SARS-CoV-2 infection and thrombotic complications: a narrative review

Abstract

The current, global situation regarding the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic and its potentially devastating clinical manifestations, i.e. coronavirus disease 2019 (COVID-19), took the world by storm, as millions of people have been infected worldwide and more than 1,600,000 patients have succumbed. Infection induced by various respiratory viruses may lead to thrombotic complications. Infection-elicited thrombosis may involve a repertoire of distinct, yet interconnected pathophysiological mechanisms, implicating a hyperinflammatory response, platelet activation and triggering of the coagulation cascade. In the present review, we present current knowledge on the pathophysiological mechanisms that may underlie thrombotic complications in SARS-CoV-2 infection. Furthermore, we provide clinical data regarding the incidence rate of thrombotic events in several viral respiratory infections that cause acute respiratory distress syndrome, including SARS-CoV-2 infection and finally we summarize current recommendations concerning thromboprophylaxis and antithrombotic therapy in patients with thrombotic complications related to SARS-CoV-2 infection.

Keywords: Acute respiratory distress syndrome; Antithrombotic therapy; COVID-19; Endothelium; Inflammation; Respiratory viruses; SARS-CoV-2; Thrombosis; Venous thromboembolism.

Fig. 1

Possible pathophysiological mechanisms implicated in thrombotic complications during respiratory viral infections. The presence of viruses, such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and influenza A, triggers a series of cellular and molecular events that may be accountable for thrombotic complications in such infections. For example, SARS-CoV-2 enters endothelial cells via simultaneous binding to angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) (1), causing widespread endothelial disruption (2). Moreover, respiratory viral infections induce the membrane expression of tissue factor (TF) by endothelial cells, monocytes and monocyte-derived microparticles (MMPs), thus initiating the coagulation cascade which culminates in thrombin generation, which activates protease-activated receptors (PARs) and enhances the coagulation cascade in a positive feedback loop (3). Thrombin and other platelet agonists (e.g. adenosine diphosphate [ADP] and arachidonic acid [AA]), as well as viruses directly, activate platelets to express on their surface and release a plethora of pro-inflammatory and pro-thrombotic mediators, e.g. P-selectin and CD40L (not shown), more ADP and AA, von Willebrand factor (vWF) and various chemokines, which in turn activate endothelial cells and leukocytes. Notably, activated neutrophils form neutrophil extracellular traps (NETs), which arrest viruses but also bear pro-thrombotic properties, for example by activating more platelets in a vicious cycle (4). Other factors that contribute to the manifestation of a pro-thrombotic phenotype are the existence of cytokine storm syndromes (i.e. an overwhelming rise of cytokine levels, such as interleukins and other pro-inflammatory molecules) and possibly antiphospholipid antibodies, in a virus-related antiphospholipid syndrome