Study selection
A thorough and systematic search was conducted according to the pre-defined search protocol as specified in the methods section of this manuscript (Fig. 1). The search yielded a total of 2246 studies, of which 1537 studies remained after deduplication. Following title and abstract screening, we identified 23 studies for full-text review. After completion of full-text review, we included 14 studies into this systematic review and meta-analysis.[12–25]
Risk of bias assessment
Risk of bias was assessed by using the ROBINS-I tool (Table 1).[10] A single study (Fraissé et al.) was assessed to have a low risk of bias across all domains, and hence deemed to have a low overall risk of bias.[14] Nine studies were considered to have a moderate overall risk of bias, as one or more domains were deemed to be at moderate risk.[13, 16, 17, 19–22, 24, 25] Four studies were considered to have serious overall risk of bias due to the presence of missing data such as patient comorbidities and ICU characteristics.[12, 15, 18, 23]
Characteristics of included studies
We included 14 studies with a total of 1182 patients into this systematic review and meta-analysis.[12–25] A summary of study characteristics can be seen in Table 2, whereas a summary of patient characteristics can be seen in Table 3. Four studies were conducted in France (Fraissé et al., Helms et al., Llitjos et al. and Poissy et al.), three in the Netherlands (Beun et al., Klok et al. and Middeldorp et al.), two in Italy (Lodigiani et al. and Tavazzi et al.), two in the United Kingdom (Desborough et al. and Thomas et al.), two in the United States of America (Hippensteel et al. and Maatman et al.), and one in Switzerland (Grandmaison et al.). All studies were conducted between February 2020 and April 2020. Only five studies had reported the duration of follow-up, which varied from seven to 28 days.[13, 16, 18, 22, 25]
Table 2
Summary of study characteristics
Study | Study location | Study period | Indication for ICU admission | N (ICU) | Prophylactic anticoagulation agent | Patients receiving therapeutic anticoagulation on ICU admission (%) | Patients receiving prophylactic anticoagulation on ICU admission (%) | Patients receiving at least anticoagulation on ICU admission (%) | Imaging Modality for PTE diagnosis | Indication for PTE imaging | Incidence of PTE (%) | Follow-up (days) |
Beun et al.[12] | Netherlands | 16 March – 9 April | NR | 75 | NR | NR | NR | NR | CT scan | NR | 26.7 | NR |
Desborough et al.[13] | United Kingdom | 1 March – 31 March | NR | 66 | Dalteparin | 16.7 | 83.3 | 100 | CT scan | NR | 7.6 | 28 |
Fraissé et al.[14] | France | 6 March – 22 April | Respiratory failure | 92 | NR | 53.3 | 46.7 | 100 | CT scan | Clinical suspicion | 20.7 | NR |
Grandmaison et al.[15] | Switzerland | NR | NR | 29 | Enoxaparin, UFH | 3.4 | 89.7 | 93.1 | CT scan | Clinical suspicion | 6.9 | NR |
Helms et al.[16] | France | 3 March – 31 March | Acute respiratory distress syndrome based on Berlin definition | 150 | LMWH, UFH | 30 | 70 | 100 | CT scan | Worsening PaO2/FiO2 ratio, haemodynamic instability, dilated right ventricle, rapid increase in D-dimer | 16.7 | ≥ 7 |
Hippensteel et al.[17] | United States of America | 18 March – 14 April | NR | 91 | NR | NR | NR | NR | CT scan | NR | 5.5 | NR |
Klok et al.[18] | Netherlands | 7 March – 5 April | NR | 184 | Nadroparin | 9.2 | 90.8 | 100 | CT scan | NR | 13.6 | 7 (1–13) |
Llitjos et al.[19] | France | 19 March – 11 April | Respiratory failure | 26 | LMWH, UFH | 69.2 | 30.8 | 100 | CT scan | Persistent respiratory failure | 23.1 | NR |
Lodigiani et al.[20] | Italy | 13 February – 10 April | NR | 61 | LMWH | 3.3 | 96.7 | 100 | CT scan | Worsening PaO2/FiO2 ratio, rapid increase in D-dimer | 3.3 | NR |
Maatman et al.[21] | United States of America | 12 March – 31 March | SpO2 ≤ 94%, RR ≥ 30, PaO2/FiO2 ratio ≤ 300 mmHg, or requiring mechanical ventilation | 109 | Enoxaparin, UFH | 6.4 | 93.6 | 100 | CT scan | NR | 4.6 | NR |
Middeldorp et al.[22] | Netherlands | 2 March – 12 April | NR | 75 | Nadroparin | 9.3 | 90.7 | 100 | CT scan | Worsening hypoxaemia | 14.7 | 15 (9–20) |
Poissy et al.[23] | France | 27 February – 31 March | NR | 107 | LMWH, UFH | NR | NR | NR | CT scan | Acute deterioration of haemodynamic and respiratory status | 20.6 | NR |
Tavazzi et al.[24] | Italy | NR | NR | 54 | LMWH | 0 | 100 | 100 | CT scan | NR | 3.7 | NR |
Thomas et al.[25] | United Kingdom | 15 March – 14 April | NR | 63 | Dalteparin | 0 | 100 | 100 | CT scan | Unexplained hypotension or hypoxia disproportionate to pneumonia | 7.9 | 8 (1–28) |
