Human Factor VIII Concentrates in Hemophiliac Dogs

Human factor VIII corrects the clotting defect in dog hemophilic plasma in vitro. The present studies were undertaken to see if this happened in vivo and to look for and document the development of an inhibitor. Four hemophiliac dogs were infused with factor VIII concentrates, the first two on five occasions, the others three times. Factor VIII:C, VIIIR:Ag (defined with antibody to human VIII) and VIIIR:vW were followed at pre, 10 minutes, 2 and 24 hours post infusion. The pre-infusion VIII:C (assayed with human substrate) averaged 0.23 U/ml compared to 6.93 U/ml for normal dogs; VIIIR:Ag was absent in both. VIIIR:vW was low but variable. Following the first injection, all four dogs responded in VIII:C about as calculated. The amounts of VIIIR:Ag and vW were much greater than VIII:C in the concentrates and in the post-first infusion samples from the dogs. On subsequent infusions rises in VIIIR:Ag were not detected and increases in VIII:C and VIIIR:vW were minimal. Precipitating anti-human VIII was found on the third infusion and thereafter. After the first infusion reactions were marked. Vomiting and diarrhea occurred in all, and one dog died in anaphylactic shock about one hour after the third infusion. Lack of response in VIIIR:Ag occurred before anti-VIII could be demonstrated in vitro. This rapid development of an inhibitor suggests that prolonged cross-species VIII therapy will not be successful. The ability of the precipitating anti-VIII elicited in the dogs to destroy VIII:C, VIIIR:Ag and VIIIR:vW is analagous to the in vitro effects of heterologous anti-VIIIs (rabbit and goat).