key: cord-0775510-4kxf5u21
authors: Lobbes, Hervé; Mainbourg, Sabine; Mai, Vicky; Douplat, Marion; Provencher, Steeve; Lega, Jean-Christophe
title: Risk Factors for Venous Thromboembolism in Severe COVID-19: A Study-Level Meta-Analysis of 21 Studies
date: 2021-12-08
journal: Int J Environ Res Public Health
DOI: 10.3390/ijerph182412944
sha: 4df6ab95874c7ec617b893988dc336d70dd2d936
doc_id: 775510
cord_uid: 4kxf5u21

Venous thromboembolism (VTE) in patients with COVID-19 in intensive care units (ICU) is frequent, but risk factors (RF) remain unidentified. In this meta-analysis (CRD42020188764) we searched for observational studies from ICUs reporting the association between VTE and RF in Medline/Embase up to 15 April 2021. Reviewers independently extracted data in duplicate and assessed the certainty of the evidence using the GRADE approach. Analyses were conducted using the random-effects model and produced a non-adjusted odds ratio (OR). We analysed 83 RF from 21 studies (5296 patients). We found moderate-certainty evidence for an association between VTE and the D-dimer peak (OR 5.83, 95%CI 3.18–10.70), and length of hospitalization (OR 7.09, 95%CI 3.41–14.73) and intubation (OR 2.61, 95%CI 1.94–3.51). We identified low-certainty evidence for an association between VTE and CRP (OR 1.83, 95% CI 1.32–2.53), D-dimer (OR 4.58, 95% CI 2.52–8.50), troponin T (OR 8.64, 95% CI 3.25–22.97), and the requirement for inotropic drugs (OR 1.67, 95% CI 1.15–2.43). Traditional VTE RF (i.e., history of cancer, previous VTE events, obesity) were not found to be associated to VTE in COVID-19. Anticoagulation was not associated with a decreased VTE risk. VTE RF in severe COVID-19 correspond to individual illness severity, and inflammatory and coagulation parameters.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an outbreak of respiratory disease called Coronavirus Infectious disease 2019 (COVID-19) [1] , which is now a worldwide global burden for public health. Severe cases of COVID-19 are characterized by sepsis-related coagulopathy [2] , platelet activation, and endothelial dysfunction [3] . The reported incidence of venous thromboembolic events (VTE) in COVID-19 is highly variable, suggesting that individual risk factors influence the thrombotic risk. We recently demonstrated that patients admitted to the intensive care units (ICU) had higher risk of venous thromboembolism (VTE) than patients admitted in general ward [4] Two reviewers (H. L. and J-C. L.) independently applied these criteria to the titles and abstracts of all citations obtained. If pertinent, each reviewer retrieved and explored the complete articles to make a final decision about their inclusion in the meta-analysis. In case of disagreement, a third reviewer (S. M.) was consulted to reach a consensus. Throughout this process, reviewers were blinded to author and journal names. In case of cohorts reported in multiple papers, the analysis was limited to the largest cohort, unless the necessary data had appeared only in another paper. A log of reasons for rejection of citations identified from the searches was kept. In case of doubt or apparent inconsistency, a reviewer (H. L.) would contact the corresponding author to remove any ambiguity.

The quality and risk of bias were assessed using the Quality In Prognostic Studies (QUIPS) tool as recommended by the Cochrane Prognosis Methods [10] . Two reviewers (H.L. and J.-C.L.) independently evaluated the risk of bias for each item. If needed, a discussion was planned to reach a consensus. Risk of publication bias was additionally assessed visually using funnel plots and an Egger's test (using a threshold at p < 0.05). We assumed that the effect of publication bias should be minor if the plot of the magnitude of the effect size in each study versus its precision estimate (i.e., standard error) showed a roughly symmetrical funnel shape (if number of studies >10).

The main outcomes were VTE, as defined by the investigators, including deep vein thrombosis (DVT) or pulmonary embolism (PE). We investigated all the prognostic factors tested in individual studies, including the clinical characteristics, biological testing, disease severity markers, and the drug or procedure exposures.

