The complement cascade is another important arm of the innate immune system that has been implicated in COVID-19-associated thrombosis. Activation of the complement system, and vascular deposition of complement components, is linked to a range of thrombotic microangiopathies, including antiphospholipid syndrome and atypical hemolytic uremic syndrome.120 Recent histological findings from biopsies obtained from patients with severe COVID-19 have demonstrated the extensive deposition of the terminal complement components, C5b-9 (membrane attack complex) and C4d, in addition to the MASP-2 (mannose-binding lectin-associated serine protease) within the microvasculature.121 Strikingly, these vessels largely exhibited microvascular thrombi and, furthermore, the SARS-CoV-2 spike glycoprotein colocalized with C5b-9 and C4d in a subset of cases.121 These findings appear consistent with a recent Chinese study where lung sections from patients with severe COVID-19 all revealed strong complement staining, while patients with severe COVID-19 have also been described to have elevated serum C5a levels.122 Mechanistically, it has been suggested that the nucleocapsid (N) protein of SARS-CoV-2 binds to MASP-2 thereby triggering complement activation and amplifying tissue injury. The activation of the complement pathway leads to enhanced production of endothelial cytokines, such as IL-1, IL-8, RANTES, IL-6, and MCP-1, and also upregulates the expression of important endothelial adhesion molecules, such as P-selectin and VWF.120,123 Moreover, the anaphylatoxins C5a and C3a, act to facilitate the recruitment and activation of monocytes and neutrophils. Complement activation also directly induces a prothrombotic phenotype via C5a induction of neutrophil TF expression, C5b-7 monocyte TF expression, and C5b-8/C5b-9 mediated platelet activation.124,125 Furthermore, CRP has been described as a complement pathway activator and the correlation of its plasma level with COVID-19 severity highlights another potential link between immune and complement system.72 These observations have attracted major interest in exploring the role of complement directed therapies in COVID-19 patients, in particular, in COVID-19 mediated thrombosis.126