The mechanistic basis linking cytokine storm to thrombosis in COVID-19

Abstract

It is now well established that infection with SARS-CoV-2 resulting in COVID-19 disease includes a severely symptomatic subset of patients in whom an aggressive and/or dysregulated host immune response leads to cytokine storm syndrome (CSS) that may be further complicated by thrombotic events, contributing to the severe morbidity and mortality observed in COVID-19. This review provides a brief overview of cytokine storm in COVID-19, and then presents a mechanistic discussion of how cytokine storm affects integrated pathways in thrombosis involving the endothelium, platelets, the coagulation cascade, eicosanoids, auto-antibody mediated thrombosis, and the fibrinolytic system.

Keywords: COVID-19; Clots; Coagulopathy; Cytokine storm; SARS-CoV2; Thrombosis.

Fig. 1

Overview of T-Cell Differentiation and Cytokine Profiles. Primed Th0 cells differentiate into specific T-cell subsets including Th1 cells that secrete IL-2 IL-12, IFN-γ, and TNFα and Th2 cells that secrete Th2 inflammatory cytokines, including, IL-6, IL-10, IL-13, MIP-1 all of which play crucial roles in the development of COVID-19 cytokine storm. T-Reg cells may also play a role through TGF-β-mediated downstream effects.

Fig. 2

Relationship Between Procoagulant vs Anticoagulant Factors in COVID 19. Thrombosis in COVID-19 appears to be a complex interplay developing from functional imbalance between pro-thrombotic and anti-thrombotic factors driving significant clinical thrombotic risk. Elevated cytokines and chemokines promote endothelitis, formation of NETS, enhance eicosanoid expression, enhance platelet interactions, and upregulate the coagulation proteins thereby promoting thrombosis. Potentiating this thrombosis is downregulation or “escape” from anti-thrombotic mechanisms through alterations in fibrinolytic pathways and through reduction in anti-thrombin III, the key endothelial derived anticoagulant.

Fig. 3

Pathways Linking Cytokine Storm to Thrombosis in COVID-19. SARS-CoV2 induction of cytokine storm leads to alterations in the endothelium, platelets, coagulation cascade and fibrinolytic system. Infection with SARS-Cov2 results in very early hyper-expression of Type 1 interferons, Th1, and Th2 cytokines leading to activation of neutrophils and macrophages, resulting in secretion of pro-inflammatory cytokines such as TNFα and IL-6. This “cytokine bath” can induce platelet activation, secretion of eicosanoids, result in direct endothelial damage, and induce thrombin generation through reductions in anti-thrombin III activity. Enhanced thrombin promotes thrombosis through potent platelet activation and generation of mature clot through production of fibrin monomers that cross link to become fibrin polymers. Angiotensin II release from SARS-CoV2 activated endothelium leads to additional activation of platelets, direct endothelial damage, and induction of PAI-1. PAI-1 is also significantly enhanced through mechanisms linked to cytokine storm. The resulting over-expression of PAI-1 results in reduced tPA and uPA secretion from the endothelium, leading to a decrease in plasmin generation and resulting potentiation of fibrin polymers.