Role of SARS-CoV-2 -induced cytokines and growth factors in coagulopathy and thromboembolism

Abstract

Severe COVID-19 patients frequently present thrombotic complications which commonly lead to multiorgan failure and increase the risk of death. Severe SARS-CoV-2 infection induces the cytokine storm and is often associated with coagulation dysfunction. D-dimer, a hallmark of venous thromboembolism (VTE), is observed at a higher level in the majority of hospitalized COVID-19 patients. The precise molecular mechanism of the disproportionate effect of SARS-CoV-2 infection on the coagulation system is largely undefined. SARS-CoV-2 –induced endotheliopathy and, induction of cytokines and growth factors (GFs) most likely play important roles in platelet activation, coagulopathy, and VTE. Generally, viral infections lead to systemic inflammation and induction of numerous cytokines and GFs and many of them are reported to be associated with increased VTE. Most importantly, platelets play key thromboinflammatory roles linking coagulation to immune mediators in a variety of infections including response to viral infection. Since the pathomechanism of coagulopathy and VTE in COVID-19 is largely undefined, herein we highlight the association of dysregulated inflammatory cytokines and GFs with thrombotic complications and coagulopathy in COVID-19.

SARS-CoV-2 infection- induced growth factors play differential roles in COVID-19 pathogenesis

“…They regulate several pathophysiological conditions including tissue injury and repair through binding to specific receptors on the cell via paracrine and/or autocrine mechanisms [3] , [4] . SARS-CoV-2-induced cytokines and GFs mediate coagulation dysfunction and tissue injury, which contribute to the clinical severity of COVID-19 [5] , [6] . Changes in plasma cytokines and GFs level increases the risk of venous thromboembolism (VTE) [7] , [8] , characterized by elevated D-dimer and, a major cause of tissue injury in the severe COVID-19.…”

Prothrombotic Phenotype in COVID-19: Focus on Platelets

“…In the presence of bacterial or viral infections, the immune system reacts through the release of both proinflammatory and anti-inflammatory cytokines essential to control and eliminate pathogens. However, following exposure to cells presenting SARS-CoV-2 antigen, T-cell reactivity has been shown to amplify cytokine release (cytokine storm) resulting in a positive feedback between immune cells and cytokines [92,93]. Indeed, in an infectious clinical setting, platelets express a number of immunoreceptors that enable them to act as specialized sentinels able to sense and, via receptors, recognize pathogens from all major classes of microorganisms invading the bloodstream [94].…”

COVID-19 and Venous Thromboembolism: From Pathological Mechanisms to Clinical Management

“…In COVID-19, some of the dysregulated pro-inflammatory cytokines (IL-1β, IL-6, and IL-8) play a pathological role in promoting platelet activation and causing platelet dysfunction. For example, IL-1β could regulate platelet aggregation through its receptor IL-1R1 expressed on platelets [33]. In addition, other mechanisms related to the pathogenesis of COVID-19 include hypoxemia, increased inflammation, immune system activation, platelet apoptosis, and endothelial cell dysfunction, [34,35], which might further promote platelet activation, ultimately leading to thrombosis [36].…”

“…Previous articles have demonstrated that SARS-CoV-2-induced pathological inflammation promotes the increased expression of P-selectin and the release of sCD40L, which together with thrombin promotes platelet activation. This, in turn, further increases thrombin, p-selectin, and sCD40L levels, creating a positive feedback loop that promotes platelet activation and thrombosis [33].…”