A ferric chloride induced arterial injury model used as haemostatic effect model.
A number of experimental bleeding models have been applied to animal models of haemophilia in order to evaluate the acute haemostatic effect of procoagulant compounds. In contrast, in vivo thrombosis models (including the FeCl(3) induced injury model) have mainly been used to study antithrombotic pharmacological intervention. However, as there are limitations to existing bleeding models and as new recombinant FVIII, FIX, and FVIIa variants with increased and prolonged activity are generated there is an increasing need for new and optimized in vivo animal models for testing the efficacy of these haemostatic drug candidates. This led us to look at existing thrombosis models in a new perspective. We have studied the effect of a FeCl(3) induced arterial injury in both F8-KO and F9-KO mice using optimized conditions where exposure to FeCl(3) induces occlusion within 4.2 +/- 0.2 min in wild type mice with a normal coagulation system. In contrast, no occlusion was observed in haemophilic mice providing a therapeutic window in the model making it suitable for pharmacological testing of therapeutic intervention. We demonstrate that replacement therapy with a clinical relevant dose of rFVIII (Advate 20-80 U kg(-1)) and rFIX [(0.75 mg kg(-1) BeneFIX) approximately 50 IU kg(-1)] restored coagulation and normalized the time to occlusion following FeCl(3) induced injury in F8-KO mice and restored coagulation and nearly normalized the time to occlusion in F9-KO mice. In conclusion, we have demonstrated that under optimized conditions the FeCl(3) induced arterial injury model provides a therapeutic window that makes it an useful effect model for evaluation of the haemostatic potential of procoagulant drugs.
Møller
F
F
Haemostasis Pharmacology, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Maaloev, Denmark. flmq@novonordisk.com
Tranholm
M
M
D000818:Animals; D002340:Carotid Artery Diseases / Q000139:chemically induced*; D002712:Chlorides / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005164:Factor IX / Q000276:immunology / Q000627:therapeutic use*; D005169:Factor VIII / Q000378:metabolism / Q000627:therapeutic use*; D005290:Ferric Compounds / Q000008:administration & dosage; D006467:Hemophilia A; D006487:Hemostasis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000627:therapeutic use*; D013927:Thrombosis / Q000188:drug therapy*
D002712:Chlorides; D005290:Ferric Compounds; D011994:Recombinant Proteins; D005169:Factor VIII; D005164:Factor IX; C024555:ferric chloride