Rethinking coagulation: from enzymatic cascade and cell-based reactions to a convergent model involving innate immune activation

Advancements in the conceptual thinking of hemostasis and thrombosis have been catalyzed by major developments within health research over several decades. The cascade model of coagulation was first described in the 1960s, when biochemistry gained prominence through innovative experimentation and technical developments. This was followed by the cell-based model, which integrated cellular coordination to the enzymology of clot formation and was conceptualized during the growth period in cell biology at the turn of the millennium. Each step forward has heralded a revolution in clinical therapeutics, both in procoagulant and anticoagulant treatments to improve patient care. In current times, the COVID-19 pandemic may also prove to be a catalyst: thrombotic challenges including the mixed responses to anticoagulant treatment and the vaccine-induced immune thrombotic thrombocytopenia have exposed limitations in our preexisting concepts while simultaneously demanding novel therapeutic approaches. It is increasingly clear that innate immune activation as part of the host response to injury is not separate but integrated into adaptive clot formation. Our review summarizes current understanding of the major molecules facilitating such a cross talk between immunity, inflammation and coagulation. We demonstrate how such effects can be layered upon the cascade and cell-based models to evolve conceptual understanding of the physiology of immunohemostasis and the pathology of immunothrombosis.