Rethinking Coagulation: from Enzymatic Cascade and Cell-Based Reactions to a Convergent Model Involving Innate Immune Activation.

Advancements in the conceptual thinking of haemostasis and thrombosis have been catalysed 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 conceptualised 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 COVID19 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 pre-existing concepts whilst 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 summarises 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 immunohaemostasis and the pathology of immunothrombosis.