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Correction of human hemophilia A whole blood abnormalities with a novel bypass agent: zymogen‐like FXa I16L
Author(s) -
George L. A.,
Thalji N. K.,
Raffini L. J.,
Gimotty P. A.,
Camire R. M.
Publication year - 2015
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.13059
Subject(s) - thromboelastometry , thromboelastography , medicine , prothrombinase , recombinant factor viia , zymogen , whole blood , gastroenterology , anesthesia , recombinant dna , coagulation , surgery , platelet , thrombin , chemistry , biochemistry , enzyme , gene
Summary 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 n m 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 n m 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.