title: Improved coagulation and haemostasis in haemophilia with inhibitors by combinations of superFactor Va and Factor VIIa.
abstract: Bypassing inhibitors in haemophilia patients is limited to activated (a) Factor(F)VII products. We introduced "FVa activity augmentation" as another bypassing strategy and studied effects of an engineered FVa variant designated superFVa. Procoagulant and clot stabilising properties of superFVa and recombinant human (rh)FVIIa, either alone or in combination, were studied in thrombin generation and clot lysis assays in normal human plasma (NHP) with or without anti-FVIII inhibitors, in haemophilia plasma, and in FVIII-deficient mice or in wild-type mice with anti-FVIII inhibitors. SuperFVa was as effective as rhFVIIa to improve thrombin generation or clot lysis. Furthermore, procoagulant effects were significantly enhanced when these compounds were combined. RhFVIIa at 40 nM (a therapeutic concentration) improved thrombin generation mildly, but markedly improved thrombin generation when combined with a low concentration (e. g. 3 nM) of superFVa. In clot lysis studies, the concentration of rhFVIIa to normalise clot lysis times could be reduced by 100-fold (e. g. from 40 nM to 0.4 nM) when combined with a low concentration (0.37 nM) of superFVa. In haemostasis studies of FVIII-deficient mice, blood loss was dose-dependently reduced by either superFVa or rhFVIIa. SuperFVa (200 U/kg) corrected mean blood loss indistinguishably from rhFVIII. Blood loss correction by rhFVIIa was greatly improved when combined with superFVa. Similar blood loss correction results were observed for therapies in wild-type mice after infusion with anti-FVIII inhibitors. Thus, superFVa may be an effective procoagulant agent in the setting of haemophilia with inhibitors and it merits further evaluation for new bypassing strategies.
authors.forename: Vikas
authors.initials: V
authors.lastname: Bhat
authors.affiliation: Annette von Drygalski, MD, Pharm D, The Scripps Research Institute, Department of Molecular and Experimental Medicine, MEM 180, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA, Tel.: +1 858 784 8220, Fax: +1 858 784 2243, E-mail: avondrygalski@ucsd.edu.
authors.forename: Annette
authors.initials: A
authors.lastname: von Drygalski
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gale
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.forename: Laurent O
authors.initials: LO
authors.lastname: Mosnier
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry; D001777:Blood Coagulation / Q000187:drug effects*; D003029:Coagulants / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000037:antagonists & inhibitors; D015942:Factor VIIa / Q000008:administration & dosage*; D015943:Factor Va / Q000008:administration & dosage*; D005260:Female; D006467:Hemophilia A / Q000097:blood / Q000276:immunology*; D006487:Hemostasis; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000008:administration & dosage; D013917:Thrombin / Q000378:metabolism
chemical_list: D000906:Antibodies; D003029:Coagulants; D011994:Recombinant Proteins; D015943:Factor Va; D005169:Factor VIII; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin
keywords: Factor V; Factor VIII; Haemophilia; bleeding; haemostasis; inhibitors