To the Editors
Arterial thrombotic disease (atherosclerotic cardiovascular disease, CVD) and venous
thromboembolism (VTE) (comprising of deep vein thrombosis (DVT) and pulmonary embolism
(PE)), two distinct but closely related diseases, [1] constitute major public health
problems and are associated with substantial morbidity, premature mortality, and high
economic costs. The coronavirus disease 2019 (COVID-19) pandemic which is one of the
most significant modern-day public health challenges, predominantly affects the respiratory
system, causing severe pneumonia and respiratory distress syndrome. Emerging data
suggests COVID-19 adversely affects multiple organs; gastrointestinal, liver, kidney,
neurological and cardiac complications have been reported [[2], [3], [4]]. Apart from
pre-existing comorbidities such as CVD, hypertension, chronic kidney disease, chronic
liver disease and diabetes being linked to increased risk of severe illness or death;
[5] some extrapulmonary complications of COVID-19 such as acute myocardial injury
have been shown to be associated with fatal outcomes [6]. Recently, COVID-19 has been
linked to venous and arterial thromboembolic disease (henceforth referred to as thromboembolic
complications). Three recent most downloaded and key studies published in the journal
reported a high incidence of thromboembolic complications in COVID-19 patients, particularly
in those admitted to the intensive care unit (ICU) [[7], [8], [9]]. Given the sparseness
of the data and evolving nature of the disease, the thromboembolic complications of
COVID-19 and their incidence is not clearly defined. There is a need for robust aggregation
of data on thromboembolic complications of COVID-19, which will be of great value
for policy makers, healthcare providers and clinicians to aid decision making and
implementing more efficacious preventative strategies. In this context, we conducted
a systematic review and meta-analysis to attempt to address the following questions:
(i) what are the thromboembolic complications associated with COVID-19 and (ii) what
is the incidence of these complications overall and in those who develop severe disease?
The review was conducted in accordance with PRISMA and MOOSE guidelines (Supplementary
Materials 1–2). We searched MEDLINE and Embase from January 2020 to 6 August 2020
for published studies reporting on venous and arterial thromboembolic complications
(e.g., VTE, PE, myocardial infarction (MI), acute coronary syndrome (ACS), ischemic
stroke, disseminated intravascular coagulation (DIC)) in patients with COVID-19. Studies
based on selected patients/populations (eg, cancer patients) were not included. Details
of the search strategy are reported in Supplementary Material 3. The incidence of
thromboembolic complications (estimated from the number of patients experiencing the
specific complication within period of follow-up (hospital stay)/total number of patients
with COVID-19) across studies with their 95% confidence intervals (CIs) were pooled
using Freeman-Tukey variance stabilising double arcsine transformation and random-effects
models. STATA release MP 16 (StataCorp LP, College Station, TX, USA) was used for
all statistical analyses.
Thirty-five observational cohort studies comprising of 9249 hospitalised patients
with COVID-19 were eligible (Table 1
; Supplementary Materials 4–5). Seven studies were based in China and France each,
6 each in Italy and USA, 4 in the UK, 2 in the Netherlands and one each in Germany,
Spain, and Switzerland. The average age at baseline ranged from 53 to 71 years. Severe
COVID-19 was defined as requiring Intensive Care Unit (ICU) care or admission and
this was consistent across all studies.
Table 1
Baseline characteristics of 35 eligible studies.
Table 1
Author, year of publication
Source of patients
Country
Date of data collection
Mean/median age (years)
% males
No. of patients
NOS
Klok, 2020
Dutch Univesity Hospitals
Netherlands
March–April 2020
64.0
76
184
6
Thomas, 2020
Adenbrooke's Hospital
UK
Up to April 2020
20–89*
69
63
4
Lodigiani, 2020
University Hospital, Milan
Italy
Feb - April 2020
66.0
68
388
4
Cui, 2020