ICU intensive care unit, BMI body-mass index, PTE pulmonary thromboembolism, CT computed tomographic, NR not reported, LMWH low molecular weight heparin, UFH unfractionated heparin, RR respiratory rate |
Table 3
Summary of patient characteristics
Study | Age (years) | Male (%) | BMI (kg/m2) | DM (%) | Hypertension (%) | Malignancy (%) | Previous VTE (%) | Platelet count (x109/L) | D-dimer (mg/L) | Patients intubated (%) | Patients on inotropes (%) | Patients on RRT (%) | Patients on ECMO (%) |
Beun et al.[12] | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR |
Desborough et al.[13] | 59 (49–66) | 72.7 | 28 (24–34) | 40.9 | 45.5 | 7.6 | 7.6 | 207 (154–272) | 2.4 (1.1–6.2) | 78.8 | 47 | 27.3 | 12.1 |
Fraissé et al.[14] | 61 (55–70) | 79.3 | 30 (26–35) | 38 | 64.1 | NR | 5.4 | 227 (182–307) | 2.4 (1.7–7.9) | 89.1 | 62 | 23.9 | NR |
Grandmaison et al.[15] | NR | 72.1 | NR | NR | NR | 6.9 | 6.9 | NR | NR | NR | NR | NR | NR |
Helms et al.[16] | 63 (53–71) | 81.3 | NR | 20 | NR | 6 | 5.3 | 200 (152–267) | 2.3 (1.2–20) | 100 | NR | NR | 8 |
Hippensteel et al.[17] | 56 ± 16 | 58.2 | 32.4 ± 9.9 | 30.8 | NR | 3.3 | NR | 200 ± 91 | 3.0 ± 10.3 | 84.6 | 67 | NR | NR |
Klok et al.[18] | 64 ± 12 | 75.5 | NR | NR | NR | 2.7 | NR | NR | NR | NR | NR | 12.5 | NR |
Llitjos et al.[19] | 68 (52–75) | 76.9 | 30.2 (25.5–33.5) | NR | 84.6 | 0 | 3.8 | 234 (169–306) | 1.8 (1.1–2.9) | 100 | 88.5 | 15.4 | 7.7 |
Lodigiani et al.[20] | 61 (55–69) | 80.3 | NR | 18 | 42.6 | 3.3 | 0 | NR | NR | NR | NR | NR | NR |
Maatman et al.[21] | 61 ± 16 | 56.9 | 34.8 ± 11.8 | 39.4 | 67.9 | NR | NR | 207 (152–255) | 0.5 (0.3-1.0) | 94.5 | 64.2 | 14.7 | 2.8 |
Middeldorp et al.[22] | 62 ± 10 | 77.3 | 27 (24–29) | NR | NR | 4 | 2.7 | 251 ± 89 | 2 (0.8–8.1) | NR | NR | NR | NR |
Poissy et al.[23] | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR |
Tavazzi et al.[24] | 68 ± 7 | 83.3 | 29.3 ± 4.4 | NR | NR | NR | NR | NR | NR | 100 | NR | NR | NR |
Thomas et al.[25] | NR | 69.8 | NR | NR | NR | 1.6 | 1.6 | NR | 3.9* (1.2–36.3) | 82.5 | NR | 36.5 | NR |
BMI body-mass index, DM diabetes mellitus, CKD chronic kidney disease, VTE venous thromboembolism, RRT renal replacement therapy, ECMO extracorporeal membrane oxygenation, NR not reported |
Unless otherwise stated, all values are represented in percentages (%), mean ± standard deviation, or median (interquartile range) |
*Value represented as median (range) |
Indication for ICU admission
Only four studies had reported their indication for ICU admission.[14, 16, 19, 21] Two studies (Fraissé et al., and Llitjos et al.) defined their ICU admission criteria as any patient with respiratory failure.[14, 19] Helms et al. defined their ICU admission criteria as patients who have acute respiratory distress syndrome based on the Berlin 2012 definition, whereas the study by Maatman et al. defined their ICU admission criteria as any patient with an oxygen saturation of 94% or less, respiratory rate of 30 breaths per minute or more, PaO2/FiO2 ratio of 300 mmHg or less, or if requiring mechanical ventilation.[16, 21]
Prophylactic anticoagulation regime and compliance
Eleven studies reported the use of either low-molecular-weight heparin (enoxaparin, nadroparin, dalteparin or unspecified) or unfractionated heparin for venous thromboembolism prophylaxis in varying doses.[13, 15, 16, 18–25] The majority of studies had also reported information on the proportion of patients receiving therapeutic or prophylactic anticoagulation in ICU. The proportion of patients that was started on therapeutic anticoagulation in ICU varied from 0–69.2%, whilst the proportion of patients that was started on prophylactic anticoagulation varied from 30.8–100%. Overall, in ten out of the 11 studies that had sufficient information on anticoagulation practices, 100% of patients received at least prophylactic anticoagulation.[13, 14, 16, 18–22, 24, 25] In the study by Grandmaison et al., 93.1% of patients received at least prophylactic anticoagulation.[15]
Modality and indication for pulmonary thromboembolism imaging
Contrast-enhanced computed tomographic scan was the principal modality used to diagnose PTE in all included studies.[12–25] Eight studies specifically reported the indication for performing PTE imaging. [14–16, 19, 20, 22, 23, 25] All eight studies adopted a selective approach based on the patient’s clinical condition to decide if PTE imaging was required. In these studies, PTE imaging was only performed if there was a clinical suspicion of PTE, for example, if patients had persistent respiratory failure, deteriorating respiratory function or haemodynamic status, or if there was a rapid increase in D-dimer levels.
