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Thromb Haemost 2016; 115(03): 551-561
DOI: 10.1160/th15-07-0525
Coagulation and Fibrinolysis
Schattauer GmbH

Improved coagulation and haemostasis in haemophilia with inhibitors by combinations of superFactor Va and Factor VIIa

Vikas Bhat   *
1   The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, California, USA
2   University California San Diego, Department of Medicine, Division of Hematology/Oncology, San Diego, California, USA
,
Annette von Drygalski   *
1   The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, California, USA
2   University California San Diego, Department of Medicine, Division of Hematology/Oncology, San Diego, California, USA
,
Andrew J. Gale
1   The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, California, USA
2   University California San Diego, Department of Medicine, Division of Hematology/Oncology, San Diego, California, USA
,
John H. Griffin
1   The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, California, USA
2   University California San Diego, Department of Medicine, Division of Hematology/Oncology, San Diego, California, USA
,
Laurent O. Mosnier
1   The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, California, USA
› Author Affiliations Financial support: This work was funded by grant support from an Early Career Development Award from Bayer Hemophilia (A. v. D. and V. B.), by National Institutes of Health grants HL104165 (L. O. M.) and HL03195 and HL052246 (J. H. G.).
Further Information

Publication History

Received: 01 July 2015

Accepted after major revision: 23 September 2015

Publication Date:
20 March 2018 (online)

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Summary

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.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Haemophilia - Factor VIII - Factor V - bleeding - haemostasis - inhibitors

* Both authors contributed equally to this work.


Supplementary Material

 

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