ArticleArteriosclerosis, thrombosis, and vascular biology2025
Tapping Into the Natural PZ-Independent Anticoagulant Function of ZPI to Inhibit Thrombosis With Minimal Effect on Hemostasis.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Abstract
backgroundThe protein ZPI (Z-dependent protease inhibitor) binds to PZ (protein Z), which enables ZPI to inhibit membrane-bound FXa (activated factor X). ZPI also inhibits FXIa (activated factor XI) independently of PZ.
methodsTo study the PZ-independent ZPI function, we tested the in vitro and in vivo effect of disrupting the ZPI-PZ interaction by mutating ZPI Asp 293 to Ala (D293A).
resultsD293A mutation reduced PZ-dependent FXa inhibition without affecting FXIa inhibition. D293A also diminished FXIIa (activated FXII)-induced thrombin generation but reduced TF (tissue factor)-induced thrombin generation only at low TF concentrations. This suggests that D293A selectively inhibits the intrinsic pathway and the thrombin-FXI (factor XI) feedback loop that enhances low-dose TF-initiated coagulation. Wild-type and D293A ZPI both showed selectivity in inhibiting activated partial thromboplastin time but not prothrombin time. Increasing PZ in plasma enhances activated partial thromboplastin time inhibition and enables prothrombin time inhibition by wild-type but not D293A ZPI, further indicating that D293A ZPI selectively inhibits the intrinsic pathway independently of PZ. In mouse models, D293A inhibited FeCl
conclusionsThe PZ-binding defective variant of ZPI, D293A, selectively inhibits the intrinsic coagulation pathway and is a new anticoagulant with reduced bleeding risk.
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