Since evidence of an increased risk of thromboembolism in hospitalized COVID-19 patients emerged, several observational studies have reported specific outcomes on venous or arterial thrombosis. We systematically searched and illustrated the pooled incidence of venous and arterial thromboembolism in various clinical settings. We found that in patients requiring ICU admission had a higher incidence of VTE (27%) than those in a non-ICU setting (8%). Several studies demonstrated a significant increase in D-dimer and fibrinogen levels, which reflected the hypercoagulability state in COVID-19 ICU patients. (19, 33) It is hypothesized that in severe clinical COVID-19 pneumonia, the massive release of inflammatory mediators caused by viral replication might be contributed to endothelial injury and intravascular thrombosis.(34) Our findings support the association between clinical severity and hypercoagulable state causing by COVID-19.
In the ICU setting, the pooled incidence of VTE was 29% with high heterogeneity. Prespecified subgroup analyses, including anticoagulant prophylaxis, provided similar results as the primary analysis. The interpretation of this subgroup analysis requires caution since two studies did not utilize anticoagulant prophylaxis. In addition, among studies that utilize anticoagulant prophylaxis, criteria for anticoagulant prophylaxis and the dosage are varied. However, our data demonstrated that breakthrough VTE on anticoagulant prophylaxis occurred in approximately 27% in the ICU setting. In patients with COVID-19 with severe clinical severity or required ICU admission, prophylactic-intensity anticoagulation might not be sufficient. Whether a higher intensity anticoagulant could effectively prevent the venous thrombotic events in critically ill patients with COVID-19 is unknown. Several randomized controlled trials looking at the appropriate intensity of LMWH prophylaxis are still ongoing.
Our finding of a high incidence of VTE in the ICU setting was likely driven by the incidence of DVT rather than PE. The pooled incidence of PE was lower than we expected. When we performed post hoc subgroup analysis based on countries, there was a significant interaction between studies. This is interesting since most studies from the Netherland, France, Switzerland, and UK had a higher pooled incidence of PE ranged from 8–26%, whereas the studies from Italy and China reported the lower incidence of PE, which ranged from 2–3%. Other confounding factors could contribute to this finding. The indications for CTPA were varied between studies. Most studies performed CTPA based on clinical suspicion, whereas some studies based on a high D-dimer level or only in patients with DVT. Several studies did not mention performing CTPA or the indication for CTPA, which could underestimate the incidence of PE.
In China, the incidence of VTE in the ICU setting was 26%. Here in our academic center in Thailand, we also found a significant number of PE in severe COVID-19 pneumonia patients. There were 3 symptomatic PE out of 14 severe COVID-19 pneumonia requiring ICU admission. At the time of events, all three patients did not receive anticoagulant prophylaxis. Therefore, the incidence of VTE in severe COVID-19 requiring ICU admission in our center was 21.4%. There was no VTE among 130 non-severe COVID-19 (unpublished data). It is noted that we did not perform routine CUS screening in our patients.
The incidence of DVT in the ICU setting was significantly higher in studies that performed CUS screening than those studies which did not (27% vs. 3%, respectively). Though this finding was as expected since the more imaging performed, the more DVT events detected. The significance of asymptomatic DVT in the ICU setting detected by CUS is still debating. Whether a high incidence of DVT detected on CUS has an impact on the development of PE or mortality was unknown. Given the high risk of transmission of SARS-CoV-2 to health care personnel, recent expert guidance suggests against routine CUS screening in patients with COVID-19 requiring ICU admission.(35)
The incidence of VTE in COVID-19 in the non-ICU setting was 8%. Subgroup analysis based on CUS screening revealed significant interaction. However, the credibility of the subgroup analysis was low. Most VTE incidences were driven by DVT dominating by Zhang et al. study (DVT incidence = 42%).(21) In this study, anticoagulant prophylaxis was given in 37% of patients. In most studies, anticoagulant prophylaxis was utilized in more than 80% of patients. In another study by Xu and coworkers (10), anticoagulant prophylaxis was also partially given in 22% of patients, but the incidence of DVT was quite low (1%). This could be explained by a difference in the baseline risk of VTE. In a study by Zhang et al., the proportion of patients with high-risk VTE (Padua score ≥ 4) was much higher than those in the study by Xu et al. (65% vs. 7%). Overall, the incidence of VTE is low in the non-ICU setting. Anticoagulant prophylaxis should be considered in the non-ICU setting, especially in patients with high risk for VTE.
Among the imaging studies which reported PE events detected by CTPA or DVT detected by CUS, the incidences of PE and DVT were 26% and 33%, respectively. Most studies selected patients who underwent CTPA or CUS regardless of clinical severity status. Thus, the interpretation was limited. Findings of imaging on CTPA demonstrated that thrombus was more commonly occurred in the distal part (subsegmental and segmental artery) rather than a more proximal pulmonary artery. This could reflect the microvascular thrombosis “in situ” caused by endothelial injury and local inflammation.(34, 36)
Data on VTE-related death were limited. Few studies reported the outcome of death in patients with VTE, but it could not be assumed to be VTE-related death in all patients. Many clinical and laboratory factors, including older age, sex, clinical severity assessed by using SOFA score, and high D-dimer were associated with mortality.(37, 38)
Few arterial thrombotic events have been reported. Most events were ischemic stroke, and few were myocardial infarction. Though several case reports and case series demonstrated the possibly increased risk of arterial thrombosis, we did not include those studies in the analysis since there was no data available for incidence calculation, and the study designs are subjected to selection bias.
To our knowledge, this is the first systematic review and meta-analysis on the incidence of thromboembolism in COVID-19. We performed a systematic literature search, including grey literature with no language restriction. Full-text eligibility and risk of bias were reviewed by two independent researchers. However, there are some limitations. Most studies were retrospective in design with a small sample size. Thus they were subjected to risk of selection bias. High heterogeneity between groups was presented in most analyses, although I2 is possibly not a reliable indicator of true heterogeneity among prevalence meta-analyses.(39) One post hoc subgroup analysis was able to demonstrate the subgroup effect but prespecified subgroup analyses did not reveal significant interaction. CTPA for PE detection was not routinely performed in all patients in the ICU. Hence, the true incidence of PE could be underestimated. However, most studies performed CTPA based on clinical suspicion, which represented the clinically significant PE.