research question or the objective, the study
population was clearly specified and defined, all the subjects were
selected from similar populations. The detailed result of the qualit y
assessment is provided in Supplementary File 1.
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In order to assess the association between VTE and disease severity,
four cohor t studies qualified for inclusion in quantitative analysis. The
pooled estimate of four cohort studies with substantial heterogeneity
revealed nearly three times more risk of ICU care requirement in pa-
tients with VTE compared to n on- VT E patients (RR: 2.78; 95% CI: 1.75-
4.39; P < .001; I2: 65.1%) (Figu res 2 and S2). The mort ality outcome was
assessed in one retrospective study indicative of a higher risk of VTE in
ICU patients (RR: 50.19; 95% CI: 3.05- 832.75; P < .001).
PRISMA flow diagram of
study selection
n, number.
Records identified through database
searching (n=1606)
Du
p
licates records removed
(
n=407
)
Records excluded based on
exclusion criteria (n=371)
Review (n=390)
Commentary (n=220)
Summary article (n=10)
Editorial (n=89)
Studies in other language (n=2)
Case reports (n=105)
Records retrieved for more detailed evaluation
(
n=13
)
Total records included in the final analysis (n=13)
Records screened (n=1200)
/ĚĞŶƟĮĐĂƟŽŶ
Additional records identified through
other sources
(
n=1
)
^ĐƌĞĞŶŝŶŐ
ůŝŐŝďŝůŝƚLJ
/ŶĐůƵĚĞĚ
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S RIVASTAVA eT Al.
Baseline characteristics
Middeldorp, 2020 Cohort 61 (14 ) 198 130 (6 6) 68 (34) 136 (69) 16 (8) 8 (4) 38 (19) Active cancer 7 (3.5)
Grillet, 2020 Retrospective 66 (13) 100 70 30 NA NA NA NA Cardiovascular Disease 39
Chronic Respiratory
Insufficiency
15
T2DM 20
Malignancy 20
Zhang, 2020 Retrospective 63 (14) 143 74 (51.71) 69 (48.25) 92 (64.3) 19 (13.3) NA 32 (22.4) HTN 56 (39.2)
DM 26 (18.2)
CAD 17 (11.9)
Malignancy 7 (4.9)
Cerebal Infarction 5 (3.5)
Chronic Liver Disease 5 (3.5)
CKD 4 (2.8)
Lorant, 2020 Retrospective 64 (22) 106 70 (66) 36 (34) NA NA NA NA NA
Demelo, 2020 Cohort 6 8.1 (14. 5) 156 102 (66) 54 (34) NA NA NA NA Active Cancer 16 (10.3 )
Lodigiani, 2020 Cohort 66 388 264 (68) 124 (32) NA NA NA NA HTN 18 3 (4 7. 2)
DM 88 (22.7 )
Dyslipidemia 76 ( 19. 6)
Chronic Renal Dysfunction 61 (15 .7 )
Active Cancer 25 (6.4)
Poyiadi, 2020 Retrospective 62 (16) 328 148 (45) 180 (55) NA NA NA NA Cancer History 14
DM 38
HTN 61
COPD 13
CHF 9
Cui, 2020 Retrospective 59.9 81 37 (46) 44 (54) 9 (11) 64 (79) 8 (10) HTN 20 (25)
DM 8 (10)
CHD 10 (12)
Coronary Heart Disease 10 (12)
(Continues)
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SRIVASTAVA eT Al.
Bilalogu et al, 2020 Retrospective
Study
64 3334 2014 (60 .4) 1320 (39.6) NA NA NA NA Myocadial Infarction 195
Congestive Heart failure 279
HTN 1676
Diabetes 1246
Hyperlipidemia 1285
Coronary artery disease 617
Fauvel et al, 2020 Cohort Study 64 1240 721 (58.1) 519 (41.9) NA NA NA 151 (1 2. 2) HTN 559 (45.4)
Diabetes 268 (21.7)
Dyslipidemia 316 (25.6)
Cardiovascular disease 19 (1. 6)
COPD 77 (6.2)
CKD 126 (10 .3)
Stroke 9 4 (7. 7)
Peripheral arterial disease 60 (4.9)
Atrial fibrillation 117 (9. 5)
CHF 117 (9. 5)
CAD 133 (10.7)
Malignancy 167 (13.7)
Trimaille et al, 2020 Cohort Study 62.2 289 171 (59. 2) 118 (40. 8) 236 (88.7) NA NA 24 (8.3) NA NA
Whyte et al, 2020 Cohort Study 63.5 214 129 85 NA 36 NA 31 Malignancy 16
Haemoptysis 12
Artifoni et al, 2020 Cohort Study 64 71 43 (60.6) 28 (39.4) NA NA NA NA HTN 32 (60)
Diabetes 14 (20)
Cancer 4 (6)
Note: Data are presented as median (IQR) or number (%).
