Incidence of venous and arterial thromboembolic complications in COVID-19: A systematic review and meta-analysis.

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 estimates are 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.

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.

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 estimates 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 estimates were under-reported due to inability to perform diagnostic imaging tests in all patients as a result of 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 at University Hospitals Bristol and Weston NHS Foundation Trust and the (BRC-1215-20011). 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.