Complement activation generates the proinflammatory polypeptides, C3a and C5a, and recruits neutrophils as well as monocytes. Activated neutrophils generate web-like extracellular traps (NETs), in a process known as NETosis, that contain components such as C3, properdin (P), and factor B (B) that activate the alternative complement pathway and engage an inflammatory feedback loop. Although NETs assist in host defense against pathogens, a sustained response, such as that seen in COVID-19, may incite ongoing inflammation and a hypercoagulable state. Additionally, the membrane attack complex (MAC) also induces endothelial inflammation and tissue injury, leading to the generation of IL-6 and IL-1β, which continue to propagate NETosis. Endothelial injury leads to the generation of vWF multimers. Excess ultralong vWF stabilizes factor VIII activity and prevents the binding of factor I. Endothelial damage also results in the release of plasminogen activator inhibitor-1 (PAI-1), which exacerbates thrombosis, along with C5a-induced release of tissue factor and other prothrombotic proteins. These changes then can augment a complement-coagulation pathway crosstalk, due to serine proteases, such as thrombin and kallikrein, activating the complement system in a convertase-independent manner. Such interactions among endothelial injury, hypercoagulability, and complement activation cause tissue damage, such as acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and stroke, and are often associated with a thrombotic microangiopathy.