Preclinical evaluation of recombinant von Willebrand factor in a canine model of von Willebrand disease.
Dutch Kooiker dogs with hereditary von Willebrand disease (vWD) have undetectable levels of von Willebrand factor (vWF), resulting in spontaneous hemorrhage of mucosal surfaces similar to the clinical picture of vWD in humans. We used this canine model of vWD to study the in vivo effects of a new recombinant von Willebrand factor (rvWF) preparation that contained all species of vWF multimers compared with an rvWF fraction containing only low molecular weight multimers (LMW-rvWF) and with a plasma-derived factor VIII/vWF concentrate (pdvWF). Administration of rvWF in these vWF-deficient dogs resulted in a vWF:Ag half-life of 21.6 hours in one dog and 22.1 hours in a second dog. Administration of pdvWF resulted in a half-life for vWF:Ag of 7.7 hours, and LMW-rvWF, 9 hours. The in vivo recovery of vWF:Ag after administration of rvWF was 59, 64 and 70% in three dogs, respectively; 33% after pdvWF, and 92% after LMW-rvWF. The in vivo recovery of ristocetin cofactor (RCoF) was 78, 110 and 120% for rvWF, and 25% for pdvWF. Both rvWF and pdvWF caused increases in factor VIII. Although no effect was seen on bleeding time at the dosages used, the rate of blood flow from cuticle wounds was reduced after a single bolus administration of rvWF. The rvWF was able to control a severe nose bleed in one dog.
Schwarz
H P
HP
Baxter Hyland Immuno, Vienna, Austria. schwarh@baxter.com
Dorner
F
F
Mitterer
A
A
Mundt
W
W
Schlokat
U
U
Pichler
L
L
Turecek
P L
PL
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001760:Bleeding Time; D003429:Cross Reactions; D019281:Dimerization; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004587:Electrophoresis, Agar Gel; D005169:Factor VIII / Q000032:analysis; D006207:Half-Life; D006801:Humans; D011994:Recombinant Proteins / Q000097:blood / Q000627:therapeutic use*; D014842:von Willebrand Diseases / Q000188:drug therapy*; D014841:von Willebrand Factor / Q000627:therapeutic use*
D000906:Antibodies; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D005169:Factor VIII