We standardized the units of measurement for each prognostic factor, unifying the direction of the predictors, adjusting the weights of the studies, and calculating crude-effect estimates when not provided. When possible, we performed meta-analysis of all the risk factors to assess their association with VTE occurrence, when reported by more than one study. For a dichotomous outcome, we presented the effect estimate as an OR and the corresponding 95% confidence interval (CI). We conducted a meta-analysis of associations using the generic inverse variance-based method and random-effects model to produce an overall measure of association. For a continuous outcome, we estimated the standardized mean difference. The standardized mean difference was re-expressed as an OR using the method of Chinn et al. [13] . The mean and standard variance were estimated from the an overall measure of association. For a continuous outcome, we estimated the standa ized mean difference. The standardized mean difference was re-expressed as an OR usi the method of Chinn et al. [13] . The mean and standard variance were estimated from medians, and the sample size if needed [14] . A sensitivity analysis was performed usi the Bonferroni correction to control the type 1 error (i.e., false positive results related multiple statistical tests). We explored the consistency of the associations between the sults of our meta-analysis. All analyses were performed with R (R Foundation for Sta tical Computing, Vienna, Austria).

No funding was received to perform this meta-analysis. All authors had full acc to all the data and the final responsibility to submit for publication. The authors decl no conflict of interest related to this study.

All data relevant to the study are included in the article; raw data will be made ava able upon reasonable request.

This section may be divided by subheadings. It should provide a concise and prec description of the experimental results and their interpretation, as well as the expe mental conclusions that can be drawn.

A total of 5690 articles were retrieved using the search terms. After reviewing titles a abstracts, 75 articles were selected for full text eligibility. Overall, 12 retrospective and 9 p spective studies (5296 patients) were included in the meta-analysis ( Figure 1 ). The main characteristics of the included studies are described in Table 1 . Risk factors for PE (n = 3), DVT (n = 5), or both (n = 13) were assessed. In 10 studies, VTE incidence was evaluated as routine care, whereas in 11 studies VTE was evaluated only in case of clinical suspicion. The median number of patients was 81 (range . The median follow-up duration was 23 days (range [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] . The included studies took place in France (n = 6), the United States of America (n = 5), the United Kingdom (n = 3), China (n = 2), and other various counties (n = 5). Six studies were multicentric.

As shown in Table 2 , a serious risk of bias was present in all selected studies, with a moderate-high risk of bias in at least one of the six domains of the QUIPS tool. The risk of confounding factors was also considered as moderate-high for all studies.

Conversely, the visual inspection of the funnel plot and the Egger's regression (p > 0.05) test were not in favour of publication bias for the variables reported in >10 studies (Supplementary Material Figures S1-S6). 

We found no association between the risk of VTE and age [15, [17] [18] [19] [20] [21] 23, [25] [26] [27] [28] [29] [30] [31] [32] [33] 35] , male sex [15, 17, [19] [20] [21] [22] [23] [25] [26] [27] [28] [29] [30] [31] [32] 35] , body mass index (OR 1.04, 95% CI 0.85-1.25) [15, 17, [19] [20] [21] 23, 25, [27] [28] [29] [31] [32] [33] or obesity (OR 1.41, 95% CI 0.64-3.09) [17, 27, 28, 32] , history of previous VTE (OR 0.90, 95% CI 0. 27-2.98 ) [17, 19, 21, 23, 35] , cancer (0.84, 95% CI 0.51-1.38) [15, 17, 19, 23, 25, 29, 31, 35] , and tobacco consumption [15, [25] [26] [27] [28] 35] .

Furthermore, we found no association between numerous medical conditions and risk of VTE, including cerebrovascular disease [21, 35] , chronic kidney disease [15, 19, 21, 25, 26, 28, 31, 35] , chronic respiratory disease-including asthma and COPD [15, 19, 21, 25, 26, 28, 29] , diabetes mellitus [15, 17, 19, 21, [25] [26] [27] [28] [29] 31, 32, 35] , hypertension [15, 17, 19, 21, [26] [27] [28] [29] 32, 35] , immunodeficiency [15, 25, 28] , and use of ACE inhibitors [19, 29] .

