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Suppressing protein Z‐dependent inhibition of factor Xa improves coagulation in hemophilia A
Author(s) -
Girard T. J.,
Lasky N. M.,
Grunz K.,
Broze G. J.
Publication year - 2019
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14337
Subject(s) - hemostasis , coagulation , protein c , thrombin , chemistry , knockout mouse , microbiology and biotechnology , antibody , gene knockout , pharmacology , medicine , immunology , platelet , biochemistry , gene , biology
Essentials Protein Z (PZ) catalyzes PZ‐dependent proteinase inhibitor (ZPI) inactivation of factor (F)Xa. Gene‐deletion of PZ or ZPI improves coagulation in hemophilia (FVIII knockout) mice. A PZ blocking antibody enhances thrombin generation in human hemophilia plasma. Suppression of the PZ/ZPI pathway may ameliorate the phenotype of severe hemophilia.Summary Background Hemostasis requires a balance between procoagulant and anticoagulant factors. Hemophiliacs bleed because of a procoagulant deficiency. Targeted reduction in the activity of endogenous anticoagulant pathways is currently being investigated as a means of improving hemostasis in hemophilia. Protein Z ( PZ ) is a cofactor that serves as a catalyst for PZ ‐dependent protease inhibitor ( ZPI ) inactivation of activated factor X at phospholipid surfaces. Objectives To evaluate the effects of PZ or ZPI gene deletion in hemophilic mice, and of blocking PZ in human hemophilic plasma. Methods A tail vein rebleeding assay ( TVRB ) was developed on the basis of the serial disruption of clots forming over a period of 15 min following tail vein laceration in an anesthetized mouse. Wild‐type ( WT )/ FVIII knockout FVIIIKO , PZ knockout PZKO / FVIIIKO and ZPI knockout ZPIKO / FVIIIKO mice were evaluated in this model, and their plasmas were tested in thrombin generation assays. A mAb against PZ was evaluated in human hemophilic plasma thrombin generation assays. Results The numbers of clot disruptions (mean ± standard error of the mean) in the TVRB were: 4.0 ± 0.9 for WT / FVIIIKO mice; 23.8 ± 1.1 for WT / FVIIIKO mice supplemented with 100% FVIII ; 15.2 ± 1.1 for PZKO / FVIIIKO mice; and 14.7 ± 1.2 for ZPIKO / FVIIIKO mice. Thrombin generation in PZKO / FVIIIKO and ZPIKO / FVIIIKO mouse plasmas was similar to that in FVIIIKO plasma supplemented with ~ 15% recombinant FVIII . A mAb against PZ added to human hemophilic plasma enhanced thrombin generation to an extent similar to the addition of ~ 15% FVIII . Conclusions Blockade of the PZ / ZPI system may be sufficient to ameliorate the phenotype of severe hemophilia.