Venous Thromboembolism, Corticosteroids and COVID-19: A Systematic Review and Meta-Analysis

Abstract

The novel coronavirus disease 2019 (COVID-19) predisposes patients to venous thromboembolism (VTE) due to risk factors, severe infection, and severe inflammatory responses. The objective is to determine the risk of developing VTE after corticosteroid administration during COVID-19 treatment. Using PRISMA reporting guidelines, a review was conducted from inception until 20 September 2020 with MESH terms including "venous thromboembolism" and "covid-19," using MEDLINE, Scopus, CINAHL Plus, and WHO Global Database. The inclusion criteria included studies with COVID-19 patients aged 18 years and older with VTE diagnosed by duplex ultrasonography or computed tomography pulmonary angiography (CTPA). Exclusion criteria were studies with non COVID-19 patients and non-VTE patients aged less than 18 years. Quality appraisal was conducted of included studies using the Newcastle-Ottawa Scale (NOS). A random-effect model using 95% confidence intervals, and significance of findings was assessed using Review Manager V5.4.We included 12 observational studies with 2801 patients (VTE n = 434; non-VTE; n = 2367). Patients had a higher risk of presenting with VTE when being administered corticosteroids during treatment of COVID-19 (RR = 1.39, 95% CI = 1.10 to 1.77, I² = 0%). A positive effect size was found (SMD = 1.00, 95% CI = 0.67 to 1.32, I² = 85%) for D-dimer laboratory values (µg/mL) in the VTE group. While critically ill COVID-19 patients are more likely to require corticosteroid treatment, it may be associated with increased risk of VTE, and poor clinical prognosis. Risk assessment is warranted to further evaluate patients as case-by-case in reducing VTE and worsening clinical outcomes.

Keywords: coronavirus; deep vein thrombosis; mortality; pulmonary embolism; venous thromboembolism.

Figure 1.

PRISMA flowchart.

Figure 2.

Forrest plot for corticosteroids use.

Figure 3.

Forrest plot for D-dimer values.

Figure 4.

Forrest plot for mortality.

Figure 5.

Funnel plot for publication bias.

Figure 6.

Postulated pathophysiology of venous thromboembolism and Covid-19. SARS-CoV2 gains entry into the host cell via the ACE-2 receptor which causes inflammation and cytokine storm associated with the release of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-α) are released. As a response to viral infection, there is endothelial injury and thrombin formation contributing to a hypercoagulable state. Stasis in critically ill patients with pneumonia and ARDS further contributes to the formation of emboli. Hence, Virchow’s triad drives the development of thrombosis. Down regulation of fibrinolytic and anti-coagulation pathways leads to an increased risk of VTE. Hemostatic abnormalities including elevated levels of d-dimer, C-reactive protein (CRP), fibrin degradation products (FDPs) and prothrombin time (PT) suggesting an underlying coagulopathy process and a high burden of thrombosis.