ArticleJournal of thrombosis and haemostasis : JTH2019
Suppressing protein Z-dependent inhibition of factor Xa improves coagulation in hemophilia A.
Article in Journal of thrombosis and haemostasis : JTH, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 14 citations in OpenAlex.
- Advancements in CRISPR-basedFrontiers in genome editing · 2026Review
- Unveiling the Evolutionary History and Functional Significance of the Protein Z-Dependent Protease Inhibitor (ZPI) Across Vertebrates.Journal of molecular evolution · 2025Article
- Not so fast, antithrombin!Blood · 2023Article
- Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis.Frontiers in cardiovascular medicine · 2022Review
- Serpins in Hemostasis as Therapeutic Targets for Bleeding or Thrombotic Disorders.Frontiers in cardiovascular medicine · 2020Review
- Engineering a protein Z-dependent protease inhibitor (ZPI) mutant as a novel antagonist of ZPI anticoagulant function for hemophilia treatment.Journal of thrombosis and haemostasis : JTH · 2019Article
- Protein Z-dependent protease inhibitor (ZPI) is a physiologically significant inhibitor of prothrombinase function.The Journal of biological chemistry · 2019Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
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.
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