Substrates, Cofactors, and Cellular Targets of Coagulation Factor XIa

Abstract

Coagulation factor XI (FXI) has increasingly been shown to play an integral role in several physiologic and pathological processes. FXI is among several zymogens within the blood coagulation cascade that are activated by proteolytic cleavage, with FXI converting to the active serine protease form (FXIa). The evolutionary origins of FXI trace back to duplication of the gene that transcribes plasma prekallikrein, a key factor in the plasma kallikrein–kinin system, before further genetic divergence led to FXI playing a unique role in blood coagulation. While FXIa is canonically known for activating the intrinsic pathway of coagulation by catalyzing the conversion of FIX into FIXa, it is promiscuous in nature and has been shown to contribute to thrombin generation independent of FIX. In addition to its role in the intrinsic pathway of coagulation, FXI also interacts with platelets, endothelial cells, and mediates the inflammatory response through activation of FXII and cleavage of high-molecular-weight kininogen to generate bradykinin. In this manuscript, we critically review the current body of knowledge surrounding how FXI navigates the interplay of hemostasis, inflammatory processes, and the immune response and highlight future avenues for research. As FXI continues to be clinically explored as a druggable therapeutic target, understanding how this coagulation factor fits into physiological and disease mechanisms becomes increasingly important.

Activation of coagulation FXI promotes endothelial inflammation and amplifies platelet activation in a nonhuman primate model of hyperlipidemia

“…These functions range from degradation of inhibitors of thrombin generation (eg, tissue factor pathway inhibitor) to activation of “upstream” members of the coagulation cascade (eg, FXII) [ [10] , [11] , [12] ]. In fact, it has become apparent that FXIa acts on a litany of substrates to amplify local thrombin generation, platelet activation, and endothelial cell barrier function, thereby serving as a valued member in the maintenance of homeostasis [ 13 ]. In the setting of hyperlipidemia, these processes are imbalanced, creating a pathologic thromboinflammatory phenotype.…”

Contact Activation: Where Thrombosis and Hemostasis Meet on a Foreign Surface, Plus a Mini-editorial Compilation (“Part XVI”)

“…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.…”