Abbreviations: CAD, coronary artery disease; CHD, coronary heart disease; CKD, chronic kidney disease; CHF, coronary heart failure; COPD, chronic obstructive pulmonary disease; DM, diabetes
mellitus; HTN, hypertension; IQR , interquartile range; NA , not available; No., number; T2DM, diabetes mellitus t ype 2.
(Continued)
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S RIVASTAVA eT Al.
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To assess the association between pulmonary embolism and disease
severity, eight studies (four cohor t and four retrospective studies)
qualified for inclusion in quantitative analysis. The pooled estimate
of four cohor t and four retrospective studies with substantial het-
erogeneity study showed that patients with pulmonary embolism
are at nearly three times increased risk of being admitted to ICU (RR:
2.21; 95% CI: 1.86- 2.61; P < .001; I2: 41.2%) (Figure 2). The subgroup
pooled analysis of four cohort studies demonstrated nearly two
times higher risk of ICU c are in patients with pulmonary embolism
(RR: 1.97; 95% CI: 1.44- 2.70; P < .001; I2: 57.6%) (Figure S2). The sub-
group pooled estimate of four retrospective studies highlighted that
patients with pulmonary embolism are around three times higher
risk of being admitted to ICU (RR: 2.39; 95% CI: 1.91- 2.99; P < .001;
I2: 37.8%) (Figure S2).
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For the outcome, in order to assess the association between deep
vein thrombosis and disease severity, five studies (three cohort
studies and two retrospective studies) qualified for inclusion in
quantitative analysis. The pooled estimate of three cohort and two
retrospective studies demonstrated around three times higher risk
of deep vein thrombosis in ICU patients (RR: 2.69; 95% CI: 2.37-
3.06; P < .001; I2: 0.0%) (Figure 2). The subgroup pooled analysis of
three cohort studies highlighted a higher risk of requiring ICU care
in patient s with deep vein thrombosis (RR: 2.57; 95% CI: 1.53- 4.30;
P < .001; I2: 30.7%) (Figure S2). The subgroup pooled estimate of two
retrospective studies showed that the need for ICU care was higher
in patient s with deep vein thrombosis (RR: 2.61; 95% CI: 2.19- 3.11;
P < .001; I2: 1.1%) (Figure S2).
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Recent evidence on COVID- 19 postulated that the high mort al-
ity observed among COVID- 19 patients may be partly because of
unrecognised pulmonary embolism and pulmonary in situ throm-
bosis.1,13 Several studies have demonstrated a higher incidence of
VTE in COVID- 19 patients,17, 18 however, the effect of the incidence
of VTE on the severit y of disease needs further exploration. Thus,
the present meta- analysis was conducted to assess the association
of VTE either pulmonary embolism or deep vein thrombosis with
disease severity in COVID- 19 patients. The present meta- analysis
demonstrated a high incidence of pulmonary embolism, deep vein
thrombosis and VTE in patients requiring ICU care.
The present meta- analysis demonstrated a positive association
betwee n COVID- 19 and the incidence of pulmonar y embolism in ICU
patients. Whyte et al performed a cohort study on 214 COVID- 19
patients and revealed that the overall proportion of patients with
pulmonary embolism was 5.4%, increasing to 16.2% in ICU patients.
