Evolutionary hemostasis in the response to injury. This figure shows how DAMPs, being the foundation upon which other hemostatic components are layered, have been evolutionarily embedded and regulated as a component of coagulation. The injury response coevolved in tandem with the complexity of the multicellular organism and its circulatory tree. Evolutionary emergence of key hemostatic components, based on comparative studies in extant animals performed by Doolittle and others (referenced in main text), is charted on a timeline (left) in parallel with DAMP interactions with each emerging hemostatic component (right). (A) DAMPs have vital intracellular function. Some, for example, RNA, DNA, and histones, are the very foundation of multicellular life. (B) Exemplified by the horseshoe crab, the most primitive injury response is facilitated by cells, undifferentiated by hemostatic or immune purpose. Injury-derived LPS activates and aggregates circulating amoebocytes. LPS also triggers formation of a coagulin (CLN) protein gel from amoebocyte-released coagulation proteins. (C) TF, FVII, FX, prothrombin (FII), and FGN evolved before the appearance of jawed animals, followed by FV, FIX (D), and the TM-PC pathway (E). (F-G) The emergence of FXII and FXI is more recent and links coagulation to the contact pathway, activatable by negatively charged DAMPs, including polyphosphates, cfRNA, and cfDNA. aCE, activated coagulogen enzyme; CGN, coagulogen; M.Y.A., million years ago.