Union Hospital, Wuhan
China
Jan - March 2020
59.9
46
81
4
Chen, 2020
Tongji Hospital in Wuhan
China
Jan - Feb 2020
62.0
62
274
4
Du, 2020
Hannan Hospital and Wuhan Union Hospital
China
Jan - Feb 2020
65.8
72.9
85
4
Aggarwal, 2020
UnityPoint Clinic
USA
March–April 2020
67.0
75
16
4
Poissy, 2020
Lille Hospital
France
Feb - March 2020
NR
NR
107
4
Middeldorp, 2020
Amsterdam Academic Medical Center
Netherlands
March–April 2020
61.0
66
198
6
Mao, 2020
Union Hospital of Huazhong University of Science and Technology
China
Jan - Feb 2020
52.7
40.7
214
4
Llitjos, 2020
2 French ICUs
France
March–April 2020
68.0
77
26
4
Leonard-Lorant, 2020
Strasbourg University Hospital
France
March 2020
64.0
66
106
4
Helms, 2020
French Tertiary Hospital
France
March 2020
63.0
81.3
150
4
Grillet, 2020
Centre Hospitalier Universitaire de Besancon
France
March – April 2020
66.0
70
100
4
Artifoni, 2020
Nantes University Hospital and Châteaubriant Hospital
France
March–April 2020
64.0
60.6
71
4
Demelo-Rodríguez, 2020
Third-level hospital in Madrid
Spain
April 2020
68.1
65.4
156
5
Faggiano, 2020
NR
Italy
NR
71.0
84
25
4
Longchamp, 2020
Sion hospital ICU
Switzerland
March–April 2020
68.0
64
25
4
Mazzaccaro, 2020
IRCCS Ospedale San Raaele
Italy
March–April 2020
68.6
71.9
32
4
Bilaloglu, 2020
NYU Langone Health
USA
March–April 2020
64.0
60.4
3334
6
Merkler, 2020
Academic Hospitals in New York
USA
March–May 2020
64.0
57.5
1916
6
Ren, 2020
Zhongnan and Leishenshan Hospitals
China
Feb - March 2020
70.0
54.2
48
4
Rieder, 2020
University Medical Center—University of Freiburg
Germany
March–April 2020
60.0
61.2
49
4
Santoliquido, 2020
Fondazione Policlinico Universitario A. Gemelli IRCCS
Italy
April 2020
67.6
72.6
84
4
Tavazzi, 2020
ICU of a Hub Hospital
Italy
Up to Feb 2020
68.0
83.0
54
4
Trigonis, 2020
IU Health Methodist Hospital
USA
March–April 2020
60.8
NR
45
4
Moll, 2020
Brigham and Women's Hospital
USA
March–April 2020
62.2
48.1
210
4
Fang, 2020
King's College Hospital NHS Foundation Trust
UK
March–April 2020
59.2
64.5
93
4
Mei, 2020
Yichang Central People's Hospital
China
Jan - March 2020
55.5
51.2
256
4
Li, 2020
Union Hospital of Huazhong University of Science and Technology
China
Jan - March 2020
53.3
40.6
219
4
Stoneham, 2020
Brighton and Sussex University Hospitals NHS Trust
UK
March–April 2020
NR
NR
274
5
Inciardi, 2020
Civil Hospitals of Brescia
Italy
March 2020
67.0
81.0
99
4
Fraisse, 2020
Centre Hospitalier Victor Dupouy
France
March–April 2020
61.0
79.0
92
4
Desborough, 2020
Guy's and St Thomas' NHS Foundation Trust
UK
March 2020
59.0
73.0
66
4
Maatman, 2020
Indianapolis area academic hospitals
USA
March–May 2020
61.0
57.0
109
4
ICU, intensive care unit; NOS, Newcastle Ottawa Scale; NR, not reported; *, age range.
Fig. 1
portrays incidence of thromboembolic complications overall in COVID-19 patients over
hospital stays/follow-up periods ranging from 2 to 30 days. The pooled incidence was
18.4% (12.0–25.7) for VTE (n = 19 studies), 13.5% (8.4–19.5) for PE (n = 22 studies)
and 11.8% (7.1–17.4) for DVT (n = 18 studies) (Fig. 1A). The incidence of DVT subtypes
are reported in Supplementary Material 6. The incidence of distal, bilateral, proximal,
symptomatic and upper extremity DVT was 13.6% (2.6–31.0), 7.6% (4.9–10.9), 3.3% (1.2–6.2),
2.6% (0.5–5.9) and 1.7% (0.4–3.6) respectively. For PE subtypes, the incidence was
9.1% (5.0–14.3) for segmental PE, 7.5% (0.5–19.9) for central/lobar PE, 6.3% (2.3–11.8)
for subsegmental PE, 4.1% (2.0–6.9) for main pulmonary artery PE and 1.9% (0.0–6.5)
for multiple segmental PE (Supplementary Material 7).
Fig. 1
(A) Incidence of venous thromboembolic complications in COVID-19 patients; (B) Incidence
of other venous and arterial thromboembolic complications in COVID-19 patients.
ACS, acute coronary syndrome; CI, confidence interval (bars); DIC, disseminated intravascular
coagulation; DVT, deep vein thrombosis; MI, myocardial infarction; PE, pulmonary embolism;
VTE, venous thromboembolism.
Overt DIC was defined as International Society on Thrombosis and Haemostasis (ISTH)
score ≥ 5.
Composite outcome refers to the composite outcome of arterial and venous thromboembolic
disease.
