Schematic model of the role of complement activation, cell damage, and thrombosis in various severe diseases or conditions with major thrombotic problems. Activation of complement can occur via the alternative pathway (in the absence of antibodies) or the classical pathway (in the presence of target-bound antibodies). In each of the indicated diseases or conditions, endothelium, red cells, or platelets are damaged. This may contribute to coagulation and thrombosis, and direct procoagulative effects may also participate (red arrows). Thrombosis can lead to further tissue damage and increasing complement activation. The process can enhance itself via positive feedback loops and form a vicious cycle. Although complement is involved in each of these diseases, its impact needs to be clarified in clinical studies. CAPS, catastrophic antiphospholipid syndrome, DIC, disseminated intravascular coagulation; PLG, plasminogen; THBD, thrombomodulin.