A Vicious Cycle: In Severe and Critically Ill COVID-19 Patients

Abstract

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is one of the fastest-evolving viral diseases that has instigated a worldwide pandemic. Severe inflammatory syndrome and venous thrombosis are commonly noted in COVID-19 patients with severe and critical illness, contributing to the poor prognosis. Interleukin (IL)-6, a major complex inflammatory cytokine, is an independent factor in predicting the severity of COVID-19 disease in patients. IL-6 and tumor necrosis factor (TNF)-α participate in COVID-19-induced cytokine storm, causing endothelial cell damage and upregulation of plasminogen activator inhibitor-1 (PAI-1) levels. In addition, IL-6 and PAI-1 form a vicious cycle of inflammation and thrombosis, which may contribute to the poor prognosis of patients with severe COVID-19. Targeted inhibition of IL-6 and PAI-1 signal transduction appears to improve treatment outcomes in severely and critically ill COVID-19 patients suffering from cytokine storms and venous thrombosis. Motivated by studies highlighting the relationship between inflammatory cytokines and thrombosis in viral immunology, we provide an overview of the immunothrombosis and immunoinflammation vicious loop between IL-6 and PAI-1. Our goal is that understanding this ferocious circle will benefit critically ill patients with COVID-19 worldwide.

Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

“…Besides directly infected by SARS-CoV-2, the ECs also undergo injury by systemic inflammation caused by over-activation of innate immune response, referring to “cytokine storm” [ 91 , 92 ]. Severe COVID-19-induced cytokine storm (such as IL-6, IL-1β, TNF-α, MCP-1, etc) is a good predictor of the severity of COVID-19, which also aggravates multi-organ injury by propagating the vicious cycle of ECs damage, inflammation and thrombosis [ 93 ].…”

“…In addition to rehabilitation and exercise-based approaches [ 6 ], several categories of endothelium-targeted therapies have potential to ameliorate endothelial dysfunction in COVID-19 patients. Evidently, based on the cytokine storm in severe or critically ill COVID-19 patients, targeted inhibition of pro-inflammatory cytokines, such as IL-1β, IL-6 and downstream signal transduction pathways appears to be important avenues [ 93 ].…”

Effects of the circulating environment of COVID-19 on platelet and neutrophil behavior

“…PAI-1 is a driver of hypofibrinolysis in COVID-19 ( 42 ). Interestingly, PAI-1 has been suggested to regulate and be regulated by inflammatory biomarkers, namely IL-6, thus linking thrombotic and inflammatory processes ( 43 , 44 ). A large reservoir of PAI-1 resides in platelets themselves, and active PAI-1 is displayed on the platelet membrane on activation ( 45 – 47 ).…”

COVID-19 and Pulmonary Embolism

“…По-прежнему вызывает интерес связь между воспалительным ответом и развитием прокоагулянтного статуса, которая ранее была установлена при других нозологиях [16,19,20]. Повышение уровня провоспалительных цитокинов -интерлейкина-6 (ИЛ-6), интерлейкина-1β, фактора некроза опухоли альфа (ФНО-α), приводит к активации тромбоцитов, увеличению содержания компонентов свертывающей системы крови и системы комплемента, что является возможным патогенетическим механизмом тромбоза у пациентов с инфекционной патологией, в том числе с COVID-19 [21][22][23][24].…”