Contact activation: Where thrombosis and hemostasis meet on a foreign surface, plus a mini-editorial compilation ("Part XVI")

Welcome to the latest issue of Seminars in Thrombosis and Hemostasis (STH); this issue primarily devoted to highlighting the contact activation pathway of coagulation. Developed to provide an overview of the current body of knowledge
around the roles, applications, and new knowledge of the contact pathway, this compilation serves as an appetizer for the modern thrombosis and inflammation enthusiast.
This issue begins with a contribution from Dr. Shamanaev and colleagues, who start at the top of the coagulation cascade and examine the structure and function of coagulation factor XII (FXII), a serine protease, as it relates to
disease.1 The zymogen FXII can convert prekallikrein and factor XI to the proteases kallikrein and activated FXI (FXIa); this process is instrumental in certain disease states to facilitate abnormal incidents like angioedema and thrombotic events. Drawing on its homolog—pro-hepatocyte growth factor activator—a combination of isolated domains was selected for replacement and then assessed for resulting FXII activation and FXIIa activity. This review acts to establish the circulating closed and bound open conformations of FXII
that are resistant to and expedite activation, respectively. Such information may prove integral as we proceed to unravel the complexities of key pathological processes in the quest to ultimately develop treatments for thromboinflammatory disorders.
The second manuscript in this issue, by Kearney and colleagues, refocuses the spotlight on plasma kallikrein (PKa) and its additional role within the coagulation cascade in directly activating coagulation factor IX (FIX).2 Three
independent studies corroborate a classic canonical intrinsic pathway (FXII–FXI–FIX) and a noncanonical pathway (PKa–FIX). With the existence of PKa as a coagulation clotting factor established, the next step is the investigation of the
products of its cleavage as it relates to the functioning of the body. This manuscript will eventually inform on novel anticoagulant compounds to be researched, tested, and developed for future use.
In the third manuscript, Dr. Lira and colleagues shift our attention to coagulation factor XI (FXI)—a zymogen of plasma protease FXIa, which is key in facilitating normal physiological functions and driving some abnormal pathological processes.3 On top of sharing a convergence history, mirroring PKa, FXI has also been demonstrated to play additional roles, in this case, promoting the generation of thrombin, lending to its versatility in function. Furthermore,
FXI activity ventures beyond the intrinsic pathway of coagulation into the world of platelets, endothelial cells, and inflammation. This work summarizes FXI’s many responsibilities and informs potential future research direction targeting FXI as a focus for therapeutic intervention.