rFVIIa and NN1731 reduce bleeding in hydroxyethyl starch hemodiluted rabbits.
BACKGROUND
Colloid plasma expanders are used to maintain blood pressure and ensure tissue perfusion during hypovolemia, e.g., caused by traumatic bleeding. Although colloids stabilize the cardiovascular system, they can also potentially cause coagulopathy. Consequently, bleeding tendency may increase, as well as the associated risk of morbidity and mortality. Thus, there is a need for hemostatic treatment options for these patients. rFVIIa (NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) is a hemostatic agent that effectively controls bleedings in patients with inhibitor-complicated hemophilia. rFVIIa works by enhancing thrombin generation on the activated platelet surface at the site of injury, leading to the formation of a stable fibrin clot. NN1731 is an rFVIIa analog with increased hemostatic potential and is currently under clinical development.


METHODS
In this study, the effect of rFVIIa and NN1731 on cuticle bleeding in rabbits 50% hemodiluted with hydroxyethyl starch (molecular weight ∼ 200,000) was tested. Cuticle bleeding was induced after a two-stage hemodilution procedure. After 5 minutes, the animals were treated with rFVIIa (2, 5, or 10 mg/kg), NN1731 (1 or 2 mg/kg), or vehicle, followed by 30 minutes of observation.


RESULTS
Hemodilution caused a significant increase in bleeding time and blood loss. rFVIIa dose-dependently reduced bleeding time and blood loss, reaching statistical significance at 10 mg/kg. However, 2 mg/kg NN1731 reduced bleeding time and blood loss significantly and to a similar extent as 10 mg/kg rFVIIa. This increased hemostatic potential of NN1731 compared with rFVIIa and was confirmed by findings using thromboelastography on ex vivo hemodiluted whole blood.


CONCLUSIONS
In summary, rFVIIa and NN1731 significantly and dose-dependently reduced bleeding in extensively hemodiluted rabbits.
Lauritzen
Brian
B
Haemostasis Pharmacology, Novo Nordisk AS, Maaloev, Denmark. blz@novonordisk.com
Viuff
Dorthe
D
Tranholm
Mikael
M
Ezban
Mirella
M
D000818:Animals; D001760:Bleeding Time; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005167:Factor VII / Q000008:administration & dosage*; D015942:Factor VIIa / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D006438:Hemodilution / Q000009:adverse effects / Q000379:methods; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D006895:Hydroxyethyl Starch Derivatives / Q000633:toxicity; D010952:Plasma Substitutes / Q000633:toxicity; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage; D013053:Spectrophotometry; D013916:Thrombelastography; D016896:Treatment Outcome
D006895:Hydroxyethyl Starch Derivatives; C519901:NN1731; D010952:Plasma Substitutes; D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa