Venous Thromboembolic Events in Patients With COVID-19

A Systematic Review and Meta-analysis

Ting Wu; Zhihong Zuo; Deyi Yang; Xuan Luo; Liping Jiang; Zanxian Xia; Xiaojuan Xiao; Jing Liu; Mao Ye; Meichun Deng

Disclosures

Age Ageing. 2021;50(2):284-293. 

In This Article

Abstract and Introduction

Abstract

Background: High incidence of venous thromboembolic complications in coronavirus disease 2019 (COVID-19) patients was noted recently.

Objective: This study aimed to explore the factors associated with prevalence of venous thromboembolism (VTE) in COVID-19 patients.

Methods: A literature search was conducted in several online databases. Fixed effects meta-analysis was performed for the factors associated with prevalence of VTE in COVID-19 patients.

Results: A total of 39 studies were analysed in this analysis. The incidence of pulmonary embolism and VTE in severe COVID-19 patients were 17% (95% CI, 13–21%) and 42% (95% CI, 25–60%), respectively. VTE were more common among individuals with COVID-19 of advance age. Male COVID-19 patients are more likely to experience VTE. Higher levels of white blood cell (WBC; WMD = 1.34 × 109/L; 95% CI, 0.84–1.84 × 109/L), D-dimer (WMD = 4.21 μg/ml; 95% CI, 3.77–4.66 μg/ml), activated partial thromboplastin time (APTT; WMD = 2.03 s; 95% CI, 0.83–3.24 s), fibrinogen (WMD = 0.49 μg/ml; 95% CI, 0.18–0.79 g/L) and C-reactive protein (CRP; WMD = 21.89 mg/L; 95% CI, 11.44–32.34 mg/L) were commonly noted in COVID-19 patients with VTE. Patients with lower level of lymphocyte (WMD = −0.15 × 109/L; 95% CI, −0.23-−0.07 × 109/L) was at high risk of developing VTE. The incidence of severe condition (OR = 2.66; 95% CI, 1.95–3.62) was more likely to occur among COVID-19 patients who developed VTE.

Conclusion: VTE is a common complication in severe COVID-19 patients and thromboembolic events are also associated with adverse outcomes.

Introduction

Up to 23 September 2020, 30 million coronavirus disease 2019 (COVID-19) cases and more than 970,000 deaths were reported globally. The virus that causes COVID-19 is a new type of highly diverse enveloped positive single-stranded RNA virus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[1] The clinical manifestations of COVID-19 are varied, ranging from asymptomatic to severe, including acute respiratory distress syndrome and multi-organ failure,[2,3] of which some severe cases developed into death due to hyperinflammation and respiratory dysfunction.[4] Histopathology of COVID-19 patients indicated diffuse alveolar damage and inflammatory infiltrates in lungs and pathological changes in extra-pulmonary sites, such as gastrointestinal and cardiovascular organs.[5–7] Even though the pathogenesis of COVID-19 was not fully uncovered, direct viral damage,[8] systemic hyperinflammation,[9] dysregulation of immune system[10] and angiotensin-converting enzyme 2 (ACE2)-related pathway[11] were believed to participate in the process.[12] In term of therapeutics, remdesivir, a promising antiviral agent, gives the potential reduction in time to clinical improvement.[13] Patients treated with remdesivir got better clinical status than the standard group.[14] Corticosteroid also plays its role in reducing escalation of care and improving clinical outcomes.[15,16] Besides, convalescent plasma therapy was well tolerated and could potentially improve the clinical outcomes through neutralising viremia in severe COVID-19 cases.[17,18] Currently, several vaccines also have gone through different stages of clinical trials.[19,20] Although both treatment and vaccination are encouraging, large clinical trials are needed for next validation.

Coagulation function in patients with COVID-19 is significantly deranged compared with healthy people.[21] Hyperinflammation caused by SARS-CoV-2 infection elevated level of many pro-inflammatory cytokines,[22,23] which triggers multiple procoagulant pathways and disrupts anticoagulant system, leading to thrombotic microangiopathy.[24] IL-6 is reported to be the most important mediator for cytokine-induced coagulation activation.[25] It is well-known that endothelial cell injury caused by SARS-CoV-2 can strongly activate the coagulation system via exposure of tissue factor (TF). Moreover, the spike protein of the virus downregulates the expression of ACE2 by mediating its engagement, resulting in activation of the renin-angiotensin system, followed by facilitating platelet adhesion and aggregation.[26] In addition, complement system activation partly functions in the disordered coagulant network, founded on the observation of terminal complement components deposit in lungs.[27] In clinical practice, approximately 20% of COVID-19 patients, and almost all patients with severe and critical COVID-19, had severe coagulation abnormalities.[28,29] Patients with COVID-19 and coagulopathy were characterised by increased D-dimer levels, a modest decrease in platelet count, and a prolongation of the prothrombin time, some of which are positively associated with disease severity[30,31] and an increased risk of death.[32,33] Recently, high rates of venous thromboembolism (VTE) in critically ill patients with COVID-19 were reported.[34] Researches showed COVID-19 patients developed venous thrombosis and embolism in lungs, lower extremities, heart, brain and even skin, contributing to tissue necrosis, ischemic stroke and even death.[35–37] It is urgent to pay much attention to venous thromboembolic complications in COVID-19 patients.

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