Fig. 1
Other thromboembolic complications are reported in Fig. 1B. The incidence of the composite
outcome of arterial and venous thromboembolic disease was 17.8% (9.9–27.4). The incidence
of superficial vein thrombosis, DIC, ACS/MI, catheter-related thrombosis, ischemic
stroke, overt DIC, systemic arterial embolism, mesenteric and limb ischemia was 7.7%
(1.7–16.5), 5.6% (3.4–8.3), 3.3% (0.3–8.5), 2.4% (0.2–6.2), 1.8% (1.3–2.4), 1.7% (0.5–3.5),
1.6% (0.4–3.6), 1.4% (0.2–3.5) and 1.1% (0.1–3.0) respectively. Other outcomes reported
were symptomatic VTE and portal vein thrombosis, but these were based on single reports
(Fig. 1B).
The incidence of thromboembolic complications in patients with severe COVID-19 are
reported in Supplementary Materials 8–11. The pooled incidence for VTE, PE and DVT
was 21.6% (14.3–29.8), 11.8% (6.4–18.5) and 18.2% (9.6–28.6) respectively (Supplementary
Material 8). The incidence of distal, proximal and upper extremity DVT was 21.5% (0.0–72.8),
7.8% (1.8–16.9) and 3.5% (1.2–6.9) respectively (Supplementary Material 9). For PE
subtypes, the incidence was 7.7% (3.9–12.4) for segmental PE, 4.0% (0.7–9.3) for subsegmental
PE, 2.8% (0.1–7.4) for central/lobar PE and 1.9% (0.0–6.5) for multiple segmental
PE (Supplementary Material 10). The incidence of the composite outcome of arterial
and venous thromboembolic disease, ACS/MI, ischemic stroke, catheter-related thrombosis,
mesenteric and limb ischemia was 22.9% (14.5–32.4), 4.7% (0.0–14.6), 3.3% (2.5–4.2),
3.1% (0.8–6.5), 1.4% (0.2–3.5) and 1.1% (0.1–3.0) respectively (Supplementary Material
11).
Based on the most up-to-date published evidence on patients with COVID-19, there is
a high incidence of thromboembolic complications in these patients (ranging from 7.2
to 40.8%), which appears to be driven by venous thromboembolic disease. These thromboembolic
complications are remarkably high in COVID-19 infection despite the use of thromboprophylaxis
in patients. The most frequently diagnosed venous thromboembolic complication in the
overall population is PE, with segmental and central/lobar PE being more common than
other subtypes. Furthermore, it appears the incidence of thromboembolic complications
is substantially higher in severe COVID-19 disease compared to the overall population,
with a higher incidence of DVT than PE. Though arterial thrombosis and VTE have historically
been viewed as two distinct diseases with different pathophysiology, they appear to
be closely related via some shared risk factors (obesity and smoking) and mechanistic
pathways (such as coagulation, platelet activation and dyslipidaemia) [1]. Though
the mechanistic pathways are still not very clear, the predisposition to venous and
arterial thromboembolism by COVID-19 especially in severe infection has been attributed
to the overwhelming inflammatory response, hypoxia, DIC and immobilisation [2]. There
is an on-going discussion that pulmonary thrombotic events in COVID-19 may not be
due to emboli but rather as a result of in-situ pulmonary thrombosis [10].
The high incidence of thromboembolic complications in COVID-19 patients is a big source
of concern, especially given the fact that systemic thromboprophylactic agents were
administered to patients. Furthermore, it has been acknowledged by some studies that
the thromboembolic incidence estimates reported are actually underestimates [7,8].
Aggressive monitoring of markers of thromboembolic complications such as D-dimer during
admission, use of sensitive and specific VTE diagnostic tools and effective pharmacological
thromboprophylaxis may be required in the management of patients with COVID-19. Given
the bleeding risks associated with anticoagulants, clinical decisions to initiate
thromboprophylaxis should also be individualised and tailored to each patient.
There were some limitations in this study, but these were all inherent. These included
the low methodological quality of some of the studies and small sample sizes; however,
this was not unexpected given the urgency to understand the clinical course of COVID-19.
Other limitations included some findings being based on single reports and the fact
that some of the incidence data were under-reported due to inability to perform diagnostic
imaging tests in all patients due to strict isolation procedures.
Aggregate analysis of the available literature suggests a high incidence of thromboembolic
complications in patients hospitalised with COVID-19, particularly in those with severe
disease. The incidence is higher for venous thromboembolic events compared to arterial
thromboembolic complications. There is an urgent need for improved diagnostic strategies
as well as determining the most effective thromboprophylactic agents and their optimal
dosages to be used in these patients.
Funding sources
SKK acknowledges support from the NIHR
10.13039/100014461
Biomedical Research Centre
at
10.13039/100012141
University Hospitals Bristol NHS Foundation Trust
and the
10.13039/501100000883
University of Bristol
. The views expressed in this publication are those of the authors and not necessarily
those of the NHS, the National Institute for Health Research or the Department of
Health and Social Care. These sources had no role in design and conduct of the study;
collection, management, analysis, and interpretation of the data; and preparation,
review, or approval of the manuscript.
Declaration of competing interest
None.