Schematic representation of results by Keshari et al and extended interpretation integrating platelets. (A) “Pure coagulopathy” model: infusion of preactivated FXa and surrogate procoagulant PCPS vesicles led to robust induction of coagulation and fibrinolytic pathways, with fulminant turnover of prothrombin, plasminogen, and fibrinogen, but did not drive measurable complement activation in the circulation. (B) Escherichia coli sepsis model: infusion of a lethal dose of E coli induced protracted activation of coagulation and fibrinolytic pathways when compared with the “pure coagulopathy” model, as evidenced by delayed but strong consumption of prothrombin, plasminogen, and fibrinogen. In addition, the sepsis model also fueled strong complement activation. Given the observed lack of complement activation in the “pure coagulopathy” model (see panel A), Keshari et al propose that lipopolysaccharide (LPS) and bacteria drive complement independently from coagulation and fibrinolysis. (C) Extended interpretation integrating platelets: bacteria, thrombin, and complement can all contribute to platelet activation, and platelet activation is strong during sepsis. The activated platelet surface provides a procoagulant surface for the prothrombinase complex (represented by FXa) and equally promotes complement activation. Thus, the activated platelet surface offers a microenvironment where factors of the coagulation and complement systems can closely and simultaneously interact. In turn, complement activation promotes platelet activation, creating a positive feedback cycle that matches the pathological exacerbations observed during sepsis.