Membrane phospholipids in the regulation of tissue factor procoagulant function

This review is crucial because growing evidence has shifted our understanding of the regulation of tissue factor (TF) procoagulant function more towards a view that emphasizes membrane lipid remodeling as a critical determinant of TF procoagulant activity. Advances in biophysical, mechanistic, and functional studies have enabled detailed interrogation of TF-lipid interactions, necessitating an updated synthesis of current mechanistic models.

Classical studies have established that TF exists predominantly in an encrypted, low-activity state. Recent studies have highlighted the requirement for membrane reorganization for TF procoagulant function. Phospholipid remodeling, particularly phosphatidylserine externalization and sphingomyelin hydrolysis, emerges as a central driver of TF decryption. High-resolution imaging, molecular dynamics simulations, and functional studies reveal that lipid modulation alters protein-lipid interactions, membrane curvature, and microdomain organization, thereby optimizing the spatial and conformational alignment of clotting factors.

These findings underscore the role of membrane phospholipids as active regulators of TF function in both resting and pathological states. Thus, defining phospholipid-dependent TF decryption may guide future research on coagulation regulation and support the development of targeted antithrombotic strategies that selectively modulate membrane-driven TF activity.