Conversely, we identified low-certainty evidence for an association between a decreased risk of any VTE and history of cardiovascular disease (OR 0.32, 95% CI 0.10-0.99) [15, 17, 19, 21, 25, 29, 31, 32, 35] , and congestive heart failure (OR 0.57, 95% CI 0. 35-0.95) [15, 26, 28, 31] .

We identified an association between VTE risk and requirement for intubation [15, [19] [20] [21] 25, 29, 31] (OR 2.61, 95% CI 1.94-3.51), duration of neuromuscular blockade [31] (OR 2.64, 95% CI 1.57-4.47) with moderate-certainty evidence, and low-certainty evidence for an association between VTE risk and the use of inotropic drugs (OR 1.67, 95% CI 1.15-2.43, low-certainty evidence) [15, 17, [19] [20] [21] 25, 29] .

The requirements for ECMO [19, [27] [28] [29] 31] , the PaO2/FiO2 ratio [17, 20, 23, 31] , the duration of mechanical ventilation [23, 25] , and renal replacement therapy [15, 17, 19, 21, 31] were not found to be associated with the risk of VTE with low-certainty evidence. The SOFA score [17, 21, 23] was associated to VTE risk (OR 3.69, 95% CI 1.22-11.2, low-certainty evidence) when the score was established the day of VTE screening (single study). APACHE-II was associated with the risk of VTE in a single study [30] (OR 1.76, 95% CI 1.04-3.00, very low-certainty evidence).

We found no association between the use of anticoagulation regardless of the dosage used and risk of VTE [16, 21, 23, 24, 28, 30, 32] with low-certainty evidence. We identified moderate-certainty evidence for an association between VTE risk and the length of stay in hospitalization (OR 7.09, 95% CI 3.41-14.73) [19, 25] , whereas the disease duration before hospitalization [19, 26, 35] , the disease duration before admission to the intensive care units [17, 26] , the length of stay in the intensive care unit [19, 28, 30] , or the disease duration before VTE screening [17, 23] were not found to be associated with the risk for VTE. In contrast, we identified low-certainty evidence for an association between the time from intensive care unit (ICU) admission to VTE screening [17, 33] with a decreased risk of VTE (OR 0.29, 95% CI 0.12-0.70).

We identified low-certainty evidence for an association between VTE risk and CRP [15, 19, 20, 22, 23, [25] [26] [27] 29, 30, 32, 35] (OR 1.83, 95% CI 1.32-2.53) and procalcitonin levels [15, 19, 26, 35] (OR 2.61, 95% CI 1.05-6. 36 ). Furthermore, we found an association between IL-6 levels and the risk of VTE (OR 0.58 95% CI 0.37-0.97) with low-certainty evidence [15, 22, 26] . Conversely, we found no association between the risk of VTE and the fibrinogen [15, 17, [19] [20] [21] [22] [23] [26] [27] [28] [29] [30] 34] nor ferritin levels [15, 19, 23, 26, 27, 30, 32 ].

We found moderate to low-certainty evidence for an association between VTE and the D-dimer levels (OR 4.58, 95% CI 2.52-8.50, low-certainty evidence) [15, [17] [18] [19] [20] [21] [22] [23] [25] [26] [27] [28] [29] [30] 32, 34, 35] , D-dimer peak (OR 5.83, 95% CI 3.18-10.7, moderate-certainty evidence) [26, 32, 33] , and D-dimer at VTE screening (OR 5.14, 95% CI 1.95-13.6, low-certainty evidence) [28, 33] . We found no evidence for the PT value [18, 20, 27, 30, 32, 35] , PT percentage [21, 29] , APTT value [18, 20, 27, 32, 35] , and APTT ratio [19, 29] .

In a single study, an association was found between the platelets peak count and a decreased risk of VTE with low certainty-evidence (OR 0.25, 95% CI 0.12-0.55). We found no association between the risk of VTE and the haemoglobin levels [15, 18, 19, [25] [26] [27] 30, 35] , leukocytes count [15, 18, 19, [25] [26] [27] 29, 30, 35] , lymphocytes count [18, 25, 27, 29, 30, 35] , and platelets count [15, [17] [18] [19] [20] [21] 23, [25] [26] [27] 29, 30, 35] .

