This timely rapid meta-analysis provides a comprehensive synthesis of the existing evidence highlighting the high prevalence rates of VTE in COVID-19 patients. Our main findings were the VTE incidences of 15.2% and 40.8% in two predefined groups: suspected screening group and routine screening group, respectively. Furthermore, our analysis revealed that COVID-19 patients admitted to the ICU ward had a higher VTE prevalence.
To our knowledge, this is the first meta-analysis study to assess the incidence of VTE in patients with COVID-19. Our meta-analysis reported that the incidence of VTE in COVID-19 patients from the suspected screening group was 15.2% (95% CI: 10.5–21.6%) and that in COVID-19 patients from the routine screening group was 40.8% (95% CI: 20.6–64.7%). Our findings indicate a high prevalence of VTE in COVID-19 patients, which is consistent with previous clinical and post-mortem reports. Histologic analysis of pulmonary vessels in patients with COVID-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were nine times as prevalent in patients with COVID-19 as in patients with influenza (P < 0.001) [23]. This confirms that VTE is an important complication in COVID-19 patients. Physicians need to recognize the significant possibility of VTE in COVID-19 patients and should maintain a low threshold for investigating this complication in all patients. The concrete mechanisms underlying the increased risk of VTE in COVID-19 patients are not yet identified. Several mechanisms may explain the hypercoagulability in COVID-19 patients, which may involve multiple pathogenetic mechanisms. Endothelial cells are known to play an important role in regulating hemostasis, fibrinolysis, and vessel wall integrity. Profound hypoxemia in the pulmonary capillaries may induce endothelial dysfunction and platelet dysfunction [24]. Endothelial cell injury activates a large number of pro-inflammatory cytokines, contributing to microvascular thrombosis including plugging of the pulmonary microvasculature and the occurrence of VTE [25, 26]. A better knowledge of the pathogenesis of abnormal coagulation in COVID-19 patients is urgently needed to provide the potential basis of targeted treatments.
VTE is a common complication in the ICU. Critically ill patients are prone to developing VTE as they are susceptible to both general risk factors of VTE and risk factors specific to ICU patients, such as sedation, immobilization, and vasopressor use [27]. As mentioned in Sect. 3, COVID-19 patients in the ICU were more susceptible to VTE than non-ICU patients, which is in agreement with the previous study. However, the prevalence of VTE in COVID-19 patients in the ICU seemed to be in the higher range than that in published reports on ICU patients admitted for other disease conditions [28–30]. In a meta-analysis of seven studies including 1783 ICU patients, the mean rate of VTE diagnosis was 12.7% (95% CI: 8.7–17.5%) [31]. In our meta-analysis, the incidence of VTE in ICU-admitted COVID-19 patients was 19.6% (95% CI: 14.3–26.4%). A previous study identified that abnormal coagulation in critically ill COVID-19 patients is associated with a poorer outcome, indicating that VTE may influence the outcome of critically ill patients with COVID-19[32]. However, the relationship between VTE and the prognosis of COVID-19 patients needs further studies.
The clinical value of ultrasound screening of the lower extremities in ICU patients with COVID-19 is a matter of debate. Our meta-analysis revealed that the VTE incidence was 40.8% (95% CI: 20.6–64.7%) in the routine screening group, which was much higher than that in the suspected screening group. In addition, the incidence of VTE in ICU-admitted COVID-19 patients routinely screened for VTE was as high as 61.4% (95% CI: 40.3–78.9%). A recent autopsy study found DVT in 7 of 12 patients (58%) in whom VTE was not suspected before death, and PE was the direct cause of death in 4 patients [33]. This suggests that the incidence may have been highly overlooked owing to the low number of specific imaging tests performed. From the above, when hemodynamic deterioration occurs in a patient with COVID-19, VTE, especially PE, should always be suspected. It is important to routinely screen for VTE in COVID-19 patients, particularly in severe cases.
Almost all patients from 19 of the 20 included studies underwent thromboprophylaxis. However, the patients, especially those who were seriously ill, had a high incidence of VTE despite the application of thromboprophylaxis. Thus, physicians should maintain a high suspicion for VTE in COVID-19 patients, even when VTE prophylaxis had been performed. A previous meta-analysis has been conducted to determine whether antithrombotic therapies improve the outcomes of COVID-19. Overall, the meta-analysis identified a small number of studies, each with serious methodological limitations or inadequate reporting. It indicated that new evidence on thromboembolism in COVID-19 does not warrant a change in the current guidelines on thromboprophylaxis among COVID-19 patients [34]. The results implied that prospective studies on thromboprophylaxis for hospitalized patients with COVID-19 are urgently needed. Additional studies investigating whether higher doses of heparinoids or combination prophylaxis with both heparinoids and mechanical devices may be more effective in patients with COVID-19 are also required.
Our study had several limitations. First, most of the included studies had a small sample size. Second, the heterogeneity among the studies was high in the analysis of the VTE incidence. We failed to find clear sources of heterogeneity through subgroup analyses. Several sources of heterogeneity should be considered in the design and conduct of the individual studies. We postulated that the potential sources of heterogeneity may be related to the different population sources, thromboprophylaxis use, and VTE screening strategies among the included studies. Accordingly, the results need to be interpreted with caution.