Correction of human hemophilia A whole blood abnormalities with a novel bypass agent: zymogen-like FXa(I16L).

Abstract

BACKGROUND:

Approximately 30% of hemophilia A (HA) and 5% of hemophilia B patients develop inhibitors to protein replacement therapy, and this is the major cause of disease-related morbidity in the developed world. We previously developed zymogen-like factor Xa (FXa) molecules with impaired active site maturation, enabling a greater half-life than wild-type FXa while maintaining full procoagulant function in the prothrombinase complex. Here we evaluated the ability of zymogen-like FXa(I16L) to correct whole blood thromboelastometry abnormalities of severe HA subjects with and without inhibitors.

METHODS:

Fourteen severe HA subjects without and five with inhibitors were enrolled at baseline (

FVIII:

C < 1%) > 5 half-lives from factor or bypass therapy. The subjects' whole blood was evaluated by thromboelastography (ROTEM(®) ) using INTEM analysis with two concentrations of FXa(I16L) or recombinant factor VIIa (rFVIIa).

RESULTS:

With 0.1 nm FXa(I16L) , clot time (CT, in minutes [min]) among HA subjects without and with inhibitors (mean = 2.87 min, 95% CI = 2.58-3.15 min, and mean = 2.9 min, 95% CI = 2.07-3.73 min, respectively) did not significantly differ from control CT (mean = 2.73 min, 95% CI = 2.62-2.85 min). Addition of 20 nm rFVIIa, simulating a 90-μg/kg dose, resulted in significantly prolonged CTs for HA subjects without and with inhibitors (mean = 5.43 min, 95% CI = 4.53-6.35 min, and mean = 4.25 min, 95% CI = 3.32-5.17 min, respectively) relative to controls.

CONCLUSIONS:

FXa(I16L) restored thromboelastometry CT to control values in severe HA subjects with and without inhibitors. The findings corroborate previous animal data and demonstrate the first evidence of zymogen-like FXa(I16L) correcting human HA subjects' whole-blood abnormalities and support the use of FXa(I16L) as a novel hemostatic agent.

• Authors: L A George, N K Thalji, L J Raffini, P A Gimotty, R M Camire
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 13 Issue 9 Pg. 1694-8 (Sep 2015) ISSN: 1538-7836 [Electronic] England
• PMID: 26190406 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 International Society on Thrombosis and Haemostasis.

Chemical References

• Hemostatics
• Isoantibodies
• Recombinant Proteins
• Factor VIII
• recombinant FVIIa
• Factor VIIa
• Factor Xa

Topics

• Blood Coagulation (drug effects)
• Blood Coagulation Tests
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Factor VIII (immunology)
• Factor VIIa (pharmacology)
• Factor Xa (pharmacology)
• Hemophilia A (blood, drug therapy, immunology)
• Hemostatics (pharmacology)
• Humans
• Isoantibodies (immunology)
• Male
• Mutagenesis, Site-Directed
• Recombinant Proteins (pharmacology)
• Thrombelastography
• Time Factors