We found no association between VTE and the creatinine levels [22, [25] [26] [27] 29, 35] , hepatic enzymes levels [25] [26] [27] 35] , creatine kinase levels [27] , lactate dehydrogenase levels [23, [25] [26] [27] 30, 32, 35] , and N-terminal pro-brain natriuretic peptide levels [27, 29] . Lowcertainty evidence was found with troponin T [26] (OR 8.64, 95% CI 3. 25-22.97 ) in a single study, whereas no evidence was found for troponin I [27, 30, 35] .

Levels of evidence and the estimated OR are summarized in Tables 3 and 4 . ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. Table 4 . Evidence summary for prognostic factors related to venous thromboembolism (discrete variables).

Overall Certainty

Medical history ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. Table 4 . Evidence summary for prognostic factors related to venous thromboembolism (discrete variables).

Overall Certainty

Medical history ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disavascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care leukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; -terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure ISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for n that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty indicates moderate-certainty evidence.

. Evidence summary for prognostic factors related to venous thromboembolism (discrete variables).

Overall Certainty -terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxthrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure ISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for en that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty ○ indicates moderate-certainty evidence.

Overall Certainty N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxthrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% e interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for en that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty ○ indicates moderate-certainty evidence.

Overall Certainty ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.

ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. 

The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak

Coagulopathy in COVID-19

Endotheliopathy in COVID-19-associated coagulopathy: Evidence from a single-centre, cross-sectional study

Arterial and venous thromboembolism in COVID-19: A study-level meta-analysis

Venous thromboembolism in COVID-19 compared to non-COVID-19 cohorts: A systematic review with meta-analysis

Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: A multi-center, open-label, randomized controlled trial

Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19

Significant Major Bleeding in Hospitalized Patients with COVID-19

A guide to systematic review and meta-analysis of prognostic factor studies

GRADE Guidelines 28: Use of GRADE for the assessment of evidence about prognostic factors: Rating certainty in identification of groups of patients with different absolute risks

The PRISMA 2020 statement: An updated guideline for reporting systematic reviews

A simple method for converting an odds ratio to effect size for use in meta-analysis

Estimating the mean and variance from the median, range, and the size of a sample

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19

COVID-19 Infection in Critically Ill Patients Carries a High Risk of Venous Thrombo-embolism

Pulmonary embolism or thrombosis in ARDS COVID-19 patients: A French monocenter retrospective study

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

Image-proven thromboembolism in patients with severe COVID-19 in a tertiary critical care unit in the United Kingdom

Biomarkers for the prediction of venous thromboembolism in critically ill COVID-19 patients

Thrombotic and hemorrhagic events in critically ill COVID-19 patients: A French monocenter retrospective study

Probative Value of the D-Dimer Assay for Diagnosis of Deep Venous Thrombosis in the Coronavirus Disease

Systematic Screening for Venous Thromboembolic Events in COVID-19 Pneumonia

Higher anticoagulation targets and risk of thrombotic events in severe COVID-19 patients: Bi-center cohort study

Prevalence of Venous Thromboembolism in Critically Ill Patients with COVID-19

Routine Venous Thromboembolism Prophylaxis May Be Inadequate in the Hypercoagulable State of Severe Coronavirus Disease

Prevalence of Thrombotic Complications in ICU-Treated Patients With Coronavirus Disease 2019 Detected With Systematic CT Scanning

Pulmonary artery thrombi are co-located with opacifications in SARS-CoV2 induced ARDS

Venous Thrombosis Among Critically Ill Patients With Coronavirus Disease 2019 (COVID-19)

Thrombotic and haemorrhagic complications in critically ill patients with COVID-19: A multicentre observational study

Factors Associated With Pulmonary Embolism Among Coronavirus Disease 2019 Acute Respiratory Distress Syndrome: A Multicenter Study among 375 Patients

Asymptomatic deep vein thrombosis in critically ill COVID-19 patients despite therapeutic levels of anti-Xa activity

Incidence of Venous Thromboembolism in Critically Ill Coronavirus Disease 2019 Patients Receiving Prophylactic Anticoagulation