Primary outcome: Incidence of pulmonary thromboembolism
The reported incidence of PTE ranged from 3.3–26.7%. Including all 14 studies, the weighted average incidence of PTE in COVID-19 patients after admission to the intensive care unit was 11.09% (95% CI 7.72–15.69%, I2 = 78%, Cochran’s Q test P < 0.01) after random-effects meta-analysis of proportions (Fig. 2).[12–25] Significant statistical heterogeneity was present as evidenced by high I2 value and a Cochran’s Q test P value of less than 0.1.
Meta-regression and moderator assessment
Meta-regression with a mixed-effects model was performed to examine if the observed heterogeneity could be contributed by possible moderators such as patient or study characteristics (Table 4). Univariate meta-regression revealed that the proportion of male patients, platelet count on admission to ICU, and proportion of patients on therapeutic anticoagulation were possible significant moderators. These three significant moderators were added into the multivariable meta-regression model for further analysis. Multivariable meta-regression revealed that the proportion of male patients remained as the only significant moderator in this meta-analysis. A higher proportion of males was associated with a higher incidence of PTE.
Table 4
| Univariate analysis | Multivariate analysis |
Variables | Coeff | SE | 95% CI | P | Coeff | SE | 95% CI | P |
Sample size | 0.00 | 0.00 | -0.01–0.01 | 0.55 | - | - | - | - |
Age (years) | 0.06 | 0.08 | -0.09–0.22 | 0.40 | - | - | - | - |
Male gender (%) | 0.06 | 0.02 | 0.03–0.09 | < 0.01 | 0.05 | 0.02 | 0.00–0.09 | 0.03 |
Body-mass index (kg/m2) | -0.14 | 0.12 | -0.37–0.10 | 0.25 | - | - | - | - |
Diabetes mellitus (%) | 0.00 | 0.04 | -0.08–0.08 | 0.95 | - | - | - | - |
Hypertension (%) | 0.04 | 0.03 | -0.01–0.09 | 0.15 | - | - | - | - |
Active malignancy (%) | -0.06 | 0.09 | -0.24–0.13 | 0.54 | - | - | - | - |
Previous VTE (%) | 0.08 | 0.11 | -0.13–0.28 | 0.48 | - | - | - | - |
Platelet count | 0.03 | 0.01 | 0.01–0.05 | 0.01 | 0.01 | 0.01 | -0.01–0.02 | 0.42 |
D-dimer level | 0.00 | 0.00 | -0.00–0.01 | 0.44 | - | - | - | - |
Patients on therapeutic anticoagulation (%) | 0.02 | 0.01 | 0.01–0.03 | < 0.01 | 0.01 | 0.01 | -0.01–0.03 | 0.24 |
Patients intubated (%) | 0.03 | 0.04 | -0.04–0.10 | 0.43 | - | - | - | - |
Patients on inotropes (%) | 0.03 | 0.03 | -0.03–0.09 | 0.36 | - | - | - | - |
Patients on RRT (%) | -0.02 | 0.04 | -0.09–0.06 | 0.66 | - | - | - | - |
Patients on ECMO (%) | 0.07 | 0.15 | -0.21–0.35 | 0.63 | - | - | - | - |
BMI body mass index, Coeff coefficient, CI confidence interval, ECMO extracorporeal membrane oxygenation, RRT renal replacement therapy, SE standard error, VTE venous thromboembolism |
Publication bias
We assessed publication bias by using a funnel plot and the rank correlation test. The funnel plot of all included studies is as shown in Fig. 3. The rank correlation test proved that there was no significant funnel plot asymmetry. (P = 0.19).