The interplay between inflammation and thrombosis in COVID-19: Mechanisms, therapeutic strategies, and challenges

Abstract

Coronavirus disease 2019 (COVID-19), caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause life-threatening pathology characterized by a dysregulated immune response and coagulopathy. While respiratory failure induced by inflammation is the most common cause of death, micro-and macrovascular thrombosis leading to multiple organ failure are also causes of mortality. Dysregulation of systemic inflammation observed in severe COVID-19 patients is manifested by cytokine release syndrome (CRS) - the aberrant release of high levels of proinflammatory cytokines, such as IL-6, IL-1, TNFα, MP-1, as well as complement. CRS is often accompanied by activation of endothelial cells and platelets, coupled with perturbation of the balance between the pro-and antithrombotic mechanisms, resulting in thrombosis. Inflammation and thrombosis form a vicious circle, contributing to morbidity and mortality. Treatment of hyperinflammation has been shown to decrease thrombosis, while anti-thrombotic treatment also downregulates cytokine release. This review highlights the relationship between COVID-19-mediated systemic inflammation and thrombosis, the molecular pathways involved, the therapies targeting these processes, and the challenges currently encountered.

Keywords: Acid sphingomyelinase inhibitors; Anti-NETosis; Anticoagulant; Antiinflammation; Antiplatelet; COVID-19; Cytokine; Fibrinolytic; Therapeutic plasma exchange; Tissue factor inhibitors; von Wlliebrand factor.

Fig. 1

Physiological antithrombotic properties of endothelial cells and the blood. (A) Anticoagulant properties: TFPI inhibits TF-mediated clotting by binding and neutralizing TF-FVIIa and FXa. Heparan sulphates located on endothelial cell surfaces enhance the capacity of ATIII-mediated inhibition of thrombin, factors IXa, Xa, XIa and XIIa. Thrombin (T)-mediated activation of PC is initiated by thrombin binding to TM on endothelial cell surfaces. EPCR enhances PC activation by binding PC and presenting it to the thrombin-TM complex for activation. Activated PC (APC) then detaches from the EPCR and interacts with PS to inactivate factors Va and VIIIa. (B) Fibrinolytic properties: tPA released from endothelial cells coverts plasminogen into plasmin, which lyses insoluble fibrin into degradation products, including D-dimer. (C) Antiplatelet properties: endothelial production and release of NO and PGI₂, as well as expression of CD39, an ectonucleotidase, inhibit platelet activation. TFPI, tissue factor pathway inhibitor; HS, heparan sulphate; ATIII, antithrombin III; TM, thrombomodulin; EPCR, endothelial protein C receptor; PC, protein C; APC, activated protein C; PS, cofactor protein S; tPA, tissue plasminogen activator; NO, nitric oxide; PGI2, prostacyclin.