High Prevalence of Deep Vein Thrombosis in Mechanically Ventilated COVID-19 Patients

Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan

Failure of anticoagulant thromboprophylaxis: Risk factors in medical-surgical critically ill patientS

Nonleg Venous Thrombosis in Critically Ill Adults: A Nested Prospective Cohort Study

Keus, F. Incidence, prognostic factors, and outcomes of venous thromboembolism in critically ill patients: Data from two prospective cohort studies

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial

ATTACC Investigators

ACTIV-4a Investigators; REMAP-CAP Investigators

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial

Empiric use of anticoagulation in hospitalized patients with COVID-19: A propensity score-matched study of risks and benefits

Prognostic factors for VTE and bleeding in hospitalized medical patients: A systematic review and meta-analysis

Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia

Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19

COVID-19 and coagulation: Bleeding and thrombotic manifestations of SARS-CoV-2 infection

ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. Table 4 . Evidence summary for prognostic factors related to venous thromboembolism (discrete variables).

Overall Certainty

Medical history ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated partial thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-ISTH: Disseminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: intensive care unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not serious; NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional inspired oxygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Failure Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboembolism; 95% CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downgraded for risk of bias, given that confounders were not excluded.ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-certainty evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-ce evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. ALAT: alanine aminotransferase; APACHE: Acute Physiology And Chronic Health Evaluation; APTT: activated thromboplastin time; ASAT: aspartate aminotransferase; BMI: body mass index; CRP: C reactive protein; DIC-IS seminated Intravascular Coagulation from the International Society on Thrombosis and Haemostasis; ICU: inten unit; IL-6: interleukin 6; LDH: lactate dehydrogenase; MV: mechanical ventilation; N: number of studies; NS: not NT-proBNP: N-terminal pro-brain natriuretic peptide; PaO2/FiO2: arterial oxygen partial pressure/fractional insp ygen; PT: prothrombin time; S: serious; SAPSII: Simplified Acute Physiology Score II; SOFA: Sepsis-related Organ Assessment; TISS10: Therapeutic Intervention Scoring System; Undetec: undetected; VTE: venous thromboemboli CI: confidence interval 95%; OR: odds ratio; SMD: standardized mean difference; * Certainty in evidence was downg risk of bias, given that confounders were not excluded.ꚛ○○○ indicates very low certainty-evidence, ꚛꚛ○○ indicates low-c evidence, ꚛꚛꚛ○ indicates moderate-certainty evidence. 

We performed 92 statistical tests. Using the Bonferonni correction, only the hospital stay duration (p < 0.0001), peak of D-dimer (p < 0.0001), D-dimer (p < 0.0001), troponin T (p < 0.0001), and mechanical ventilation (p < 0.0001) remained statistically significant.

