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25 The interface of complement and coagulation pathways

The most menacing challenge to survival faced by organisms throughout the animal kingdom is injury accompanied by invasion of foreign pathogens To survive these threats, organisms have developed effective means to contain wounds by simultaneously and coordinately limiting bleeding with clot formation, restricting and fighting infections, while facilitating rapid initiation of healing This finely tuned, synchronized activation of coagulation and complement -- the latter, a major component of innate immunity -- supports the notion that common molecular mechanisms regulate these multi-protein, blood-borne cascade systems, and that dysregulation of either, may negatively impact on both, causing disease The last couple of decades has seen major progress in identifying cellular and molecular links between the complement and coagulation systems, yielding diagnostic insights and strategies for the design of innovative therapies We and others have delineated mechanisms by which complement activation promotes coagulation 1 For example, the complement-mediated anaphylatoxin C5a, triggers activation of endothelial cells, platelets and monocytes, and upregulates the coagulation initiator, tissue factor (TF) The lytic membrane attack complex (C5b-9), generated terminally by activation of complement, also induces TF expression, while the complement lectin pathway serine proteases (MASPs) directly activate clotting factors Notably, the key coagulation-induced clotting protease, thrombin,2 feeds back and amplifies complement activation, thereby sustaining a vicious, escalating cycle, that may result in profound damage to the host The physiologic relevance of the interplay between coagulation and complement is evident in many metabolic, malignant, inflammatory, infectious (e g COVID-19),3 thrombotic and immune (e g systemic lupus erythematosus)4 disorders, but underscored by the thrombotic diathesis associated with the rare but devastating genetic complement-mediated disorders, paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) 5 Both of these complement-mediated disorders that feature thrombosis, are extraordinarily responsive to treatment with a highly specific inhibitor of complement, highlighting the importance of delineating the relationship between complement and coagulation Describe the cellular and molecular links between the complement and coagulation systemsDiscuss the role of complement in different diseasesExplain the importance of delineating the relationship between complement and coagulationReferencesConway EM Reincarnation of ancient links between coagulation and complement J Thromb Haemost 2015;13(Suppl 1):S121-S32 Krisinger MJ, Goebeler V, Lu Z, et al Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway Blood 2012;120(8):1717–25 Conway EM, Pryzdial EL Is the COVID-19 thrombotic catastrophe complement-connected?Journal of Thrombosis and Haemostasis 2020;18(11):2812–22 Luo S, Hu D, Wang M, Zipfel PF, Hu Y Complement in Hemolysis- and Thrombosis- Related Diseases Front Immunol 2020;11:1212 Wong EKS, Kavanagh D Diseases of complement dysregulation-an overview Semin Immunopathol 2018;40(1):49–64