Pulmonary embolism was diagnosed in 3.5% patient s receiving
ward- based care. The higher incidence of pulmonary embolism in
ICU patients is consistent with previous studies (16.7%- 47%).28 A
cohort study reported a high incidence of pulmonary embolism in
the critically ill COVID- 19 patients, also it was found to be one of
the major thrombotic complications in this study.13 Therefore, pul-
monary thromboembolism may be considered in COVID- 19 patients
Relative risk of ICU
admission in venous thromboembolism
(A), pulmonary embolism (B) and deep
vein thrombosis subgroups (C)
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SRIVASTAVA eT Al.
with sudden onset of oxygenation deterioration, respiratory distress
and reduced blood pressure as these patients are of ten immobile
and present with an acute inflammatory state.29
The present meta- analysis demonstrated the positive associa-
tion between COVID- 19 ICU patients and deep vein thrombosis. A
systematic literature review of four prospective studies conducted
on patient s requiring critical care reported the rate of objectively
confirmed deep vein thrombosis which ranged from 13% to 31% and
suggested a potential role for thromboprophylaxis in patients re-
quiring critical care.30 A retrospective study reported an 18.2% inci-
dence of deep vein thrombosis in COVID- 19 ICU patients.15 Various
cohort studies have reported 32%,14 13%16 and 4.1%25 incidence of
deep vein thrombosis in COVID- 19 ICU patients.
The present meta- analysis demonstrated the positive associ-
ation between COVID- 19 ICU patients and V TE. Malas et al con-
ducted a systematic review involving 8271 SARS- CoV- 2 patients
determining the overall incidence of VTE to be 21%. Amongst ICU
patients, the VTE rate was as high as 31%. Patients who developed
VTE were at 74% increased odds of death compared to those who
did not.18 Collectively, several cohort studies have reported 47%14
and 8.3%25 incidence of V TE in COVID- 19 ICU patients. A retro-
spective study reported an incidence of 25% of VTE in COVID- 19
hospitalised patients.1
There are various mechanisms explaining the risk of VTE either
deep vein thrombosis or pulmonary embolism or both in COVID- 19
patients. One such mechanism explains that the virus can bind to
the endothelial cells via angiotensin 2 receptors, which are most
commonly found in the alveolar epithelial cells, followed by endo-
thelial cells— a process that may ultimately damage blood vessels and
increase the risk of thrombogenicity.2 However, apart from the se-
vere COVID- 19 patients in ICUs, those hospitalised in hospital wards
share common predisposing factors for VTE, namely strict and long
isolation and subsequently immobilisation. Any severe infection can
predispose to VTE. However, it appears that in COVID- 19 additional
mechanisms might contribute to increased VTE risk, including en-
dothelial damage, microvascular thrombosis and occlusion, or even
autoimmune mechanisms.31 Another mechanism explains that the
abnormal expression of T cell- associated mRNA can lead to VTE.32
This means that older patients with more underlying diseases were
more likely to develop immune dysfunction and have a higher risk of
VTE because of their poor immunity.1
There are several limitations worth mentioning. First, most stud-
ies included a relatively small number of cases with a poor description
of patient characteristics, which limited the possibility to explore the
effects of concomitant risk factors on the incidence of V TE. Second,
the lack of r andomisation and the litt le data provided on t he incidence
of VTE stratified by use, type, dose and duration of anticoagulation
(ie, prophylactic, intermediate or therapeutic dose) precluded sub-
group analysis on the effect s of pharmacological prophylaxis. Third,
the nature of the data available in the individual studies did not allow
the meta- analysis to be stratified by some clinically relevant variables
such as thromboprophylaxis status, race and healthcare access/qual-
ity to assess their ef fect on the incidence of VTE and mortality.
To conclude, our findings suggest that VTE either deep vein
thrombosis or pulmonary embolism may have a negative ef fect
on the health status of COVID- 19 patients. However, large inci-
dence studies demonstrating the consequences of VTE are ur-
gently needed for decision- making with regards to the intensity of
thromboprophylaxis.
No potential conflict of interest to declare in relation to this
publication.
Conception and design: Rashmi and Rizwana; Acquisition of data:
Rashmi and Rizwana; Analysis and interpretation of data: Pinki
and Ram; Drafting the manuscript: Rashmi and Pinki; Revised
manuscript critically for important intellectual content: Nilanjan
and Nidhi; Final approval of the version to be published: Nidhi and
Rizwana; Agreed to be accountable for all aspects of the work
in ensuring that questions related to the accuracy or integrity of
any part of the work are appropriately investigated and resolved:
Rashmi and Nidhi.
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Int J Clin Pract. 2021;00:e14910. doi:10.1111/ijcp .14910