In the present meta-analysis that encompasses 5296 ICU patients from 21 observational studies, we identified low -to moderate-certainty evidence for the risk factors for VTE, including the COVID-19 severity (i.e., requirement for mechanical ventilation, use of inotropic drugs, length of hospital stay, and SOFA score at VTE screening) and biological parameters (i.e., D-dimer levels, DIC ISTH criteria, CRP level, troponin T, procalcitonin, thrombocytopenia). Some risk factors previously reported were not confirmed by our analysis, including an older age, female sex, obesity [36, 37] , and a medical history of VTE or cancer [38, 39] . Interestingly, the use of anticoagulants at any dose was not associated with a different risk of thrombosis in the univariate analysis. The level of evidence for VTE risk factors was most prominent for the D-dimer and CRP levels, followed by procalcitonin, IL-6, and markers of severity (i.e., mechanical ventilation, inotrope, or neuromuscular blockade duration). The negative correlation between VTE, congestive heart failure, and the history of cardiovascular disease might be explained by the anticoagulant use at admission for these patients, which would hamper interpretation of these results.Taken together, the present meta-analysis provides more precise estimates of the association between individual risk factors and the risk of VTE, which may help identifying ICU patients at lower and higher risk of VTE. Three randomized trials in ICU patients reported the absence of efficacy of therapeutic anticoagulation or intermediate-dose thromboprophylaxis compared to the standard dose thromboprophylaxis [6,7,40], whereas therapeutic anticoagulation was associated with increased survival in non-critically ill patients hospitalized for COVID-19 [41] . In patients with mild COVID-19 that are not mechanically ventilated, therapeutic heparin use was not associated with a decreased risk of death, intubation, ICU admission, or thromboembolism when compared to prophylactic anticoagulation [42] .These trials included patients irrespective of their D-dimer levels or inflammatory parameters. Our study identified the candidate risk factors for VTE in ICU patients with COVID-19, which is crucial for VTE screening and prevention. Indeed, the stratifications of VTE risk may increase the benefit-risk ratio of primary prevention of thrombosis using intermediate or therapeutic anticoagulant dose. This concept is supported by a retrospective monocentric study including critically ill COVID-19 patients, suggesting that this subgroup of patients with elevated D-dimer levels requiring mechanical ventilation-two risk factors identified in the present meta-analysis-may benefit from therapeutic anticoagulation [43] . Although subgroup analysis from recent trials did not show any interaction between Ddimer levels and the efficacy of full-dose anticoagulation, critically ill COVID-19 patients are likely to represent a highly heterogeneous group of patients with a diverse risk of VTE and bleeding. We thus speculate that the individual risk stratification could be useful to identify patients susceptible to benefit from systematic screening or anticoagulation intensification.Interestingly, we confirmed the increased risk of VTE amongst patients with high inflammation biomarkers, whereas "traditional risk factors" for thrombosis (i.e., cancer, history of VTE, obesity [44] ) were not associated with VTE. These observations support the concept that thrombosis in COVID-19 may result from mechanisms implicating pulmonary inflammation, intravascular coagulopathy associated with D-dimer elevation [45] , endothelial dysfunction, and immunothrombosis [46] (Figure 2 ). In our meta-analysis, the best tool to assess sepsis-related coagulopathy seemed to be CRP elevation and, to a lesser extent, procalcitonin-with regards to the risk of a false positive result for the latter. The clinical disease-related severity markers were the consequence of both sepsisrelated coagulopathy and systemic inflammation. Accordingly, targeting inflammation Int. J. Environ. Res. Public Health 2021, 18, 12944 15 of 17 may be considered as a potential additional therapeutic target to prevent COVID-19-related thrombotic complications [47] .A potential limitation of the present meta-analysis was the variability in the study sample, study design, patients' characteristics and management, and the definition of VTE events. In addition, many estimates were associated with large confidence intervals despite the increased statistical power provided by the meta-analysis. Conversely, because of the multiple statistical tests, we could not exclude fortuitous association (i.e., false positive results related to type 1 error). This may explain the protective effect of the presence of cardiovascular disease, or the effect of IL-6 levels and cardiovascular disease on VTE risk. These factors were non-significant after the Bonferroni correction. Nonetheless, this study is unique in many aspects, including its comprehensiveness, the novelty of its findings, and its rigorous methods. Finally, we produced a crude estimate of the risk factors, with a high probability of collinearity between variables between the inflammatory and coagulation parameters [47] . Multicentric studies using a multivariable model are thus warranted to validate the independent variables predicting VTE occurrence.

The present meta-analysis identified the relevant risk factors of VTE in patients admitted to the ICU for severe COVID-19, mainly inflammation profile and illness severity. These findings may help identify individual patients at higher risk of VTE, inform experts developing risk assessment models to risk-stratify patients, and ultimately, improve patients' outcomes through optimal screening and management strategies.Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/ijerph182412944/s1, Figure S1 : Funnel plot of studies reporting D-dimer as prognostic factor for VTE, Figure S2 : Funnel plot of studies reporting C-reactive protein as prognostic factor for VTE, Figure S3 : Funnel plot of studies reporting platelet level as prognostic factor for VTE, Figure S4 : Funnel plot of studies reporting age as prognostic factor for VTE, Figure S5 : Funnel plot of studies reporting body mass index as prognostic factor for VTE, Figure S6 : Funnel plot of studies reporting fibrinogen level as prognostic factor for VTE. 

The data presented in this study are available on request from the corresponding author.

The authors declare no conflict of interest.