Effects of a Minute and Regular Dose of Recombinant Human Activated Factor VII in Beagles with Hereditary Coagulation Factor FVII Deficiency.
Authors: Giger Urs , Withnall Elanor 
Published: April 2020

Many hereditary coagulopathies have been reported in various canine breeds, and dogs with naturally-occurring hemophilia A and B have served as models to elucidate the pathophysiology and evaluate the efficacy and safety of novel therapeutic options including recombinant products and gene therapy.

In this study we compared the effects of a minute and regular dose of recombinant human activated factor VII (rFVIIa) in Beagles with hereditary FVII deficiency. Affected Beagles have &lt;5% plasma FVII activity compared to normal controls due to a missense mutation which impairs FVII secretion and activity. This defect causes an increased hemorrhagic tendency, but is often discovered incidentally by an isolated prothrombin time (PT) prolongation. This is an autosomal recessive trait and a limited survey suggests a high prevalence of the mutant allele in the pet and research Beagle population which has implications for pharmacotoxicologic research studies performed in Beagles.

A total of 6 adult FVII-deficient research Beagles received on separate occasions (2–7 days apart with 4–6 dogs per group) a bolus of rFVIIa (Novo Nordisk) at 5ug/kg (Minute dose) or 30ug/kg (Regular dose) and an FFP infusion at 10ml/kg over &lt;15 min. Under mild sedation a cuticle bleeding time (CBT) test was performed prior to and 15 min post-treatment. Citrated blood samples were collected at time 0, 15, and 90 min as well as 24 hours post-treatment for immediate PT measurement in whole blood (SCA2000), and subsequent rotational thromboelastometry (Rotem), PT, partial thromboplastin time (PTT), FVII and FXI (Stago) determination on frozen plasma samples.

The pre-CBT values of FVII deficient dogs ranged from 4.3 to 9 min (m±SEM, 6.1±0.4; normal &lt;4 min) and were significantly shorter after the administration of both doses of rFVIIa (Regular 3.1±0.3, Minute 3.3±0.4), but not following FFP (5.2±0.7). The prolonged whole blood pre-PT values (27.4±0.7 sec, reference range 12–17 sec) were shortened into the normal range at 15 min and 90 min, but were again prolonged by 24 hours. Similar results were obtained with the plasma PT test measurements. Plasma FVII activity ranged from 2–5% (4.2±0.4) in deficient dogs compared to normal controls and rose at 15 min in all cases (Regular 136±14%, Minute 26±4%, FFP 30±2%). No adverse reactions were observed with human rFVIIa and no antibodies against the human recombinant protein were detected after 4 weeks.

We conclude that a single treatment with rFVIIa is highly effective in normalizing coagulation parameters in FVII-deficient Beagles, while FFP seems to cause a lesser effect. Minute amounts of rFVIIa appear to be sufficient presumably due to its ability to initiate the extrinsic cascade with subsequent sustained activation of the intrinsic cascade. While it needs to be determined whether human rFVIIa will also control more severe clinical bleeding in FVII-deficient Beagles, this disease model offers the opportunity to also evaluate the effects and pharmacokinetics of this and other long-acting rFVIIa analogues as well as gene therapy.